Cannabis (Marijuana) Research Report Is marijuana safe and effective as medicine?

The potential medicinal properties of marijuana and its components have been the subject of research and heated debate for decades. THC itself has proven medical benefits in particular formulations. The U.S. Food and Drug Administration (FDA) has approved THC-based medications, dronabinol (Marinol ® ) and nabilone (Cesamet ® ), prescribed in pill form for the treatment of nausea in patients undergoing cancer chemotherapy and to stimulate appetite in patients with wasting syndrome due to AIDS.

In addition, several other marijuana-based medications have been approved or are undergoing clinical trials. Nabiximols (Sativex ® ), a mouth spray that is currently available in the United Kingdom, Canada, and several European countries for treating the spasticity and neuropathic pain that may accompany multiple sclerosis, combines THC with another chemical found in marijuana called cannabidiol (CBD).

The FDA also approved a CBD-based liquid medication called Epidiolex ®  for the treatment of two forms of severe childhood epilepsy, Dravet syndrome and Lennox-Gastaut syndrome. It’s being delivered to patients in a reliable dosage form and through a reproducible route of delivery to ensure that patients derive the anticipated benefits. CBD does not have the rewarding properties of THC.

Researchers generally consider medications like these, which use purified chemicals derived from or based on those in the marijuana plant, to be more promising therapeutically than use of the whole marijuana plant or its crude extracts. Development of drugs from botanicals such as the marijuana plant poses numerous challenges. Botanicals may contain hundreds of unknown, active chemicals, and it can be difficult to develop a product with accurate and consistent doses of these chemicals. Use of marijuana as medicine also poses other problems such as the adverse health effects of smoking and THC-induced cognitive impairment. Nevertheless, a growing number of states have legalized dispensing of marijuana or its extracts to people with a range of medical conditions.

An additional concern with "medical marijuana" is that little is known about the long-term impact of its use by people with health- and/or age-related vulnerabilities—such as older adults or people with cancer, AIDS, cardiovascular disease, multiple sclerosis, or other neurodegenerative diseases. Further research will be needed to determine whether people whose health has been compromised by disease or its treatment (e.g., chemotherapy) are at greater risk for adverse health outcomes from marijuana use.

Medical Marijuana Laws and Prescription Opioid Use Outcomes

A 2019 analysis, also funded by NIDA, re-examined this relationship using data through 2017. Similar to the findings reported previously, this research team found that opioid overdose mortality rates between 1999-2010 in states allowing medical marijuana use were 21% lower than expected. When the analysis was extended through 2017, however, they found that the trend reversed, such that states with medical cannabis laws experienced an overdose death rate 22.7% higher than expected. 79 The investigators uncovered no evidence that either broader cannabis laws (those allowing recreational use) or more restrictive laws (those only permitting the use of marijuana with low tetrahydrocannabinol concentrations) were associated with changes in opioid overdose mortality rates.

These data, therefore, do not support the interpretation that access to cannabis reduces opioid overdose. Indeed, the authors note that neither study provides evidence of a causal relationship between marijuana access and opioid overdose deaths. Rather, they suggest that the associations are likely due to factors the researchers did not measure, and they caution against drawing conclusions on an individual level from ecological (population-level) data. Research is still needed on the potential medical benefits of cannabis or cannabinoids.

ORIGINAL RESEARCH article

Cannabis for medical use: analysis of recent clinical trials in view of current legislation.

F. Baratta

  • Department of Drug Science and Technology, University of Turin, Turin, Italy

Cannabis has long been regarded as a recreational substance in the Western world. The recent marketing authorization of some medicinal products of industrial origin and the introduction onto the market of inflorescences for medical use mean that medical doctors can now prescribe Cannabis -based medicines in those countries which allow it. Nevertheless, there is still considerable controversy on this topic in the scientific community. In particular, this controversy concerns: the plant species to be used; the pathologies that can be treated and consequently the efficacy and safety of use; the routes of administration; the methods of preparation; the type and dosage of cannabinoids to be used; and, the active molecules of interest. As such, although medical Cannabis has been historically used, the results of currently completed and internationally published studies are inconclusive and often discordant. In light of these considerations, the aim of this work is to analyse the current legislation in countries that allow the use of medical Cannabis , in relation to the impact that this legislation has had on clinical trials. First of all, a literature search has been performed (PubMed and SciFinder) on clinical trials which involved the administration of Cannabis for medical use over the last 3 years. Of the numerous studies extrapolated from the literature, only about 43 reported data on clinical trials on medical Cannabis , with these mainly being performed in Australia, Brazil, Canada, Denmark, Germany, Israel, Netherlands, Switzerland, the United Kingdom and the United States of America. Once the reference countries were identified, an evaluation of the legislation in relation to Cannabis for medical use in each was carried out via the consultation of the pertinent scientific literature, but also of official government documentation and that of local regulatory authorities. This analysis provided us with an overview of the different legislation in these countries and, consequently, allowed us to analyse, with greater awareness, the results of the clinical trials published in the last 3 years in order to obtain general interest indications in the prosecution of scientific research in this area.

1 Introduction

Cannabis was widely used in the past for its curative properties. The earliest records of its medicinal use date back to China where Cannabis has been cultivated for millennia for use as a fiber, food, and medicine. Over time, it spread to the whole of Asia, the Middle East, and Africa. In the West, the plant started to attract scientific interest only in the 20th century. However, in the last century, the cultivation, sale, and use of Cannabis was made illegal in the majority of countries ( Lafaye, et al., 2017 ; Pisanti and Bifulco, 2019 ; Romano and Hazekamp, 2019 ; Arias, et al., 2021 ).

In the last few decades, there has been revived support for its decriminalisation, and legalisation for medical uses thanks to new and scientifically founded indications of its potential therapeutic value. This is partly due to the support gained in the media, and to the high expectations for its efficacy, even though these hopes, for many diseases, are not sufficiently supported by scientific research ( Hill, 2015 ; Whiting, et al., 2015 ).

The phytocomplex of Cannabis plants is made up of more than 500 molecules, of which about a hundred belong to the Cannabinoid chemical class. Among these molecules, even small variations in molecular structure can produce significantly different effects. The molecules of greatest interest to pharmacologists are the decarboxylated forms of 9-tetrahydracannabinol (THC) and cannabidiol since these are easily absorbed in the intestine ( Grotenhermen, 2003 ; Gould, 2015 ; Baratta, et al., 2019 ; Baratta, et al., 2021 ).

Recently, Cannabis based industrial medicines have been approved for sale, and medical use inflorescences have been made available. This has given medical doctors, in those countries which allow it, the option to prescribe Cannabis -based products. At present, the most widely available products are: Marinol ® (AbbVie Inc) and Syndros ® (Benuvia Therapeutics) which contain dronabinol, an isomer of delta-9-tetrahydrocannabinol; Cesamet ® based on nabilone (Meda Pharmaceuticals Inc.), another synthetic cannabinoid; Sativex ® (GW Pharma Ltd.), based on an ethanol extraction of Cannabis sativa ; and Epidiolex ® 1 (Greenwich Biosciences), which contains CBD ( Casiraghi, et al., 2018 ).

A variety of pharmaceutical-grade inflorescence products are also available on the market. Usually, the label only indicates the concentrations of THC and CBD. This is a critical point as the phytocomplex of medical Cannabis contains many active molecules which contribute to the “Entourage effect,” a hypothesis postulating a positive synergic action between cannabinoids and terpenes ( Stella, et al., 2021 ; Baratta, et al., 2022 ).

Given the increasing availability of the above products, many countries have introduced specific legislation, regulations, and guidelines regarding the use of medical use Cannabis in the treatment of various pathologies. Nevertheless, debate continues around this subject within the scientific community. The main points of contention are the correct plant varieties to be used, the pathologies to be treated, and, consequently, the efficacy and safety of their use. There are no universally shared indications on the optimum administration route, the preparation methodology, the definitive types of cannabinoids and dosages to recommend, or even the identity of the active molecule of interest. This controversy stems in large part from the findings of the clinical trials conducted till now. Although the number of studies and publications is growing rapidly, for many diseases the results are often contradictory or inconclusive. All too often, these trials were performed on a non-homogeneous population, and utilising diverse plant material, extraction methods, dosages, pharmaceutical forms, and administration routes. Moreover, the trials were often conducted without a control group ( Stella, et al., 2021 ).

In light of all these considerations, the objective of this work is to analyse the current legislation and regulations in a number of countries where medical use Cannabis is permitted in order to evaluate any relationship of these on the design of clinical trials carried out there.

2 Materials and Methods

We carried out a literature search (PubMed and SciFinder) for clinical trials with medical Cannabis published in the last 3 years (2019/01/01–2021/12/15). We excluded literature reviews, non-clinical trials, and articles about non-medical use Cannabis . We also considered published articles about clinical trial protocols to be carried out. The key search terms used were clinical trials, medical Cannabis , and medical use.

After the publications had been selected, the countries of origin were identified in order to perform an evaluation of the current regulations in each regarding medical Cannabis . The scientific literature, and relevant official publications from government and local authorities were consulted for this analysis.

Finally, the characteristics and the results of the clinical studies were analysed to evaluate any possible link to the state legislation where the studies had been carried out.

Of the 400 matches from the literature search, only 10% (43) of the publications reported data from trials or clinical protocols regarding medical Cannabis . The relevant trials were carried out in: Australia, Brazil, Canada, Denmark, Germany, Israel, Netherlands, Switzerland, the United Kingdom, and the United States of America. Given their geographical distribution, these countries can be considered of interest despite the small number of studies available.

For each of the countries in question, the current legislation on medical Cannabis was analysed, and some specific features are reported such as: prescription procedure, indicated pathologies for medical Cannabis , products available for sale, dispensation forms, authorisation to grow Cannabis for medical use, and reimbursement procedure.

3.1 Current Legislation

3.1.1 australia.

Although there are some regulatory differences among the federal states regarding the importation of products, and the qualification required to write a prescription, medical Cannabis may be prescribed after receiving authorisation from the Therapeutic Goods Administration, through the Special Access Scheme for an individual patient, or through the Authorized Prescriber Scheme for a group of patients with the same condition. Products of industrial origin are exempt from these schemes as approval for sale has already been granted (Sativex ® and Epidiolex ® ).

As well as Sativex ® and Epidiolex ® , indicated for the treatment of spasticity in multiple sclerosis and paediatric epilepsy, herbal- Cannabis based products may also be prescribed. The most common conditions are spasticity in multiple sclerosis, nausea or vomiting caused by anti-tumoral chemotherapy, pain or anxiety in patients with terminal diseases, and refractory child epilepsy. The physician may in any case write a prescription for pathologies other than those indicated.

Pharmacies are authorised to dispense medical Cannabis -based products.

The cost of the therapy is not subsidised by the government.

Alcohol and Drug Foundation, 2021 ; Australian Capital Territory Government, 2021 ; Australian Government, 2017a ; Australian Government, 2017b ; Australian Government, 2018 ; Australian Government, 2020 ; Australian Government, 2021 ; Australian Institute of Health and Welfare, 2019 ; Castle, et al., 2019 ; Centre for Medicinal Cannabis Research and Innovation, 2021 ; Health Direct, 2019 ; Mersiades, et al., 2019 ; The Health Products Regulatory Authority, 2017 ; The Office of Drug Control, 2021 )

3.1.2 Brazil

Various products of industrial origin are available such as Epidiolex ® and Sativex ® , and the importation of Cannabis -derived products is generally authorised. However, the importation of the raw plant or parts of the plant is not permitted. Products with a concentration of THC greater than 0.2% may only be prescribed when no alternative therapy is available, and the patient has reached the irreversible or terminal stage of their disease. Prescription is under the responsibility of the prescribing medical doctor. The medication may be taken either orally or by inhalation.

The cost of the treatment is generally high and is completely at the patient’s expense.

The dispensation may take place in a pharmacy, where Cannabis may not be processed, however.

( Crippa, et al., 2018 ; Marketrealist, 2019 ; Ministério da Saúde, 2019 ; Reuters, 2019 ; Brazilian Government, 2021 )

3.1.3 Canada

The situation in Canada is quite different, medical Cannabis (with the exception of approved industrial products) is not considered as a medicine; hence, it is not dispensed in pharmacies. Medical doctors or nurses may prescribe it for individual patients. The patient can then acquire it from a licensed vendor; grow a quantity sufficient for personal use in residence after registering with the Ministry for Health; nominate a grower in their place (a grower can only cultivate for two people); or acquire it from a provincial or area level licensed retailer. The patient is allowed to prepare Cannabis -based products, but the use of organic solvents such as butane, benzene, methyl-chloride, or chlorinated hydrocarbons is forbidden.

Regarding industrial products, Sativex ® is available for sale; it is indicated for the treatment of spasticity in multiple sclerosis. Other recommended uses include additional pain relief for neuropathic pain in adult patients with multiple sclerosis, and additional pain relief for patients with late-stage cancer who experience moderate to serious pain when already undergoing palliative care with the highest tolerable dosages of opioids. Nabilone is approved for treatment of serious nausea and vomiting associated with chemotherapy, while dronabinol is approved for the treatment of AIDS-related anorexia, and for serious nausea and vomiting associated with chemotherapy. Dronabinol was withdrawn for the Canadian market by the producer in February 2012, but not for health risks.

Generally, Cannabis may be used for any symptom without demonstrating the inefficacy of the previous therapies.

The approved industrial products may be reimbursed by health insurance companies, while all the others are non-reimbursable.

( Fischer, et al., 2015 ; Ablin, et al., 2016 ; Health Canada, 2016 ; The Health Products Regulatory Authority, 2017 ; Abuhasira, et al., 2018 ; Conseil fédéral, 2018 ; Government of Canada, 2019 ; Health Canada, 2022 )

3.1.4 Denmark

All medical doctors are authorised to prescribe Cannabis -based products as part of a 4 years pilot project launched in January 2018. As part of this project, a medical doctor may prescribe medicines that are not approved for distribution or sale in Denmark. However, the medical doctor must take full responsibility for the products they prescribe and must determine the proper dosage for each patient. Medical doctors may refer to the guidelines laid out by the Danish Medicines Agency. The imported plant products available for prescription may vary in content, but they must comply with strict standards and regulations governing the cultivation of the plant species, and the production and standardisation of the Cannabis -based product.

Herbal Cannabis is available by prescription only in pharmacies, which may also prepare magistral preparations.

Regarding industrial products, neurologists may prescribe Sativex ® to treat spasticity from multiple sclerosis. In general, medical doctors may prescribe imported Cannabis -derived medicines that have not been approved for sale in Denmark, such as Marinol ® and Cesamet ® on compassionate grounds, but only if the request is approved by the Danish Medicines Agency.

In general, the Danish Medicines Agency indicates that medical Cannabis be considered as a therapy only for the following conditions: painful spasticity in multiple sclerosis, painful spasticity caused by spinal cord damage, chemotherapy-induced nausea, and neuropathic pain. As part of the pilot project, Cannabis may, however, be prescribed to any patient even outside of the guidelines. The use of Cannabis is not recommended for patients under 18 years of age.

The prices of the prescribed products within the pilot project are set freely by the manufacturers. It is possible to obtain a reimbursement as of 01/01/2019 (retroactive for 2018). Patients in the terminal stages of a disease are fully reimbursed, while patients with other illnesses receive a 50% reimbursement, up to annual maximum of 10,000 Danish Krone. The reimbursement is automatically deducted at the time of the purchase in a pharmacy.

For prescriptions that are not part of the pilot project, the medical doctor may request a reimbursement for an individual patient from the Danish Medicines Agency. It will consider the request for those patients with pathologies where Cannabis -based treatment appears to be effective, and for those whom all other treatments with approved medicines have been used without effect.

( The Health Products Regulatory Authority, 2017 ; Abuhasira, et al., 2018 ; Krcevski-Skvarc, et al., 2018 ; Danish Medicines Agency, 2020 ; Gustavsen, et al., 2021 )

3.1.5 Germany

Medical doctors may prescribe medical Cannabis using a specific “narcotics” prescription form. The prescription may be for any condition that has no standard treatment, or the standard treatment cannot be used owing to reactions, or based on the patient’s specific condition. Among the industrial products available is Sativex ® , which is indicated for spasticity in refractory multiple sclerosis. In addition, it is possible to prescribe dronabinol without particular restrictions regarding its indicated use. Nabilone is approved for nausea and vomiting associated with chemotherapy and unresponsive to conventional therapies. Finally, Epidiolex ® and many types of Cannabis inflorescences may also be prescribed. Magisterial preparations may be prescribed, and pharmacies may dispense extracts of Cannabis and inflorescences.

In the past, Cannabis could also be theoretically grown in residence by private individuals if conventional therapies had been inefficacious, no other alternative treatments were available, and/or to reduce the cost of therapy. Actually, this possibility has never been really applied. Since 2019, however, a system of checks on the production and supply of Cannabis has been introduced by the government.

The patients may request a reimbursement from health insurance companies. For this purpose the prescribing medical doctor has the task of certifying the seriousness of the disease, that the standard therapies have been ineffective, or cannot be used due to the patient’s specific condition, or that there is a reasonable likelihood that medical Cannabis will be effective for that subject.

( Grotenhermen and Müller-Vahl, 2012 ; Ablin, et al., 2016 ; The Health Products Regulatory Authority, 2017 ; Abuhasira, et al., 2018 ; Conseil fédéral, 2018 ; Federal Institute for Drugs and Medical Devices, 2018 ; Krcevski-Skvarc, et al., 2018 ; Rasche, et al., 2019 ; Federal Institute for Drugs and Medical Devices, 2022a ; Federal Institute for Drugs and Medical Devices, 2022b ; Federal Institute for Drugs and Medical Devices, 2022c ; Federal Institute for Drugs and Medical Devices, 2022d ; German Institute for Medical Cannabis , 2022 )

3.1.6 Israel

In Israel, patients with a prescription may use a licensed pharmacy to obtain medical Cannabis . There is a list of conditions for which Cannabis may be used, but the medical doctor may also prescribe it for other pathologies: in any case, it may only be used when other therapies have proved ineffective. The list includes neuropathic pain, serious cachexia in AIDS patients, spasticity from multiple sclerosis, pain associated with Parkinson’s disease, Tourette’s syndrome, treatment of metastatic cancer or chemotherapy-induced symptoms, inflammatory intestinal diseases and post-traumatic stress disorders.

In general, the products available are Cannabis inflorescences, Sativex ® and Epidiolex ® . The number of medical Cannabis patients among the Israeli population is one of the highest in the world (on February 2022 about 100,000 Israelis -about 1% of the population-were allowed to consume medical Cannabis ).

Sativex ® is recommended for spasticity from multiple sclerosis unresponsive to other treatments, or as an additional analgesic therapy in adult patients with advanced stage cancer with moderate to severe pain despite being administered the highest tolerable dosage of opioids; Epidiolex ® is used to treat convulsions in Dravet syndrome, and Lennox-Gastaut syndrome.

As for herbal Cannabis , a government-run programme produces and distributes this product. Medical Cannabis is supplied in two forms: as an oil extract for oral administration or sub-lingual deposition, and as the inflorescence which may be smoked or inhaled with vaporisers. The cost of the therapy is reimbursed in part by some private and state health insurance schemes.

( abcNEWS, 2022 ; Ablin, et al., 2016 ; Abuhasira, et al., 2018 ; Krcevski-Skvarc, et al., 2018 ; State of Israel - Minister of Health, 2017 ; State of Israel - Minister of Health, 2022 ; The Health Products Regulatory Authority, 2017 )

3.1.7 Netherlands

In Netherlands, all medical doctors may prescribe medical Cannabis . The pharmacies may also produce extracts using the plant material produced by the Office of Medical Cannabis . These are usually oil extracts to be taken orally or deposited under the tongue. Some types of inflorescences are available for this purpose: the concentration of the active molecules and granulation properties may vary. The inflorescences may also be taken in the decoction form or inhaled through vaporisers.

Sativex ® is approved for the treatment of spasticity from multiple sclerosis refractory to conventional therapies.

Cannabis is indicated for the treatment of pain (multiple sclerosis, or spinal cord injuries), chronic pain, nausea and vomiting (in chemotherapy or radiotherapy, HIV therapies, adverse reactions to hepatitis C medication), palliative care for cancer or AIDS (to increase appetite and alleviate pain, nausea and weight loss), Tourette’s syndrome, and refractory glaucoma, epilepsy and epileptic syndromes (even in children). In addition, its use is indicated in the reduction in symptomology of the following pathologies: Crohn’s disease, ulcerative colitis, itching, migraine, rheumatic conditions, ADHD, post-traumatic stress disorders, agitation in Alzheimer’s disease and cerebral trauma. Medical doctors are in any case authorised to prescribe these therapies for other conditions if they consider it fit. Cannabis -based products must, however, be considered only in cases where authorised medicines have inefficacious or provoked unacceptable adverse reactions.

As concerns the available herbal Cannabis species, Bediol ® (THC 6.3%; CBD 8%) is usually recommended as the first-choice therapy to alleviate pain or as an anti-inflammatory therapy. Bedrocan ® (THC 22%; CBD <1.0%), Bedica ® (THC 14%; CBD <1.0%) and Bedrobinol ® (THC 13.5%; CBD <1.0%) are considered more effective for the treatment of symptoms such as appetite loss, weight loss, nausea, vomiting, anorexia, cachexia, emesis, Tourette’s syndrome, and glaucoma. Bedrolite ® (THC <1.0%; CBD 7.5%) is employed for certain forms of epilepsy.

The healthcare system does not reimburse the cost of Cannabis -based medicines. In some cases, the patient may be able to claim from private insurance schemes.

( The Health Products Regulatory Authority, 2017 ; Abuhasira, et al., 2018 ; Conseil fédéral, 2018 ; Krcevski-Skvarc, et al., 2018 ; Bedrocan, 2021 ; Office of Medicinal Cannabis, 2022 )

3.1.8 Switzerland

The prescription and use of Cannabis -based magistral preparations is authorised for spasticity (multiple sclerosis), chronic pain, appetite loss in AIDS, and nausea, pain, and appetite loss from cancer.

The magistral preparations are prepared in a pharmacy.

Medical doctors may prescribe Cannabis -based medicines only after receiving authorisation from the Federal office of the Public Health System.

The cost of the therapy is not reimbursed systematically, but on a case-by-case basis.

As well as the inflorescence, it is possible to use dronabinol and Epidiolex ® . Sativex ® is also authorised for use and available for treatment of spasticity from multiple sclerosis.

( Abuhasira, et al., 2018 ; Krcevski-Skvarc, et al., 2018 ; Swiss Confederation, Federal Office of Public Health, 2020 ; Swiss Confederation, Federal Office of Public Health, 2021a ; Swiss Confederation, Federal Office of Public Health, 2021b ; Swiss Confederation, Federal Office of Public Health, 2021c )

3.1.9 United Kingdom

In the United Kingdom, medical Cannabis is generally prescribed to adults and children with rare and serious forms of epilepsy, adults suffering from nausea or vomiting from chemotherapy, and adults with muscular stiffness or spasms from multiple sclerosis. This therapy is considered only in cases in which no alternative treatment is available, or other treatments have been inefficacious. The available products are Epidiolex ® , prescribed to patients with Lennox-Gastaut syndrome or Dravet syndrome; nabilone, which is authorised for nausea and vomiting associated with chemotherapy; dronabinol is also available, but it has no marketing authorization; and Sativex ® , which is prescribed for muscular spasms in multiple sclerosis unresponsive to other treatments (even though it is discouraged by NICE in that it is not cost-effective).

The medical Cannabis therapy cannot be obtained from a general practitioner but must be prescribed by a hospital specialist registered with the General Medical Council. The medical doctor may collect data on adverse reactions, which can also be signalled directly by the patient through a yellow card system.

( Department of Health and Social Care, 2018 ; Medicines and healthcare products Regulatory Agency, 2020 ; MS Society, 2021 ; National Health Service, 2021 ; General Medical Council, 2022 ; National Health Service, 2022 ; UK Government, 2022 )

3.1.10 United States of America

There are significant legislative differences among the states concerning Cannabis in the United States. In some states the legislation in force is extremely limiting, in others significantly less restrictive. Therefore, the state laws may not be completely harmonised with federal laws.

Regarding industrial products, the FDA has approved the prescription of dronabinol and nabilone for the treatment of chemotherapy-induced nausea and vomiting. Dronabinol may also be used for the treatment of appetite and weight loss in HIV patients. Epidiolex ® may be prescribed for the treatment of epileptic disorders, Lennox-Gastaut syndrome and Dravet’s syndrome.

Concerning herbal Cannabis , only 36 states have legalised or decriminalised its use. In general, in those states which have authorised the use of medical use Cannabis , there are restrictions on its prescription. Depending to the local laws, therefore, Cannabis may be prescribed for pain, anxiety, epilepsy, glaucoma, appetite and weight loss associated with AIDS, inflammatory intestinal disturbances irritable intestine syndrome, motor disturbances due to Tourette’s syndrome or multiple sclerosis, nausea and vomiting caused by chemotherapy, sleep disorders, posttraumatic stress disorders. Some states allow the addition, at the prescribing medical doctor’s discretion, of pathologies other than those expressly stated.

Generally, medical doctors do not need specific training to prescribe Cannabis , but in many states, it is necessary to register before doing so. In other states, medical doctors must attend a short training course to be able to register. In some states, it is enough that the medical doctor gives advice verbally to take medical Cannabis , or its use may be recommended by a health care professional who is not a medical doctor. On the other hand, in some states, it is necessary that two medical doctors confirm the need for a Cannabis -based treatment for a patient. Depending on the state, Cannabis may be supplied to the patient by licensed dispensaries, or it may be grown at home by the patient or by a caregiver.

Smoking medical Cannabis is prohibited in some states. Similarly even the edible forms are prohibited in some states. Generally, the administration is performed orally or by vaporiser.

Patients are generally registered so that the possession and use of medical Cannabis is not prosecuted.

Abuhasira, et al., 2018 ; Alharbi, 2020 ; Carliner, et al., 2017 ; Choo and Emery, 2017 ; Corroon and Kight, 2018 ; Johnson, et al., 2021 ; Mead, 2017 ; National Conferences of State Legislatures, 2022 ; ProCon, 2022 ; Ryan, et al., 2021 ; The Health Products Regulatory Authority, 2017 )

3.2 Study Protocols and Clinical Trials

There are 43 publications of proposed, or executed, clinical trial protocols in those countries whose legislation has been analysed; eight of these regarded proposed clinical trial protocols.

Hence, 35 publications regarded actual clinical trial data. These were sub-divided into three groups: the first, “positive outcome,” included those studies which demonstrated the efficacy of the preparation administered, or that the actual results were in line with those expected (18). The second group, “negative outcome,” included those studies where the authors reported that the administered product was no more efficacious than the placebo (5). Finally, the third group, “inconclusive outcome,” comprised those studies where the results were not conclusive (12).

The characteristics of the taken into account clinical studies are summarized in Table 1 .

www.frontiersin.org

TABLE 1 . Characteristics of the selected clinical trials.

3.2.1 Clinical Trials With a Positive Outcome

Of the 18 studies in this category, 4 were conducted in Australia, 4 in Israel, 1 in Switzerland, 5 in the United Kingdom, and 4 in the United States.

Regarding the study design, 2 were multi-centred, 13 used the double-blind method, 14 had a randomised control design, and 14 used a placebo control group.

The sample size varied greatly, from a minimum of 8 to a maximum of 128 enrolled subjects.

As for the products used in the trials, 12 studies administer CBD, 6 studied herbal Cannabis derivatives.

CBD was administered orally in 10 cases, topically and by inhalation in only one study. The herbal Cannabis derivatives were administered by inhalation in 3 cases, and by the oral route in 2 cases. One study considered products to be administered orally, by inhalation or topically.

In 9 studies, the Cannabis derivatives were administered in addition to a standard therapy.

The most commonly studied conditions were behaviour, cerebral activity, and memory (6), pain (4), addiction or abstinence to drugs (3), epilepsy (2), pharmacokinetic studies, safety, and tolerability (2), and nausea and vomiting (1). Two studies were carried out on a paediatric population.

In general, the studies involving the administration of CBD regarded epilepsy, addiction or abstinence to drugs, behaviour, cerebral activity and memory, peripheral neuropathy, pharmacokinetic studies, and safety and tolerability.

Instead, studies administering herbal Cannabis derivatives focused mainly about pain and then about nausea and vomiting, cerebral activity and Cannabis dependence. In most cases both THC and CBD were administered in different ratios. In some cases, a herbal Cannabis strain was used with a high concentration of THC.

( Almog, et al., 2020 ; Birnbaum, et al., 2019 ; Efron, et al., 2021 ; Freeman, et al., 2020 ; Grimison, et al., 2020 ; Hotz, et al., 2021 ; Hurd, et al., 2019 ; Izgelov, et al., 2020 ; Lintzeris, et al., 2020 ; Mitelpunkt, et al., 2019 ; O'Neill, et al., 2021 ; Perkins, et al., 2020 ; Pretzsch, et al., 2019a ; Pretzsch, et al., 2019c ; Wall, et al., 2019 ; Xu, et al., 2020 ; Yassin, et al., 2019 ; Zylla, et al., 2021 )

3.2.2 Clinical Trials With a Negative Outcome

Five trials had a negative outcome. Two of these were conducted in the United States, 1 in Australia, 1 in Brazil and 1 in the United Kingdom.

All of the trials had a randomised control, used a placebo control group, and a double-blind control. The sample size ranged from 14 to 105 enrolled subjects.

As for the products used, 3 studies administered oral preparations containing CBD. 2 studies were based on the administration of inflorescences by inhalation. 4 studies out of 5 administered the product in addition to a standard therapy.

The conditions studied in these trials with CBD were pain, COVID-19 infection, and the effects on neural correlates of reward anticipation and feedback. Herbal Cannabis , in three different forms and different ratios of THC/CBD), was administered to evaluate its efficacy in the treatment of Obsessive-Compulsive Disorder (OCD) and Post-Traumatic Stress Disorder (PTSD).

None of these studies demonstrated that the administered product was more efficacious than the placebo control.

( Kayser, et al., 2020 ; Lawn, et al., 2020 ; Bebee, et al., 2021 ; Bonn-Miller, et al., 2021 ; Crippa, et al., 2021 )

3.2.3 Clinical Trials With an Inconclusive Outcome

12 studies had an inconclusive outcome: 3 were conducted in Australia, 3 in Israel, 1 in the Netherlands, 1 in the United Kingdom and 4 in the United States.

Regarding study design, 10 included a double-blind system, 11 had a randomised control, and 10 utilised a placebo control group. The sample size ranged from a minimum of 6 subjects to a maximum of 150 individuals. Two of the studies were conducted on paediatric subjects.

Concerning the products used, 2 studies administered CBD alone, one study used THC alone, 1 study administered cannabidivarin, 2 studies administered THC and CBD, both alone and in a mixture, 5 studies administered herbal Cannabis derivatives, and 1 study administered both THC and CBD as well as a herbal Cannabis extract.

CBD and cannabidivarin were administered orally; THC, and the mixtures of THC and CBD were administered by inhalation. THC was also administered orally. The herbal Cannabis derivatives were administered by inhalation in 3 studies, while they were for oral use in 2 studies. 1 study used oral administration of a herbal Cannabis extract or an equivalent mixture of THC and CBD.

Six trials predicted that the administration was additional to standard therapy.

The conditions to be studied for the efficacy of CBD were anxiety and cognitive function in patients suffering from epilepsy. THC and/or CBD were administered to evaluate the active dosage or to study its effects on problems linked to appetite and metabolism, herbal Cannabis derivatives were studied to evaluate their activity in Crohn’s disease, ulcerative colitis, pain, haemolytic anaemia, markers of wellness and clinical biomarkers in obese patients. Trials related to autism were conducted with, as well as cannabidivarin, the administration of a herbal Cannabis extract or an equivalent mixture of THC and CBD.

When herbal Cannabis derivatives were administered, the concentration of THC and CBD, and the ratio of the two varied greatly among the trials. Some used products with a high concentration of THC, while others used products with a high concentration of CBD. In 1 trial, different types of inflorescences were administered to evaluate the most efficacious ratio of THC to CBD concentrations against pain.

( Pretzsch, et al., 2019b ; Solowij, et al., 2019 ; Van de Donk, et al., 2019 ; Abrams, et al., 2020 ; Farokhnia, et al., 2020 ; Liu, et al., 2020 ; Lopez, et al., 2020 ; Thompson, et al., 2020 ; Naftali, et al., 2021a ; Anderson, et al., 2021 ; Aran, et al., 2021 ; Naftali, et al., 2021b )

3.2.4 Study Protocols

There are 8 examples of published protocols that have not yet initiated the clinical trial phase. 4 are in Australia, and 1 each in Denmark, Canada, Germany, and Netherlands. The number of enrolled subjects is between 10 and 180 in total. One study will be carried out among the paediatric population.

Concerning the study design, 3 will be multi-centre studies, 7 use a double-blind system, 8 are randomised, and 7 use a placebo control group.

Regarding the products to be used, 4 protocols will use the oral administration of THC and CBD. The ratio between the components in question varies from study to study. In 2 protocols, the administration of CBD is also foreseen. One protocol foresees the administration of both CBD and a preparation containing a high concentration of THC.

For those studies using THC and CBD mixtures, the pathologies to be studied are, pain, dementia, spasms, and the activation of the immune system in HIV patients. Instead, the CBD alone preparations will be administered for behavioural problems and phobias. The herbal- Cannabis derived product will be administered for chronic tic disorder. The protocol that foresees the administration of both CBD and a preparation with a high concentration of THC will focus on the alleviation of pain.

( Costiniuk, et al., 2019 ; Hendricks, et al., 2019 ; Urbi, et al., 2019 ; Van der Flier, et al., 2019 ; Efron, et al., 2020 ; Hardy, et al., 2020 ; Jakubovski, et al., 2020 ; Timler, et al., 2020 )

4 Discussion

From the analysis of the current legislation in states where clinical trials and proposed protocols on medical Cannabis and derived products have been published in the last 3 years, many significant differences have been found regarding the products available, the indicated pathologies for which it may be prescribed, the production of the raw plant material, as well as its reimbursement and prescription. It was evaluated to consider the studies published in the last 3 years supposing that the researchers have benefited from the latest knowledge on medical Cannabis and to make an overview of the pathologies currently under study.

In particular, regarding industrial products, practically every country, with the exception of the United States, has approved the use of Sativex ® . However, Epidiolex ® , dronabinol.Netherlands, and nabilone are also quite common.

In all the countries, the use of herbal Cannabis is also authorised. The only exception is Brazil, which is certainly the country with the most restrictive legislation. Netherlands is the only country to provide directions for use, which are not binding, but quite strict, regarding the plant strain to be used for a determined pathology based on the concentration of active molecules (THC and CBD). Instead, for the other countries, it must be pointed out that the current legislation provides for the use of inflorescences or herbal Cannabis extracts without providing specific directions concerning the recommended concentration of active molecules to treat a determined condition.

Regarding the pathologies or symptoms associated with the more or less well-defined conditions, the most common are pain, nausea, vomiting, spasticity, and epilepsy followed by spasms, and weight and appetite loss. The less frequently indicated conditions in this case include Tourette’s syndrome, PTSD, and glaucoma. In many countries, additional conditions are considered in more or less detail.

In this regard, it is interesting to note that the country with the greatest number of specifically recommended pathologies not indicated in other countries is the Netherlands: perhaps based on the longstanding use of Cannabis both for medical use and recreational purposes. Although the legislation regarding medical Cannabis is quite comprehensive in all the countries considered, some of them, namely Australia, Canada, Denmark, Germany, Israel, Netherlands, and the United States, also permit the prescription of Cannabis for any therapeutic application at the discretion of the medical doctor. However, in Germany, Netherlands and Israel, this is limited to cases in which other therapies have proved ineffective, excessive adverse reactions to standard treatments have occurred, or valid alternative treatments are not available. Instead, in Australia, Canada, Denmark, and the United States, therapeutic strategies different from those specified are authorised regardless of any prior treatment. The prescription of medical Cannabis for any condition certainly does not conform to the procedures generally in force for other medicinal products, and especially products with a psychoactive effect such as those prepared containing THC.

It is interesting to note that in Canada, and in some states in the United States, the medical inflorescences may be grown directly by the patient, and the treatment may be recommended by a health worker, and not only a medical doctor; in the event that the plant species is not home-grown, it is distributed through a licensed dispensary. In Germany, Israel and Netherlands, herbal Cannabis is grown locally under the supervision of a government agency. This is significant if one considers that, in these three countries, the prescription process is highly deregulated regarding the recommended pathologies to be treated with Cannabis , but the same does not apply to its cultivation.

The normal administration routes are oral or by inhalation. Some countries, such as Israel, authorise smoking Cannabis inflorescences as a route of administration, something that is categorically banned in some states of the United States.

In addition, regarding prescription, it is noteworthy that the United Kingdom is the only country where this must be obtained from a hospital specialist. In some states in the United States, on the other hand, the prescribing medical doctor must be registered to prescribe this therapy and have attended a specific training course. In Australia and Switzerland, medical doctors may write the prescription only after receiving authorisation from a specific agency. Therefore, there is a different focus on the prescription process and hence inhomogeneity in this aspect too. The treatment costs are generally borne by the patient, and no reimbursement is foreseen, unless it is from a private health insurance scheme. This certainly restricts access to this kind of therapy to the more privileged members of society.

Concerning the results of the clinical trials, some interesting observations may be made. In the first place, a greater number of studies have been published in certain countries. These countries are the United States (11) and Australia (9), followed by Israel (7) and the United Kingdom (7). In general, the majority of the studies featured randomisation, the use of a double-blind method, and a placebo control group: these are factors which guarantee the quality of the data gathered. On the other hand, the majority of the studies took place with a small sample size. Moreover, the studies made use of a heterogeneous population: healthy and ill volunteers, adults and children, acute and chronically ill patients, and subjects who had previously used or had never used Cannabis prior to the study. Factors that, being so numerous, make it particularly challenging to draw any conclusive evaluations of the results of these trials, and more in general, the real efficacy of medical Cannabis .

Considering only the studies with a positive outcome, it should be noted that the studied pathologies are coherent with those provided for in current legislation i.e., pain, epilepsy, nausea, and vomiting; on the contrary, psychosis, behavioural problems, memory and cerebral activity represent a novelty. Furthermore, there is a net distinction between the products used based on the different conditions to be treated: the trials on pain, nausea and vomiting with positive outcomes administered herbal Cannabis derivatives in which, in 3 cases out of 4, both THC and CBD are present; the other studies with a positive outcome administered CBD alone. In those trials with a negative outcome, CBD was administered for pain, while herbal Cannabis derivatives were used for conditions such as OCD or PTSD. This consideration supports the use of herbal Cannabis in which both THC and CBD are present for pain, even though it should be stressed that the studies with a positive outcome for this pathology had a maximum of 30 enrolled subjects.

The studies with an inconclusive outcome regarded a variegated list of conditions including anxiety, Crohn’s syndrome, ulcerative colitis, pain, and appetite loss. Many of these are already included in some national regulations although the efficacy of Cannabis in these cases according to the currently available data is not satisfactorily demonstrated.

It is evident that the only pathology present in all three study categories is pain, for which 4 studies had a positive outcome, 1 had a negative outcome, and 1 had an inconclusive outcome.

Among the study protocols to be trialled, pain and spasticity appear again, approved by legislation in most countries and the object of numerous studies, as well as a number of less-investigated conditions such as dementia, phobias, tic disorders and the activation of the immune system in HIV patients.

Based on the research conducted, it is, therefore, possible to stress that in spite of the growing number of recent studies on medical Cannabis , many of which have had a positive outcome while many others have had an inconclusive or negative outcome. The presumed broad spectrum action of Cannabis has led to the initiation of many trials and the preparation of many study protocols for a wide range of pathologies with the enrolment of subjects with diverse characteristics from study to study. This means that there is very little data for each pathology or symptomology.

Another important factor is that the products used are very diverse from each other; consequently, a comparison is extremely difficult to make, especially for the herbal products. All of the trials indicate the precise dosages used in terms of active molecules, but when it comes to inflorescences, or extracts derived from them, the concentration is provided only for the THC and CBD content and not for the other active molecules. Furthermore, the diverse administration routes make a comparison based on pharmacokinetics difficult for the molecules of interest.

Therefore, it is difficult to compare the studies and draw conclusions concerning the efficacy of the protocol for the single pathologies. However, for some, substantial evidence is emerging regarding their efficacy and the suitable products to ensure that. From the analysed data, it is clear that the best pain treatment is herbal Cannabis derivatives containing both THC and CBD, just as the best way to treat epilepsy is to administer CBD.

One interesting point is that for some of the pathologies approved for treatment with medical Cannabis under the current legislation, the data do not paint a definitive picture. This is true for conditions such as anxiety, ulcerative colitis, Crohn’s syndrome, and appetite enhancement.

On the other hand, the current legislation often authorises inflorescences or extracts without indicating the exact concentration of the active molecules. In parallel, many studies use different plant strains or study a small number of subjects, making it difficult to compare and consequently interpret the results. Moreover, in many studies, the Cannabis -based medicines were administered in addition to other treatments making any evaluation of their efficacy it even more complex.

5 Conclusion

Medical Cannabis is often considered as if it were a single active component, but, in fact, there are countless possible variations. Hence, it will be some time before the current list of pathologies that each product may be used for can be updated based on definitive clinical data on the efficacy of the various components. Certainly, the development of standardised industrial products will facilitate the execution of more meaningful trials compared to those that involve the administration of inflorescences or derived extracts prepared using a variety of methods and, thus, highly variable in terms of concentration of the active molecules.

The authors want moreover to put in evidence that, despite legislation authorising the use of medical Cannabis and instituting the national production centre for inflorescences more than 5 years ago, Italy is still among the states where clinical trials have not been conducted. This gap is due to legal restrictions on the approval and conduction of clinical trials in this field, and the difficulty in sourcing the raw plant material, of which there is always a shortage. The result of this is therapies using inflorescences and extracts which have never undergone specific clinical trialling.

In the end, the influence of the media, economic interests, and the demands of associations representing patients affected by these diseases and conditions, for whom Cannabis is a panacea, means that in many countries it is currently possible to use medical Cannabis even though the scientific data do not entirely support the signs of efficacy: certainly this is a special case where the consolidated procedures for the administration of any product in the medical field have been either overlooked or ignored. It is time that the regulatory agencies considered whether this is actually safeguarding the health of patients.

The analysis of the current legislation may not be exhaustive in that it refers only to public texts available online.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.

Author Contributions

FB and PB performed the conceptualization of the work. FB, IP and LE performed the investigation and took care of the data. FB wrote the manuscript. PB coordinated the project. All authors approved the final version of the study.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

The authors would like to thank Dr Tom O Byrne for the linguistic revision of the text.

Abbreviations

ADHD, Attention-Deficit/Hyperactivity Disorder; AIDS, Acquired ImmunoDeficiency Syndrome; CBD, CannaBiDiol; COVID-19, COronaVIrus Disease 2019; FDA, Food and Drug Administration; HIV, Human Immunodeficiency Virus; NICE, National Institute for health and Care Excellence; OCD, Obsessive-Compulsive Disorder; PTSD, Post-Traumatic Stress Disorder; THC, delta-9-TetraHydroCannabinol; United States, United States of America.

1 Epidiolex ® has received approval in the European Union under the tradename Epidyolex ® .

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Keywords: medical Cannabis , clinical trials, study protocols, legislation, law

Citation: Baratta F, Pignata I, Ravetto Enri L and Brusa P (2022) Cannabis for Medical Use: Analysis of Recent Clinical Trials in View of Current Legislation. Front. Pharmacol. 13:888903. doi: 10.3389/fphar.2022.888903

Received: 03 March 2022; Accepted: 09 May 2022; Published: 25 May 2022.

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Copyright © 2022 Baratta, Pignata, Ravetto Enri and Brusa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: F. Baratta, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Humans have cultivated and consumed the flowering tops of the female cannabis plant, colloquially known as marijuana , since virtually the beginning of recorded history. Cannabis-based textiles dating to 7,000 BCE have been recovered in northern China, and the plant’s use as a medicinal and mood-altering agent date back nearly as far. In 2008, archeologists in Central Asia discovered over two pounds of cannabis in the 2,700-year-old grave of an ancient shaman. After scientists conducted extensive testing on the material’s potency, they affirmed, “[T]he most probable conclusion … is that [ancient] culture[s] cultivated cannabis for pharmaceutical, psychoactive, and divinatory purposes.”

Modern cultures continue to indulge in the consumption of cannabis for these same purposes, despite a decades-long, virtual worldwide ban on the plant’s cultivation and use. In the United States, federal prohibitions outlawing cannabis’ recreational, industrial, and therapeutic use were first imposed by Congress under the Marihuana Tax Act of 1937 and then later reaffirmed by federal lawmakers’ decision to classify the cannabis plant — as well as all of its organic chemical compounds (known as cannabinoids) — as a Schedule I substance under the Controlled Substances Act of 1970. This classification, which categorizes the plant alongside heroin, defines cannabis and its dozens of distinct cannabinoids as possessing “a high potential for abuse, … no currently accepted medical use, … [and] a lack of accepted safety for the use of the drug … under medical supervision.” By contrast, cocaine and methamphetamine — which remain illicit for recreational use but may be consumed under a doctor’s supervision — are classified as Schedule II drugs. Both alcohol and tobacco are unscheduled.

Challenging Cannabis’ Schedule I Status

The ongoing classification of the cannabis plant as a Schedule I controlled substance is inconsistent with  scientific opinion ,  public attitudes , and the overwhelming majority of  state laws . Furthermore, there now exists ample scientific and empirical evidence to rebut the federal government’s contention. Despite the nearly century-long prohibition of the plant, cannabis is nonetheless one of the most investigated therapeutically active substances in history. To date, there are over 36,000 peer-reviewed papers in the scientific literature referencing the cannabis plant and its cannabinoids, according to a keyword search on the search engine PubMed Central, the US government repository for peer-reviewed scientific research. In recent years, this volume of research has grown exponentially, with more than 20,000 papers published just in the past decade. Much of this more recent research has been  dedicated  to exploring and verifying cannabis’ therapeutic activities in various patient populations – including in FDA-approved gold-standard clinical trials. A  summary of this clinical trial data concluded: “Evidence is accumulating that cannabinoids may be useful medicine for certain indications. … The classification of marijuana as a Schedule I drug as well as the continuing controversy as to whether or not cannabis is of medical value are obstacles to medical progress in this area. Based on evidence currently available the Schedule I classification is not tenable; it is not accurate that cannabis has no medical value, or that information on safety is lacking.”

The Shifting Focus of Cannabis Research

As clinical research into the therapeutic value of cannabinoids has proliferated so too has investigators’ understanding of cannabis’ remarkable capacity to combat disease. Whereas researchers in the 1970s, 80s, and 90s primarily assessed marijuana’s ability to temporarily alleviate various disease symptoms — such as the nausea associated with cancer chemotherapy — scientists today are exploring the potential role of cannabinoids to modulate disease .

For example, scientists are investigating cannabinoids’ capacity to moderate autoimmune disorders such as multiple sclerosis , rheumatoid arthritis , and inflammatory bowel disease , as well as their role in the treatment of neurological disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis (aka Lou Gehrig’s disease).

Investigators are also studying the anti-cancer activities of cannabis, as a growing body of preclinical data concludes that cannabinoids can reduce the spread of specific cancer cells via apoptosis (programmed cell death) and by the inhibition of angiogenesis (the formation of new blood vessels).

Researchers are also exploring the use of cannabis as a harm reduction alternative for many patients. To date, dozens of studies document patients’ use of cannabis as an alternative to various prescription drugs,  specifically opioids .

Arguably, these recent discoveries represent far broader and more significant applications for cannabinoid therapeutics than many researchers could have imagined some 30 or even 20 years ago.

The Safety Profile of Medical Cannabis

Cannabinoids possess a remarkable safety record, particularly when compared to conventional prescription drugs. Most significantly, the consumption of marijuana — regardless of quantity or potency — cannot induce a fatal overdose. States a World Health Organization review paper , “There are no recorded cases of overdose fatalities attributed to cannabis, and the estimated lethal dose for humans extrapolated from animal studies is so high that it cannot be achieved by … users.”

The use of cannabis for therapeutic purposes is also rarely associated with significant adverse side effects. A prominent review of clinical trial data “did not find a higher incidence rate of serious adverse events associated with medical cannabinoid use” compared to nonusing controls over a four decade period. A more recent review of the relevant literature concludes that among the average adult user, the health risks associated with marijuana “are no more likely to be dangerous” than many other behaviors or activities, including the consumption of acetaminophen (the pain relieving ingredient in Tylenol).

That said, cannabis should not be viewed as a “harmless” substance. Its active constituents may produce a variety of physiological and mood-altering effects. As a result, there may be some populations that may be vulnerable to increased risks from the use of cannabis, such as adolescents , pregnant or nursing mothers , and patients who have a family history of psychiatric illness or who possess a clinical high risk for developing a psychotic disorder. Patients with a history of cardiovascular disorders, heart disease , or stroke may also be at an elevated risk of experiencing adverse side effects from marijuana, particularly smoked cannabis. As with any medication, patients should consult thoroughly with their physician before deciding whether the medical use of cannabis is safe and appropriate.

How to Use This Publication

As states continue to approve legislation enabling the physician-supervised use of medical marijuana, more patients with varying disease types are exploring the use of therapeutic cannabis. Many of these patients and their physicians are now discussing this issue for the first time and are seeking guidance on whether the therapeutic use of cannabis may or may not be advisable. This report seeks to provide this guidance by highlighting hundreds of relevant, recently published scientific research (2000-2021) on the therapeutic potential of cannabis and cannabinoids for a variety of indications. This summary of the available peer-reviewed research is among the most comprehensive reviews available in the modern literature and is the result of hundreds of hours of research and writing.

In some of these cases, modern science is now affirming longtime anecdotal reports of medical cannabis users (e.g., the use of cannabis to alleviate GI disorders ). In other cases, this research is highlighting entirely new potential clinical utilities for cannabinoids (e.g., the use of cannabinoids to modify the progression of diabetes ). In all cases, science has sufficiently made the case that cannabis is safe and effective for certain patient populations. This fact should no longer be the subject of any serious debate.

For patients and their physicians, let this report serve as a primer for those who are considering using or recommending medical cannabis. For others, let this report serve as an introduction to the broad range of therapeutic applications for cannabis and its various compounds.

Paul Armentano Deputy Director NORML | NORML Foundation Washington, DC July 9, 2021

* The author would like to acknowledge Drs. Dale Gieringer , Estelle Goldstein, Dustin Sulak, Gregory Carter, Steven Karch, and Mitch Earleywine, as well as Bernard Ellis, MPH, former NORML interns John Lucy, Christopher Rasmussen, and Rita Bowles, for providing research assistance for this report. Oaksterdam University alumna Vanessa Garcia deserves special recognition for her significant contributions to the 2021 edition of this publication. The NORML Foundation would also like to acknowledge Dale Gieringer, Paul Kuhn, and Richard Wolfe for their financial contributions toward the publication of this report.

** Important and timely publications such as this are only made possible when concerned citizens become involved with NORML and make financial contributions. For more information, please visit:  norml.org/support . Tax-deductible donations in support of NORML’s public education campaigns should be made payable to the NORML Foundation .

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  • Published: 10 December 2019

Benefits and harms of medical cannabis: a scoping review of systematic reviews

  • Misty Pratt 1 ,
  • Adrienne Stevens 1 , 2 ,
  • Micere Thuku 1 ,
  • Claire Butler 1 , 3 ,
  • Becky Skidmore 4 ,
  • L. Susan Wieland 5 ,
  • Mark Clemons 6 , 7 ,
  • Salmaan Kanji 6 , 8 , 9 &
  • Brian Hutton   ORCID: orcid.org/0000-0001-5662-8647 1 , 6  

Systematic Reviews volume  8 , Article number:  320 ( 2019 ) Cite this article

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There has been increased interest in the role of cannabis for treating medical conditions. The availability of different cannabis-based products can make the side effects of exposure unpredictable. We sought to conduct a scoping review of systematic reviews assessing benefits and harms of cannabis-based medicines for any condition.

A protocol was followed throughout the conduct of this scoping review. A protocol-guided scoping review conduct. Searches of bibliographic databases (e.g., MEDLINE®, Embase, PsycINFO, the Cochrane Library) and gray literature were performed. Two people selected and charted data from systematic reviews. Categorizations emerged during data synthesis. The reporting of results from systematic reviews was performed at a high level appropriate for a scoping review.

After screening 1975 citations, 72 systematic reviews were included. The reviews covered many conditions, the most common being pain management. Several reviews focused on management of pain as a symptom of conditions such as multiple sclerosis (MS), injury, and cancer. After pain, the most common symptoms treated were spasticity in MS, movement disturbances, nausea/vomiting, and mental health symptoms. An assessment of review findings lends to the understanding that, although in a small number of reviews results showed a benefit for reducing pain, the analysis approach and reporting in other reviews was sub-optimal, making it difficult to know how consistent findings are when considering pain in general. Adverse effects were reported in most reviews comparing cannabis with placebo (49/59, 83%) and in 20/24 (83%) of the reviews comparing cannabis to active drugs. Minor adverse effects (e.g., drowsiness, dizziness) were common and reported in over half of the reviews. Serious harms were not as common, but were reported in 21/59 (36%) reviews that reported on adverse effects. Overall, safety data was generally reported study-by-study, with few reviews synthesizing data. Only one review was rated as high quality, while the remaining were rated of moderate ( n = 36) or low/critically low ( n = 35) quality.

Conclusions

Results from the included reviews were mixed, with most reporting an inability to draw conclusions due to inconsistent findings and a lack of rigorous evidence. Mild harms were frequently reported, and it is possible the harms of cannabis-based medicines may outweigh benefits.

Systematic review registration

The protocol for this scoping review was posted in the Open Access ( https://ruor.uottawa.ca/handle/10393/37247 ).

Peer Review reports

Interest in medical applications of marijuana ( Cannabis sativa ) has increased dramatically during the past 20 years. A 1999 report from the National Academies of Sciences, Engineering, and Medicine supported the use of marijuana in medicine, leading to a number of regulatory medical colleges providing recommendations for its prescription to patients [ 1 ]. An updated report in 2017 called for a national research agenda, improvement of research quality, improvement in data collection and surveillance efforts, and strategies for addressing barriers in advancing the cannabis agenda [ 2 ].

Proponents of medical cannabis support its use for a highly varied range of medical conditions, most notably in the fields of pain management [ 3 ] and multiple sclerosis [ 4 ]. Marijuana can be consumed by patients in a variety of ways including smoking, vaporizing, ingesting, or administering sublingually or rectally. The plant consists of more than 100 known cannabinoids, the main ones of relevance to medical applications being tetrahydrocannabinol (THC) and cannabidiol (CBD) [ 5 ]. Synthetic forms of marijuana such as dronabinol and nabilone are also available as prescriptions in the USA and Canada [ 6 ].

Over the last decade, there has been an increased interest in the use of medical cannabis products in North America. It is estimated that over 3.5 million people in the USA are legally using medical marijuana, and a total of USD$6.7 billion was spent in North America on legal marijuana in 2016 [ 7 ]. The number of Canadian residents with prescriptions to purchase medical marijuana from Health Canada–approved growers tripled from 30,537 in 2015 to near 100,000 in 2016 [ 8 ]. With the legalization of recreational-use marijuana in parts of the USA and in Canada in October 2018, the number of patients using marijuana for therapeutic purposes may become more difficult to track. The likely increase in the numbers of individuals consuming cannabis also necessitates a greater awareness of its potential benefits and harms.

Plant-based and plant-derived cannabis products are not monitored as more traditional medicines are, thereby increasing the uncertainty regarding its potential health risks to patients [ 3 ]. While synthetic forms of cannabis are available by prescription, different cannabis plants and products contain varied concentrations of THC and CBD, making the effects of exposure unpredictable [ 9 ]. While short-lasting side effects including drowsiness, loss of short-term memory, and dizziness are relatively well known and may be considered minor, other possible effects (e.g., psychosis, paranoia, anxiety, infection, withdrawal) may be more harmful to patients.

There remains a considerable degree of clinical equipoise as to the benefits and harms of marijuana use for medical purposes [ 10 , 11 , 12 , 13 ]. To understand the extent of synthesized evidence underlying this issue, we conducted a scoping review [ 14 ] of systematic reviews evaluating the benefits and/or harms of cannabis (plant-based, plant-derived, and synthetic forms) for any medical condition. We located and mapped systematic reviews to summarize research that is available for consideration for practice or policy questions in relation to medical marijuana.

A scoping review protocol was prepared and posted to the University of Ottawa Health Sciences Library’s online repository ( https://ruor.uottawa.ca/handle/10393/37247 ). We used the PRISMA for Scoping Reviews checklist to guide the reporting of this report (see Additional file 1 ) [ 15 ].

Literature search and process of study selection

An experienced medical information specialist developed and tested the search strategy using an iterative process in consultation with the review team. Another senior information specialist peer-reviewed the strategy prior to execution using the PRESS Checklist [ 16 ]. We searched seven Ovid databases: MEDLINE®, including Epub Ahead of Print and In-Process & Other Non-Indexed Citations, Embase, Allied and Complementary Medicine Database, PsycINFO, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and the Health Technology Assessment Database. The final peer-reviewed search strategy for MEDLINE was translated to the other databases (see Additional file 2 ). We performed the searches on November 3, 2017.

The search strategy incorporated controlled vocabulary (e.g., “Cannabis,” “Cannabinoids,” “Medical Marijuana”) and keywords (e.g., “marijuana,” “hashish,” “tetrahydrocannabinol”) and applied a broad systematic review filter where applicable. Vocabulary and syntax were adjusted across the databases and where possible animal-only and opinion pieces were removed, from the search results.

Gray literature searching was limited to relevant drug and mental health databases, as well as HTA (Health Technology Assessment) and systematic review databases. Searching was guided by the Canadian Agency for Drugs and Technologies in Health’s (CADTH) checklist for health-related gray literature (see Additional file 3 ). We performed searches between January and February 2018. Reference lists of overviews were searched for relevant systematic reviews, and we searched for full-text publications of abstracts or protocols.

Management of all screening was performed using Distiller SR Software ® (Evidence Partners Inc., Ottawa, Canada). Citations from the literature search were collated and de-duplicated in Reference Manager (Thomson Reuters: Reference Manager 12 [Computer Program]. New York: Thomson Reuters 2011), and then uploaded to Distiller. The review team used Distiller for Levels 1 (titles and abstracts) and 2 (full-text) screening. Pilot testing of screening questions for both levels were completed prior to implementation. All titles and abstracts were screened in duplicate by two independent reviewers (MT and MP) using the liberal accelerated method [ 17 ]. This method requires only one reviewer to assess an abstract as eligible for full-text screening, and requires two reviewers to deem the abstract irrelevant. Two independent reviewers (MT and MP) assessed full-text reports for eligibility. Disagreements during full-text screening were resolved through consensus, or by a third team member (AS). The process of review selection was summarized using a PRISMA flow diagram (Fig. 1 ) [ 18 ].

figure 1

PRISMA-style flow diagram of the review selection process

Review selection criteria

English-language systematic reviews were included if they reported that they investigated harms and/or benefits of medical or therapeutic use of cannabis for adults and children for any indication. Definitions related to medical cannabis/marijuana are provided in Table 1 . We also included synthetic cannabis products, which are prescribed medicines with specified doses of THC and CBD. Reviews of solely observational designs were included only in relation to adverse effects data, in order to focus on the most robust evidence available. We considered studies to be systematic reviews if at least one database was searched with search dates reported, at least one eligibility criterion was reported, the authors had assessed the quality of included studies, and there was a narrative or quantitative synthesis of the evidence. Reviews assessing multiple interventions (both pharmacological and complementary and alternative medicine (CAM) interventions) were included if the data for marijuana studies was reported separately. Published and unpublished guidelines were included if they conducted a systematic review encompassing the criteria listed above.

We excluded overviews of systematic reviews, reviews in abstract form only, and review protocols. We further excluded systematic reviews focusing on recreational, accidental, acute, or general cannabis use/abuse and interventions such as synthetic cannabinoids not approved for therapeutic use (e.g., K2 or Spice).

Data collection and quality assessment

All data were collected electronically in a pre-developed form using Microsoft Excel software (Microsoft Corporation, Seattle, USA). The form was pilot tested on three included reviews by three people. One reviewer (MP or CB) independently extracted all data, and a second reviewer (MT) verified all of the items collected and checked for any omitted data. Disagreements were resolved by consensus and consultation with a third reviewer if necessary. A data extraction form with the list of included variables is provided in Additional file 4 . All collected data has also been made available in the online supplemental materials associated with this report.

Quality assessment of systematic reviews was performed using the AMSTAR-2 [ 20 ] tool. One reviewer (MP or CB) independently assessed quality, while a second reviewer (MT) verified the assessments. Disagreements were resolved by consensus and consultation with a third reviewer if necessary. The tool consists of 16 items in total, with four critical domains and 12 non-critical domains. The AMSTAR-2 tool is not intended to generate an overall score, and instead allows for an overall rating based on weaknesses in critical domains. Reviews were rated as high (no critical flaws with zero or one non-critical flaw), moderate (no critical flaws with ≥ 1 non-critical flaw), low (one critical flaw with/without non-critical weakness), or critically low (> 1 critical flaw with/without non-critical weakness) quality.

Evidence synthesis

We used a directed content analytic approach [ 21 ] with an initial deductive framework [ 22 ] that allowed flexibility for inductive analysis if refinement or development of new categorization was needed. The framework used to categorize outcome data results is outlined in Table 2 . Where reviews had a mix of narrative and quantitative data, results from meta-analyses were prioritized over count data or study-by-study data. The extraction and reporting of data results was performed at a high level and did not involve an in-depth evaluation, which is appropriate for a scoping review [ 14 ]. Review authors’ conclusions and/or recommendations were extracted and reported narratively.

Changes from the study protocol

For feasibility, we decided to limit the inclusion of systematic reviews of only observational study designs to those that addressed adverse events data. All other steps of the review were performed as planned.

Search findings

The PRISMA flow diagram describing the process of review selection is presented in Fig. 1 . After duplicates were removed, the search identified a total of 1925 titles and abstracts, of which 47 references were located through the gray literature search. Of the total 1925 citations assessed during Level 1 screening, 1285 were deemed irrelevant. We reviewed full-text reports for the 640 reviews of potential relevance, and of these, 567 were subsequently excluded, leaving a total of 72 systematic reviews that were included; the associated data collected are provided in Additional file 5 . A listing of the reports excluded during full-text review is provided in Additional file 6 .

Characteristics of included reviews

There were 63 systematic reviews [ 4 , 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ] and nine guidelines with systematic reviews [ 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 ]. Overall, 27 reviews were performed by researchers in Europe, 16 in the USA, 15 in Canada, eight in Australia, two in Brazil, and one each in Israel, Singapore, South Africa, and China. Funding was not reported in 29 (40%) of the reviews, and the remaining reviews received funding from non-profit or academic ( n = 20; 28%), government ( n = 14; 19%), industry ( n = 3; 4%), and mixed ( n = 1; 1%) sources. Five reviews reported that they did not receive any funding for the systematic review. Tables 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , and 13 provide an overview of the characteristics of the 72 included systematic reviews.

The reviews were published between 2000 and 2018 (median year 2014), and almost half (47%) were focused solely on medical cannabis. Four (6%) reviews covered both medical and other cannabis use (recreational and substance abuse), 19 (26%) reported multiple pharmaceutical interventions (cannabis being one), six (8%) reported various CAM interventions (cannabis being one), and nine (13%) were mixed pharmaceutical and CAM interventions (cannabis being one). Multiple databases were searched by almost all of the reviews (97%), with Medline/PubMed or Embase common to all.

Cannabis use

Figure 2 illustrates the different cannabis-based interventions covered by the included reviews. Plant-based cannabis consists of whole plant products such as marijuana or hashish. Plant-derived cannabinoids are active constituents of the cannabis plant, such as tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of THC:CBD (also called nabiximols, under the brand name Sativex) [ 3 ]. Synthetic cannabinoids are manufactured rather than extracted from the plant and include drugs such as nabilone and dronabinol.

figure 2

Review coverage of the various cannabis-based interventions

Twenty-seven reviews included solely interventions from plant-derived cannabinoids, 10 studied solely synthetic cannabinoids, and eight included solely studies on plant-based cannabis products. Twenty-four reviews covered a combination of different types of cannabis, and the remaining three systematic reviews did not report which type of cannabinoid was administered in the included studies.

The systematic reviews covered a wide range of conditions and illnesses, the most notable being pain management. Seventeen reviews looked at specific types of pain including neuropathic [ 31 , 42 , 62 , 69 , 85 , 90 ], chronic [ 26 , 32 , 52 , 58 , 80 ], cancer [ 84 , 87 ], non-cancer [ 41 , 68 ], and acute [ 38 ] types of pain (one review covered all types of pain) [ 65 ]. Twenty-seven reviews (38%) also focused on management of pain as a symptom of conditions such as multiple sclerosis (MS) [ 6 , 23 , 27 , 43 , 46 , 52 , 63 , 85 , 92 ], injury [ 29 , 35 , 36 , 69 ], cancer [ 37 , 43 , 65 , 88 ], inflammatory bowel disease (IBD) [ 28 ], rheumatic disease (RD) [ 49 , 51 , 73 ], diabetes [ 68 , 69 , 70 ], and HIV [ 48 , 53 , 67 ]. In Fig. 3 , the types of illnesses addressed by the set of included reviews are graphically represented, with overlap between various conditions and pain. Some systematic reviews covered multiple diseases, and therefore the total number of conditions represented in Fig. 3 is greater than the total number of included reviews.

figure 3

Conditions or symptoms across reviews that were treated with cannabis. IBD inflammatory bowel disease, MS multiple sclerosis, RD rheumatic disease

One review included a pediatric-only population, in the evaluation of marijuana for nausea and vomiting following chemotherapy [ 54 ]. Although trials in both adult and child populations were eligible for thirteen (18%) reviews, only two additional reviews included studies in children; these reviews evaluated cannabis in cancer [ 60 ] and a variety of conditions [ 25 ]. Many of the reviews ( n = 25, 35%) included only adults ≥ 18 years of age. Almost half of the reviews ( n = 33, 46%) did not report a specific population for inclusion.

Cannabis was prescribed for a wide range of medical issues. The indication for cannabis use is illustrated in Fig. 4 . Pain management ( n = 27) was the most common indication for cannabis use. A number of reviews sought to address multiple disease symptoms ( n = 12) or explored a more holistic treatment for the disease itself ( n = 11). After pain, the most common symptoms being treated with cannabis were spasticity in MS, movement disturbances (such as dyskinesia, tics, and spasms), weight or nausea/vomiting, and mental health symptoms.

figure 4

Indications for cannabis use across included reviews

Figure 5 summarizes the breadth of outcomes analyzed in the included reviews. The most commonly addressed outcomes were withdrawal due to adverse effects, “other pain,” neuropathic pain, spasticity, and the global impression of the change in clinical status. Many outcomes were reported using a variety of measures across reviews. For example, spasticity was measured both objectively (using the Ashworth scale) and subjectively (using a visual analog scale [VAS] or numerical rating scale [NRS]). Similarily, outcomes for pain included VAS or NRS scales, reduction in pain, pain relief, analgesia, pain intensity, and patient assessment of change in pain.

figure 5

Quality of the systematic reviews

Quality assessments of the included reviews based upon AMSTAR-2 are detailed in Additional file 7 and Additional file 8 . Only one review was rated as high quality [ 45 ]. All other reviews were deemed to be of moderate ( n = 36) or low/critically low ( n = 35) methodological quality. Assessments for the domains deemed of critical importance for determining quality ratings are described below.

Only 20% of reviews used a comprehensive search strategy; another 47% were given a partial score because they had not searched the reference lists of the included reviews, trial registries, gray literature, and/or the search date was older than 2 years. The remaining reviews did not report a comprehensive search strategy.

Over half of the reviews (51%) used a satisfactory technique for assessing risk of bias (ROB) of the individual included studies, while 35% were partially satisfactory because they had not reported whether allocation sequence was truly random and/or they had not assessed selective reporting. The remaining reviews did not report a satisfactory technique for assessing ROB.

Most reviews (71%) could not be assessed for an appropriate statistical method for combining results in a meta-analysis, as they synthesized study data narratively. Approximately 19% of reviews used an appropriate meta-analytical approach, leaving 10% that used inappropriate methods.

The final critical domain for the AMSTAR-2 determines whether review authors accounted for ROB in individual studies when discussing or interpreting the results of the review. The majority of reviews (83%) did so in some capacity.

Mapping results of included systematic reviews

We mapped reviews according to authors’ comparisons, the conditions or symptoms they were evaluating, and the categorization of the results (see Table 2 ). In some cases, reviews contributed to more than one comparison (e.g., cannabis versus placebo or active drug). As pain was the most commonly addressed outcome, we mapped this outcome separately from all other endpoints. This information is shown for all reviews and then restricted to reviews of moderate-to-high quality (as determined using the AMSTAR-2 criteria): cannabis versus placebo (Figs. 6 and 7 ), cannabis versus active drugs (Figs. 8 and 9 ), cannabis versus a combination of placebo and active drug (Figs. 10 and 11 ), one cannabis formulation versus other (Figs. 12 and 13 ), and cannabis analyzed against all other comparators (Fig. 14 ). Details on how to read the figures are provided in the corresponding figure legends. The median number of included studies across reviews was four, and ranged from one to seventy-nine (not shown in figures).

figure 6

Cannabis vs. placebo. Authors’ presentations of the findings were mapped using the categorization shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

figure 7

Cannabis vs. placebo, high and moderate quality reviews. Authors’ presentations of the findings were mapped using the categorizations shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

figure 8

Cannabis vs. active drugs. Authors’ presentations of the findings were mapped using the categorizations shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

figure 9

Cannabis vs. active drugs, high and moderate quality reviews. Authors’ presentations of the findings were mapped using the categorizations shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

figure 10

Cannabis vs. placebo + active drug. Authors’ presentations of the findings were mapped using the categorizations shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

figure 11

Cannabis vs. placebo + active drug, high and moderate quality reviews. Authors’ presentations of the findings were mapped using the categorizations shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

figure 12

One cannabis formulation vs. other. Authors’ presentations of the findings were mapped using the categorizations shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

figure 13

One cannabis formulation vs. other, high and moderate quality reviews. Authors’ presentations of the findings were mapped using the categorizations shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

figure 14

Cannabis vs. all comparators combined. Authors’ presentations of the findings were mapped using the categorizations shown in Table 2 . According to the reviews’ intended scope for the condition being treated, outcomes were mapped into “pain,” “non-pain outcomes,” and “adverse events.” For each condition and outcome pair (i.e., each row in the grid), the number of reviews reporting findings is shown according to the results categorization. For pain, reviews numbered in different categories signal discordant findings across those reviews. For non-pain outcomes, reviews presenting findings in the different categories would signal different results for different outcomes, as well as discordant findings within and across reviews. Adverse events are grouped as a whole and “favors intervention” would be interpreted as a decrease in events with cannabis when compared with the control group. Favors int = favors intervention; Favors Ctrl = favors control; Not stat sig = not statistically significant

Cannabis versus placebo

Most reviews (59/72, 82%) compared cannabis with placebo. Of these reviews, 34 (58%) addressed pain outcomes and 47 (80%) addressed non-pain outcomes, with most outcomes addressed by three reviews or fewer (Fig. 6 ). Some reviews had a mix of quantitative syntheses and study-by-study data reported (13/59, 22%), while another group of reviews (14/59, 24%) only reported results study-by-study. Overall, 24% (14/59) of the cannabis versus placebo reviews had only one included study.

Pain outcomes

Reviews focused on addressing pain across conditions. In most cases, findings were discordant across reviews for the pain outcomes measured. For chronic non-cancer pain, however, two reviews favored cannabis over placebo for decreasing pain. One review assessing acute pain for postoperative pain relief found no difference between various cannabinoid medications and placebo. The distribution of findings was similar when restricting to moderate-to-high-quality reviews.

Reviews focused on treating a condition or family of related conditions . Various results were observed for pain. For MS and HIV/AIDS, one review each reported quantitative results favoring cannabis for decreased pain but with other reviews reporting results study-by-study, it is difficult to know, broadly, how consistent those findings are. For cancer, two reviews reported results favoring cannabis for decreased pain. For rheumatic disease, findings are discordant between two reviews, and another two reviews reported results study-by-study. One review that included studies of MS or paraplegia found no difference in pain between groups. For treating injury, one review showed that the placebo group had less pain and one review reported data study-by-study. No reviews addressed pain in movement disorders, neurological conditions, and IBD.

For those reviews assessing pain as part of a focus on treating a range of conditions, two showed cannabis reduced pain [ 43 , 52 ], but one showed mixed results depending on how pain was measured [ 43 ]. These reviews covered several different conditions, including injury, chronic pain, rheumatoid arthritis, osteoarthritis, fibromyalgia, HIV/AIDS, cancer, and MS or paraplegia.

When restricting to moderate-to-high-quality reviews, only one review each in multiple sclerosis and HIV/AIDS with a study-by-study analysis on pain remained. One review on cancer favored cannabis for pain reduction. Findings remained the same for MS or paraplegia and rheumatic disease. No review for injury and paint outcomes was of higher quality.

Non-pain outcomes

The types of non-pain outcomes included in the reviews varied by condition/illness. The most commonly reported outcomes (see Fig. 5 for overall outcomes) when comparing cannabis to placebo included muscle- or movement-related outcomes ( n = 20), quality of life ( n = 14), and sleep outcomes ( n = 10).

There was no consistent pattern for non-pain outcomes either within or across medical conditions. Many ( n = 24, 33%) reviews assessing non-pain outcomes reported the results of those analyses study-by-study. Conflicting results are observed in some cases due to the use of different measures, such as different ways of quantifying spasticity in patients with multiple sclerosis [ 56 , 91 ]. One review each addressing neurological conditions [ 50 ] (outcome: muscle cramps) and MS/paraplegia [ 27 ] (outcomes: spasticity, spasm, cognitive function, daily activities, motricity, and bladder function) showed no difference between groups.

Adverse effects

Adverse effects were reported in most reviews comparing cannabis with placebo (49/59, 83%). Most adverse events were reported study-by-study, with few reviews ( n = 16/59, 27%) conducting a narrative or quantitative synthesis. Serious adverse effects were reported in 21/59 (36%) reviews, and minor adverse effects were reported in 30/59 (51%) reviews. The remaining reviews did not define the difference between serious and minor adverse events. The most commonly reported serious adverse events included psychotic symptoms ( n = 6), severe dysphoric reactions ( n = 3), seizure ( n = 3), and urinary tract infection ( n = 2). The most commonly reported minor adverse events included somnolence/drowsiness ( n = 28), dizziness ( n = 27), dry mouth ( n = 20), and nausea ( n = 18). Many reviews ( n = 37/59, 63%) comparing cannabis to placebo reported both neurocognitive and non-cognitive adverse effects. Withdrawals due to adverse events were reported in 22 (37%) reviews.

Of the moderate-/high-quality reviews, adverse effect analyses were reported in reviews on pain, multiple sclerosis, cancer, HIV/AIDS, movement disorders, rheumatic disease, and several other conditions. Two reviews on pain showed fewer adverse events with cannabis for euphoria, events linked to alternations in perception, motor function, and cognitive function, withdrawal due to adverse events, sleep, and dizziness or vertigo [ 58 , 90 ]. One review on MS showed that there was no statistically significant difference between cannabis and placebo for adverse effects such as nausea, weakness, somnolence, and fatigue [ 91 ], while another review on MS/paraplegia reported fewer events in the placebo group for dizziness, somnolence, nausea, and dry mouth [ 27 ]. Within cancer reviews, one review found no statistically significant difference between cannabis and placebo for dysphoria or sedation but reported fewer events with placebo for “feeling high,” and fewer events with cannabis for withdrawal due to adverse effects [ 40 ]. In rheumatic disease, one review reported fewer total adverse events with cannabis and found no statistically significant difference between cannabis and placebo for withdrawal due to adverse events [ 51 ].

Cannabis versus other drugs

Relatively fewer reviews compared cannabis with active drugs ( n = 23/72, 32%) (Fig. 8 ). Many of the reviews did not synthesize studies quantitatively, and results were reported study-by-study. The most common conditions in reviews comparing cannabis to active drugs were pain, cancer, and rheumatic disease. Comparators included ibuprofen, codeine, diphenhydramine, amitriptyline, secobarbital, prochlorperazine, domperidone, metoclopramide, amisulpride, neuroleptics, isoproterenol, megestrol acetate, pregabalin, gabapentin, and opioids.

Reviews focused on addressing pain across conditions. When comparing across reviews, a mix of results are observed (see Fig. 8 ), and some were reported study-by-study. One review found no statistically significant difference between cannabinoids and codeine for nociceptive pain, postoperative pain, and cancer pain [ 65 ]. Another review favored “other drugs” (amitriptyline and pregabalin) over cannabinoids for neuropathic pain [ 90 ]. The distribution of findings was similar when restricting to moderate-to-high-quality reviews.

Reviews focused on treating a condition or family of related conditions. One review on cancer compared cannabinoids and codeine or secobarbital and reported pain results study-by-study. Another review on fibromyalgia comparing synthetic cannabinoids with amitriptyline also reported pain data study-by-study [ 39 ].

Two reviews on cancer favored cannabinoids over active drugs (prochlorperazine, domperidone, metoclopramide, and neuroleptics) for patient preference and anti-emetic efficacy [ 40 , 60 ]. Non-pain outcomes were reported study-by-study for the outcome of sleep in neuropathic pain [ 90 ] and rheumatic disease [ 39 , 49 ]. In a review covering various conditions (pain, MS, anorexia, cancer, and immune deficiency), results were unclear or indeterminate for subjective measures of sleep [ 46 ].

Adverse effects were reported in 20/24 (83%) of the reviews comparing cannabis to active drugs, and only 6/20 (30%) reported a narrative or quantitative synthesis. Many reviews that reported narrative data did not specify whether adverse effects could be attributed to a placebo or active drug comparator.

Of the moderate-to-high-quality reviews, two pain reviews found no statistically significant difference for cannabis compared to codeine or amitriptyline for withdrawals due to adverse events [ 65 , 90 ]. Results from one cancer review were mixed, with fewer adverse events for cannabis (compared to prochlorperazine, domperidone, or metoclopramide) or no difference between groups, depending on the type of subgroup analysis that was conducted [ 40 ].

Cannabis + active drugs versus placebo + active drugs

Two reviews compared cannabis with placebo cannabis in combination with an active drug (opioids and gabapentin) (Figs. 10 and 11 ). Both were scored to be of moderate quality. Although one review showed that cannabis plus opioids decreased chronic pain [ 80 ], another review on pain in MS included only a single study [ 81 ], precluding the ability to determine concordance of results. Cannabis displayed varied effects on non-pain outcomes, including superiority of placebo over cannabis for some outcomes. One review reported withdrawal due to adverse events study-by-study and also reported that side effects such as nausea, drowsiness, and dizziness were more frequent with higher doses of cannabinoids (data from two included studies) [ 80 ].

Cannabis versus other cannabis comparisons

Six (8%) reviews compared different cannabis formulations or doses (Figs. 12 and 13 ). Almost all were reported as study-by-study results, with two reviews including only one RCT. One review for PTSD found only observational data [ 33 ] and another review on anxiety and depression combined data from one RCT with cross-sectional study data [ 19 ]. A single review on MS reported a narrative synthesis that found a benefit for spasticity. However, it was unclear if the comparator was placebo or THC alone [ 56 ]. Four reviews reported adverse effects study-by-study, with a single review comparing side effects from different dosages; in this review, combined extracts of THC and CBD were better tolerated than extracts of THC alone [ 56 ].

Cannabis versus all comparators

One review combined all comparators for the evaluation (Fig. 14 ). The review (combining non-users, placebo and ibuprofen) covered a range of medical conditions and was rated as low quality [ 30 ]. No adverse effects were evaluated for this comparison.

Mapping the use of quality assessment and frameworks to interpret the strength of evidence

Although 83% of reviews incorporated risk of bias assessments in their interpretation of the evidence, only 11 (15%) reviews used a framework such as GRADE to evaluate important domains other than risk of bias that would inform the strength of the evidence.

Mapping authors’ conclusions or recommendations

Most reviews (43/72 60%) indicated an inability to draw conclusions, whether due to uncertainty, inconsistent findings, lack of (high quality) evidence, or focusing their conclusion statement on the need for more research. Almost 15% of reviews (10/72) reported recommendations or conclusions that included some uncertainty. One review (1%) provided a statement of the extent of the strength of the evidence, which differed according to outcome.

Eleven reviews provided clearer conclusions (14%). Four indicated that cannabis was not effective or not cost-effective compared to placebo in relation to multiple sclerosis, acute pain, cancer, and injury. Three reviews addressing various conditions provided varying conclusions: one stated cannabis was not effective, one indicated it was modestly safe and effective, and one concluded that cannabis was safe and efficacious as short-term treatment; all reviews were of low quality. The three remaining reviews stated moderate or modest effects for improving chronic pain, compared with placebo or other analgesia; two of those reviews were of medium AMSTAR-2 quality, and one used the GRADE framework for interpreting the strength of the evidence.

The eight remaining included reviews (11%) did not provide a clear conclusion statement or reported only limitations.

Mapping authors’ limitations of the research

Several of the reviews indicated that few studies, small sample sizes, short duration of treatment, and issues related to outcomes (e.g., definition, timing, and types) were drawbacks to the literature. Some reviews noted methodological issues with and heterogeneity among studies as limitations. A few authors stated that restricting eligibility to randomized trials, English-language studies, or full publications may have affected their review results.

With the increasing use of medical cannabis, an understanding of the landscape of available evidence syntheses is needed to support evidence-informed decision-making, policy development, and to inform a research agenda. In this scoping review, we identified 72 systematic reviews evaluating medical cannabis for a range of conditions and illnesses. Half of the reviews were evaluated as being of moderate quality, with only one review scoring high on the AMSTAR-2 assessment tool.

There was disparity in the reported results across reviews, including non-synthesized (study-by-study) data, and many were unable to provide a definitive statement regarding the effectiveness of cannabis (as measured by pain reduction or other relevant outcomes), nor the extent of increased side effects and harms. This is consistent with the limitations declared in general across reviews, such as the small numbers of relevant studies, small sample sizes of individual studies, and methodological weaknesses of available studies. This common theme in review conclusions suggests that while systematic reviews may have been conducted with moderate or high methodological quality, the strength of their conclusions are driven by the availability and quality of the relevant underlying evidence, which was often found to be limited.

Relatively fewer reviews addressed adverse effects associated with cannabis, except to narratively summarize study level data. Although information was provided for placebo-controlled comparisons, none of the comparative effectiveness reviews quantitatively assessed adverse effects data. For the placebo-controlled data, although the majority of adverse effects were mild, the number of reviews reporting serious adverse effects such as psychotic symptoms [ 25 , 42 ] and suicidal ideation [ 68 , 85 ] warrants caution.

A mix of reviews supporting and not supporting the use of cannabis, according to authors’ conclusions, was identified. Readers may wish to consider the quality of the reviews, the use of differing quality assessment tools, additional considerations covered by the GRADE framework, and the potential for spin as possible reasons for these inconsistencies. It is also possible that cannabis has differing effects depending on its type (e.g., synthetic), dose, indication, the type of pain being evaluated (e.g., neuropathic), and the tools used for outcome assessment, which can be dependent on variations in condition. Of potential interest to readers may be a closer examination of the reviews evaluating chronic pain, in order to locate the source(s) of discordance. For example, one review was deemed of moderate quality, used the GRADE framework, and rated the quality of evidence for the effectiveness of cannabis for reducing neuropathic pain as moderate, suggesting that further investigation of cannabis for neuropathic pain may be warranted [ 80 ]. The exploration aspects outlined in this paragraph are beyond the purview of scoping review methodology; a detailed assessment of the reviews, including determining the overlap of included studies among similar reviews, potential reasons for the observed discordance of findings, what re-analysis of study-by-study analyses would yield, and an undertaking of missing GRADE assessments would fall outside the bounds of a scoping review and require the use of overview methodology [ 14 ].

Our findings are consistent with a recently published summary of cannabis-based medicines for chronic pain management [ 3 ]. This report found inconsistent results in systematic reviews of cannabis-based medicines compared to placebo for chronic neuropathic pain, pain management in rheumatic diseases and painful spasms in MS. The authors also concluded that cannabis was not superior to placebo in reducing cancer pain. Four out of eight included reviews scored high on the original AMSTAR tool. The variations between the two tools can be attributed to the differences in our overall assessments. Lastly, the summary report included two reviews that were not located in our original search due to language [ 93 ] and the full-text [ 94 ] of an abstract [ 95 ] that was not located in our search.

This scoping review has identified a plethora of synthesized evidence in relation to medical cannabis. For some conditions, the extent of review replication may be wasteful. Many reviews have stated that additional trials of methodologically robust design and, where possible, of sufficient sample size for precision, are needed to add to the evidence base. This undertaking may require the coordination of multi-center studies to ensure adequate power. Future trials may also help to elucidate the effect of cannabis on different outcomes.

Given authors’ reporting of issues in relation to outcomes, future prospective trials should be guided by a standardized, “core” set of outcomes to strive for consistency across studies and ensure relevance to patient-centered care. Development of those core outcomes should be developed using the Core Outcome Measures in Effectiveness Trials (COMET) methodology [ 96 ], and further consideration will need to be made in relation to what outcomes may be common across all cannabis research and which outcomes are condition-specific. With maturity of the evidence base, future systematic reviews should seek and include non-journal-published (gray literature) reports and ideally evaluate any non-English-language papers; authors should also adequately assess risk of bias and undertake appropriate syntheses of the literature.

The strengths of this scoping review include the use of an a priori protocol, peer-reviewed search strategies, a comprehensive search for reviews, and consideration of observational designs for adverse effects data. For feasibility, we restricted to English-language reviews, and it is unknown how many of the 39 reviews in other languages that we screened would have met our eligibility criteria. The decision to limit the inclusion of reviews of observational data to adverse effects data was made during the process of full-text screening and for pragmatic reasons. We also did not consider a search of the PROSPERO database for ongoing systematic reviews; however, in preparing this report, we performed a search and found that any completed reviews were already considered for eligibility or were not available at the time of our literature search. When charting results, we took a broad perspective, which may be different than if these reviews were more formally assessed during an overview of systematic reviews.

Cannabis-based medicine is a rapidly emerging field of study, with implications for both healthcare practitioners and patients. This scoping review is intended to map and collate evidence on the harms and benefits of medical cannabis. Many reviews were unable to provide firm conclusions on the effectiveness of medical cannabis, and results of reviews were mixed. Mild adverse effects were frequently but inconsistently reported, and it is possible that harms may outweigh benefits. Evidence from longer-term, adequately powered, and methodologically sound RCTs exploring different types of cannabis-based medicines is required for conclusive recommendations.

Availability of data and materials

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Abbreviations

Canadian Agency for Drugs and Technologies in Health

Complementary and alternative medicine

Cannabidiol

Grading of Recommendations Assessment, Development and Evaluation

Human immunodeficiency virus

Inflammatory bowel disease

Multiple sclerosis

Numeric rating scale

Randomized controlled trial

Rheumatic disease

Risk of bias

Tetrahydrocannabinol

Visual analog scale

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Research reported in this publication was supported by the National Center for Complementary and Integrative Health of the National Institutes of Health under award number R24AT001293. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Misty Pratt, Adrienne Stevens, Micere Thuku, Claire Butler & Brian Hutton

TRIBE Graduate Program, University of Split School of Medicine, Split, Croatia

Adrienne Stevens

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, H3A 2B4, Canada

Claire Butler

Ottawa, Canada

Becky Skidmore

Center for Integrative Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

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MP, AS, and BH drafted the initial version of the report. BS designed and implemented the literature search. MP, MT, and CB contributed to review of abstracts and full texts as well as data collection. MP, AS, and BH were responsible for analyses. All authors (MP, AS, MT, CB, BS, SW, MC, SK, BH) contributed to interpretation of findings and revision of drafts and approved the final version of the manuscript.

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PRISMA Scoping Review Extension Completed Checklist.

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Literature Search Strategies.

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Grey Literature Sources.

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Data extractions from included studies.

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Listing of Studies Excluded During Full Text Screening.

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Pratt, M., Stevens, A., Thuku, M. et al. Benefits and harms of medical cannabis: a scoping review of systematic reviews. Syst Rev 8 , 320 (2019). https://doi.org/10.1186/s13643-019-1243-x

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research papers about medical marijuana

Marijuana and Cannabinoids: Health, Research and Regulatory Considerations (Position Paper)

Executive summary.

Marijuana and related substance misuse are complex issues impacting family medicine, patient health, and public health. The American Academy of Family Physicians (AAFP) believes family physicians are essential in addressing all forms of inappropriate substance use. The AAFP urges its members to be involved in the diagnosis, treatment, and prevention of substance use, as well as secondary diseases impacted or caused by use. The World Health Organization (WHO) reports approximately 2.5% of the global population uses cannabis annually, making it the most commonly used drug worldwide. 1  Simultaneously, the AAFP acknowledges preliminary evidence indicates marijuana and cannabinoids may have potential therapeutic benefits, while also recognizing subsequent negative public health and health outcomes associated with cannabis use. 2

During the 20 th  century, law enforcement and public policy activities have undermined opportunities for scientific exploration. Barriers to facilitating both clinical and public health research regarding marijuana is detrimental to treating patients and the health of the public. The lack of regulation poses a danger to public health and impedes meaningful, patient-centered research to exploring both therapeutic and negative impacts of marijuana and cannabinoids.

Relevant AAFP Policy

Marijuana Possession for Personal Use The American Academy of Family Physicians (AAFP) opposes the recreational use of marijuana. However, the AAFP supports decriminalization of possession of marijuana for personal use. The AAFP recognizes the benefits of intervention and treatment for the recreational use of marijuana, in lieu of incarceration, for all individuals, including youth. 3

The AAFP also recognizes that several states have passed laws approving limited recreational use and/or possession of marijuana. Therefore, the AAFP advocates for further research into the overall safety and health effects of recreational use, as well as the effects of those laws on patient and societal health. 4

It should be noted that cannabis and marijuana are not interchangeable terms. In this position paper, cannabis is an overarching term used to refer to the plant  Cannabis sativa . Substances derived from the cannabis   plant include marijuana, hemp, and cannabinoids.

Call to Action Family physicians have a vested interest in policies that advance and protect the health of their patients and the public. The regulatory environment surrounding cannabis, medical and recreational marijuana, and cannabidiol (CBD) is rapidly changing, along with the retail environment. This shift has not been accompanied by robust scientific research regarding the health effects of cannabis, both therapeutic or detrimental. The AAFP recognizes the need for substantial clinical, public health, and policy evidence and research regarding cannabis, marijuana, cannabinoids, and CBD to inform evidence-based practice and the impact on public health.

  • The AAFP promotes a society which is free of substance misuse, including alcohol and drugs. 3
  • The AAFP recognizes there is support for the medical use of marijuana and cannabinoids, but advocates that usage be based on high-quality, evidence-based public health, policy, and patient-centered research, including the impact on vulnerable populations. 3
  • The AAFP advocates for further studies into the use of medical marijuana and related compounds. This process should also ensure appropriate funding allocated for this research.
  • The AAFP calls for decreased regulatory barriers to facilitate clinical and public health cannabis research, including reclassifying cannabis from a Schedule I controlled substance. 3
  • The AAFP advocates for further research into the overall safety and health effects of recreational use, as well as the impact of legal recreational marijuana use laws on patient and societal health. 4
  • The AAFP advocates for robust regulation regarding labeling and child-proof packaging of all marijuana and cannabinoid products.
  • The AAFP opposes the recreational use and legalization of marijuana, but supports decriminalization of marijuana for personal use. The AAFP recognizes the benefits associated with intervention and treatment, in lieu of incarceration. 4
  • The AAFP advocates for regulation regarding marketing claims, labeling, and advertising of all marijuana and cannabinoid products.
  • The AAFP supports requirements testing current marijuana and cannabinoid products for safety, dosing, and product consistency.

In the Exam Room

  • The AAFP urges its members to be involved in the diagnosis, treatment, and prevention of substance use, as well as the secondary diseases impacted by use.
  • The AAFP calls for family physicians to discuss the health consequences of marijuana and cannabis use, as well as prevention strategies to prevent use and unintended consequences of marijuana exposure in at-risk populations.

Cannabis use, both medically and recreationally, is prevalent throughout history. Extensive evidence indicates cannabis was used by ancient civilizations, dating back more than 5,000 years ago. 1  In the U.S. in the 19th and early 20th centuries, cannabis was frequently used for medicinal purposes, often prescribed by clinicians. 1,5  Cannabis was first listed in the  United States Pharmacopoeia  in 1851, indicating use as an analgesic, hypnotic, and anticonvulsant agent. 5  After the 1937  Marihuana Tax Act , in 1942, cannabis was removed from the  United States Pharmacopoeia . 5

Attitudes and perceived risk of marijuana use have changed with the varying levels of legalization in the U.S. Surveying marijuana use is essential to gauge public health implications of increased access to marijuana, cannabinoid, and cannabis products. According to the 2018 National Institute on Drug Abuse (NIDA) Monitoring the Future Survey (MTF), daily, past month, past year, and lifetime marijuana use among 8 th  graders has declined, and remained unchanged in 10 th  and 12 th  graders, when compared to the 2013 MTF survey. 6  Despite the changing landscape of marijuana regulations nationwide, past year use of marijuana reached and maintained its lowest levels in more than two decades in 2016 among 8 th  and 10 th  graders. 6  However, marijuana vaping did significantly increase between 2017 and 2018, mirroring trends in youth tobacco use. 6  The NIDA 2017 National Survey on Drug Use and Health indicates nearly 53% of adults between the ages of 18-25 have tried marijuana at some point in their lifetime, 35% have used marijuana within the past year, and 22% within the past month. 7  While the lifetime use remains relatively stable for this cohort, from 2015-2017, past year and past month use increased 2.7% and 2.3%, respectively. 7  Nearly half of adults 26 or older reported using marijuana at some point in their lifetime. 7  Although adults ages 26 and up report the highest percentage of lifetime use, this age group has a significantly lower past year use (12%) and past month use (8%). 7

Forms and Use of Cannabis The cannabis plant,  Cannabis sativa , is comprised of both non-psychoactive and psychoactive chemicals called cannabinoids. 5  The cannabinoid commonly known for its psychoactive properties is delta-9-tetrahydrocannabinol (THC). 5  CBD is the most abundant cannabinoid in cannabis, and is considered to be largely non-psychoactive. 5  The biological system responsible for the synthesis and degradation of cannabinoids in mammals is referred to as the endocannabinoid system, which is largely comprised of two g-coupled protein receptors (GPCRs). 8  The GPCRs—CB1 and CB2—are found throughout many bodily tissues. However, CB1 is most concentrated in the neural tissues. 5,8  CB2 receptors are found in the brain, but are mostly found in immune cells, like macrophages, microglia, osteoclasts, and osteoblasts. 5,8

There are many forms of, and products derived from, the  Cannabis sativa  plant, including hemp, CBD, and marijuana.  Cannabis sativa  with less than 0.3% THC is considered industrial hemp, and can be used for industrial agriculture cultivation. 9,10  Industrial hemp can be harvested and used for many things, including fibers for textiles, food products, and building materials. 11,12  CBD, the non-psychoactive cannabinoid, is extracted from the flower of industrial hemp. 13  Marijuana and hemp, technically speaking, are the same plant. 13  However, the hemp variety of cannabis contains no more than 0.3% THC, while the marijuana variety contains 5-20% THC. 13

Marijuana and CBD are most commonly used via inhalation, ingestion, and topical absorption. 5  Inhalation can be through combustible mechanisms using dried flowers, including the use of a pipe, rolled joints, blunts, and water pipes (also called bongs). 14  Vaping marijuana and CBD concentrates are an increasingly popular inhalation method. 5,6  Concentrates, the concentrated form of marijuana and CBD, come in various forms, including oil, butter, or a dark sticky substance often referred to as shatter. 15  Concentrates can be both smoked or vaporized, and may also be used as additives or cooking agents for ingestion. 5,15  There are many different ways to ingest cannabinoids. Food products—called edibles—like brownies, gummies, cookies, and candies are common forms of cannabis ingestion, as well as liquid forms like juices, soda, and tea. 5,16  Tinctures are liquid, ultra-concentrated alcohol-based cannabis extracts commonly applied in and absorbed through the mouth. 17  Topical cannabis is applied to, and absorbed through, the skin in a cream or salve form. 18

Routes or methods of administration affect cannabis delivery. When cannabis is smoked or vaporized, onset of effect is within 5-10 minutes with a duration of 2-4 hours. 19  When ingested, effect is within 60-180 minutes with a duration of 6-8 hours. 19  The oromucosal route has an onset of 15-45 minutes and a duration of 6-8 hours. 19  Topical administration of cannabis or cannabinoids has variable onset and duration. 19  The smoked or vaporized method offers the more rapid activity for acute symptoms with the topical preparations offering less systemic effects. 19

Health Effects of Cannabis

Although there is preliminary evidence indicating cannabinoids may have some therapeutic benefit, a large portion of the evidence is very limited for many reasons. These include small sample sizes, lack of control groups, poor study design, and the use of unregulated cannabis products. There are also clear negative health and public health consequences that must be considered, as well as the need for a significant increase in evidence. More research is needed to create a robust evidence base to weigh the potential therapeutic benefits against potential negative impacts on health and public health. Currently, there are three medical formulations of cannabis approved for use in the U.S.; dronabinol, nabilone, and epidiolex. 20  Nabiximols is approved for use in the United Kingdom. 21  Dronabinol is delta-9 THC and ingested as either an oral solution or an oral capsule. 22  Nabilone is an oral capsule containing synthetic THC. 23  Epidiolex is a CBD oral solution. 24  Nabiximols is an oral mucosa spray containing the cannabinoids THC and CBD. 25

In 2015, Whiting, et al, performed a meta-analysis and systematic review of research on the medical use of cannabis. 25  This systematic review served as the basis for many recommendations in 2017 by the National Academy of Science, Engineering, and Health Report on medical marijuana. 5  Dronabinol, nabilone, and nabiximols were included in the studies. However, other cannabis formulations were found in research trials, including CBD, marijuana, and other cannabinoids. 26  Evidence is most substantial for nausea and vomiting associated with chemotherapy, chronic pain treatment, multiple sclerosis spasticity, and intractable seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. 27  There is moderate evidence for the use of cannabinoids for sleep and limited evidence for use in psychiatric conditions, such as post-traumatic stress disorder, depression, anxiety, and psychosis; appetite stimulation and weight gain; and no evidence for cancer treatment. 5

Dronabinol and nabilone were both approved in 1985 for use in treating refractory chemotherapy-induced nausea and vomiting. 5,23  Dronabinol is approved by the Food and Drug Administration (FDA) for appetite stimulation and weight gain, despite limited and often inconclusive evidence that it or other cannabinoids are effective. 22  This drug has traditionally been used in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients to mitigate weight loss and to treat anorexia-cachexia syndrome associated with cancer and anorexia nervosa. 5,22

Cannabinoids have been assessed for chronic pain management. Many forms of chronic pain management were studied, including cancer and chemotherapy-induced pain, fibromyalgia, neuropathic pain, rheumatoid arthritis, non-cancer pain, and musculoskeletal pain. Several studies indicate smoked THC and nabiximols were both associated with pain reduction. 5,25,26  There is limited, mixed evidence regarding the viability of cannabinoids for some forms of chronic pain management. 5  However, limitations exist with these studies, including the variable doses of THC and CBD; unregulated, non-FDA approved products; and conflicting evidence. Studies assessing cannabinoids in treating the spasticity due to multiple sclerosis or paraplegia have mixed results. The cannabinoids nabiximols, dronabinol, and TCH/CBD have all been associated with decreased spasticity. Nabilone and nabiximols were the only drugs with statically-significant decreases. 2,25

In 2018, the FDA approved a cannabidiol oral solution called epidiolex for the treatment of refractory seizures associated with Dravet syndrome and Lennox-Gastaut syndrome. 28  Epidiolex was associated with significant seizure reduction when compared to placebo. 29–31  Dravet syndrome and Lennox-Gastaut syndrome are disorders associated with severe seizures, impaired cognitive skills and development, and uncontrollable muscle contractions. 29–31

Moderate evidence exists for the use of cannabis for sleep. Nabilone and nabiximols have been associated with improvement in sleep from a baseline and sleep restfulness. 2,5,25  Improved sleep was also considered a secondary outcome when evaluating other conditions (chronic pain, multiple sclerosis) with various cannabinoids. 2,5,25

There is limited evidence for the use of cannabis or cannabinoids for the treatment of post-traumatic stress disorder (PTSD), anxiety, depression, or psychosis. Of the limited evidence, nabilone was associated with a decrease in PTSD related nightmares. 5,25  One small study indicated CBD improved public speaking anxiety. 5  There are no studies directly evaluating the effectiveness of cannabis in the treatment of depression. However, some studies measured depression as a secondary outcome, but indicated no difference in depression when compared to placebo. 25  Limited evidence (two studies) have shown no difference in treating psychosis with CBD, amisulpride, or placebo. 25  Evidence indicates individuals who use marijuana are more likely to experience temporary psychosis and chronic mental illness, including schizophrenia. 5,32

There was no evidence or insufficient evidence for the use of cannabis or cannabinoids in the treatment of cancer; neurodegenerative disorders like Huntington’s chorea, Parkinson’s disease, or amyotrophic lateral sclerosis; irritable bowel syndrome; or addiction. 5

Cannabis overdose is rare in adults and adolescents. 33  Children who experience acute intoxication from cannabis generally ingest marijuana or other cannabinoids through experimentation. 33  When compared to adults and adolescents, children are more likely to experience life-threatening symptoms of acute cannabis intoxication, which may include depressed respiration rates, hyperkinesis, or coma. 33  Management consists of supportive care dependent on the manifestation of symptoms. 33  Adults and adolescents may experience increased blood pressure and respiratory rates, red eyes, dry mouth, increased appetite, and slurred speech. 33

Negative health effects are also associated with marijuana and cannabinoid use. Frequent marijuana use has been associated with disorientation. In teens, it has been linked with depression, anxiety, and suicide. 5,32  However, this is not a proven causal relationship. Lung health can also be negatively impacted depending on the delivery mechanism. 34  Smoking marijuana can cause lung tissue scarring and damage blood vessels, further leading to an increased risk of bronchitis, cough, and phlegm production. 34  This generally decreases when users quit. 34

Secondhand smoke is a serious issue associated with marijuana use. However, there is limited evidence on how it impacts heart and lung health. 34  Detectable THC has been found in children who live in the home or have a caretaker who use marijuana, subjecting children to developmental risks of THC exposure. 35  Fetal, youth, and adolescent exposure to THC is associated with negative health effects, including impacting brain development. 34  There is inconsistent, insufficient evidence to determine the long-term effects of marijuana and cannabinoid use while breastfeeding. 36  However, THC has been detected in breast milk for up to six days post-cannabinoid use, and exposure to cannabinoids is known to impact development in children. 37  Evidence also suggests cannabis use during pregnancy may be linked with preterm birth. 38  Cardiovascular health may be impacted by smoked marijuana use. However, the negative health effects are associated with the harmful chemicals in smoke similar to tobacco smoke. 34

Approximately 9% of all individuals who use marijuana develop an addiction, which is variable by age of first use and frequency of use. 34  That number for addiction jumps to 17% for individuals who begin using marijuana as teenagers and 25-50% of those who smoke marijuana daily. 34  Marijuana use does not typically lead to harder drug use, like cocaine and heroin, in most individuals. 39  Further research is needed to evaluate any potential gateway effect. 39

Mental health outcomes associated with marijuana use include an increased risk of anxiety and depression. Marijuana has been linked to schizophrenia, psychoses, and advancing the trajectory of the disease, particularly in individuals with pre-existing genetic indicators. 5,34  Global research also suggests daily use of high-potency marijuana increases risk for psychotic episodes among individuals with no underlying mental health condition. 40  While it is widely accepted that marijuana acutely impairs cognitive function, studies suggest differential outcomes regarding short- versus long-term cognitive impairment. 34

Research Considerations

The regulatory environment surrounding cannabis, marijuana, and cannabinoid research creates barriers detrimental to facilitating meaningful medical, public health, policy, and public safety research. Approval for research expands beyond institutional review boards. Due to the Schedule I classification by the Drug Enforcement Agency (DEA), researchers seeking to investigate health effects associated with cannabis must follow a regimented application process. 41  Applicants must submit an Investigational New Drug (IND) application to the FDA, which will then be reviewed to determine scientific validity and research subjects’ rights and safety. 42  Researchers must also follow the NIDA regulatory procedures for obtaining cannabis for research purposes. 41  Researchers may only use cannabis supplied by the University of Mississippi, the single NIDA-approved source for cannabis research. 41  Requiring research to rely on one source of cannabis limits availability and the variety of products. While the University of Mississippi cultivates different strains of cannabis, it is unable to supply the vast array of strains of cannabis found in the evolving retail environment with varying levels of THC, CBD, and cannabinoid content. 5  Substantial funding and capacity is required for researchers to obtain all regulatory approval and remain in compliance while conducting cannabis-related research. The required processes and procedures present a serious burden, dissuading researchers from pursuing cannabis-related projects. This has led to a lack of empirical evidence regarding a myriad of health-related issues, including potential therapeutic benefits of cannabis, public health impact, health economics, and the short- and long-term health effects from cannabis use.

In order to address the research gaps associated with both beneficial and harmful effects of cannabinoids used in both medical and recreational capacities, the AAFP calls for a comprehensive review of processes and procedures required to obtain approval for cannabis research.  

The AAFP encourages the appropriate regulatory bodies, such as the DEA, NIDA, FDA, Department of Health and Human Services (DHHS), National Institutes of Health (NIH), and the Centers for Disease Control and Prevention (CDC), to collaborate with non-governmental stakeholders to determine procedures to decrease the burden of cannabis-related research while maintaining appropriate regulatory safety guards. This should include a reclassification of marijuana from Schedule I to facilitate clinical research. The AAFP calls for increased funding from both public and private sectors to support rigorous scientific research to address gaps in evidence regarding cannabis to protect the health of the public and inform evidence-based practices. 3  Future research should address the impact of cannabis use on vulnerable and at-risk populations.

Regulatory Considerations

While cannabis was federally regulated in 1906 for consumer and safety standards and labeling requirements, the  Marihuana Tax Act  of 1937 was the first federal regulation to impose a fine or imprisonment for non-medical use and distribution of cannabis. 5  The tax act also regulated production, distribution, and use of cannabis, further requiring anyone dealing with cannabis to register with the federal government. 5  In 1970, the DEA classified marijuana as a Schedule I drug, which is defined as a drug with no current acceptable medical use and a high potential for abuse. 43  Other Schedule 1 drugs include heroin, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (ecstasy), methaqualone, and peyote. 43  Since this class of substances is determined as having no medical usage, they cannot be legally prescribed and thus, there is no medical coverage for them.

Marijuana is illegal under federal law. Penalties cover possession, sale, cultivation, and paraphernalia. However, the Agriculture Improvement Act of 2018 included a U.S. Department of Agriculture (USDA) Hemp Production Program, removing hemp from the Controlled Substances Act. 10,44  As a result, CBD  sourced from hemp plants containing no more than 0.3% THC is legal to produce. 10,44  The FDA has approved three medications containing cannabinoids: epidiolex (CBD), dronabinol, and nabilone (synthetic cannabinoids). 5  No other forms of cannabis are currently regulated by the FDA. The AAFP calls upon the FDA to take swift action to regulate CBD and cannabinoid products now legal in order to protect the health of the public.

States have separate marijuana, cannabinoid, and cannabis laws, some of which mirror federal laws, while others may be more harsh, or have decriminalized and even legalized marijuana and cannabis. 45  In 1996, California was the first state to legalize the medical use of marijuana. 46  States have subsequently decriminalized and/or legalized cannabinoids, medical marijuana, and recreational marijuana. 46  As of August 2019, 30 states, along with the District of Columbia, Guam, and Puerto Rico have legalized marijuana in varying forms. 46  Decriminalization laws may include reduction of fines for possession of small amounts of marijuana, reclassification of criminal to civil infractions, excluding the infraction from criminal records and expunging prior offenses and convictions related to marijuana. 47  Thirty-three states, along with the District of Columbia, Guam, Puerto Rico, and the U.S. Virgin Islands have a comprehensive, publicly-available medical marijuana/cannabis program, and 13 of these states have also removed jail time for possessing small amounts of non-medical marijuana. 47  Adult recreational marijuana use is legal in 13 states and the District of Columbia. 47  Vermont and the District of Columbia, however, do not allow the sale of marijuana for recreational purposes. This means it is not a crime to use and possess marijuana recreationally, but commercial sales are not allowed. 47  States have also authorized the sale of products that have low levels of THC, but high levels of CBD. These products are widely available in retail locations, but are highly unregulated. 47  The benefits of CBD touted by the public and retailers are largely anecdotal. The vast majority of these claims are not substantiated by valid research.

Decriminalizing and legalizing marijuana can decrease the number of individuals arrested and subsequently prosecuted for possession and/or use. 48  However, evidence suggests that these practices are not applied equitably. People of color are more likely to be arrested and prosecuted for marijuana possession despite overall decreased arrest rates. 48  Incarceration impacts health. People who are incarcerated have significantly higher rates of disease than those who are not, and are less likely to have access to adequate medical care. 49

The AAFP “opposes the recreational use of marijuana. However, the AAFP supports decriminalization of possession of marijuana for personal use. The AAFP recognizes the benefits of intervention and treatment for the recreational use of marijuana, in lieu of incarceration, for all individuals, including youth.” 4  The AAFP calls for family physicians to advocate to prevent unnecessary incarceration by diverting eligible people from the justice system to substance abuse and/or mental health treatment. 49

There are many public health considerations when regulating cannabis products. Serious public health concerns include impaired driving, youth exposure to advertisements, and accidental poisoning in children. Second to alcohol, marijuana is the most common illicit drug associated with impaired driving and accidents. 34  Marijuana slows reaction time and decision making, substantially increasing risk for traffic accidents. 50  Some states have a zero-tolerance policy, where there is no allowable detectable level of THC while driving, while other states have set five nanograms per milliliter or higher limits of THC, or minimally-detectable amounts of THC. 51

Evidence indicates adolescents who are exposed to medical marijuana advertising are more likely to have positive views of and subsequently use marijuana. 52  Those exposed to medical marijuana advertising were more likely to report past use and expectant future use. 52  These adolescents also reported agreeing with statements like, marijuana helps people relax and get away from their problems. 52  Adolescent exposure to medical marijuana advertising was also associated with self-reporting negative consequences associated with marijuana use, including missing school and concentration issues. 52  The AAFP calls for immediate regulation of advertising of all marijuana and cannabinoid products to decrease youth exposure to aid in preventing initiation and subsequent use of marijuana.

Children are most susceptible to severe effects associated with marijuana poisoning, including decreased coordination, lethargy, sedation, difficulty concentrating, and slurred speech. 53  Exposure may also include serious, potentially life-threatening symptoms like respiratory distress and coma. 33  Unintentional exposures to marijuana in children have increased each year since 2012, likely due to legalization policies across the U.S. and popularity of edibles. 53  Edibles often look exactly like their non-THC counterparts, and come in brightly colored packaging appealing to children, often mimicking candy products. 53  Effective legislation requiring childproof packaging for edible products can help mitigate and prevent unintentional exposure in children. 54  Family physicians should discuss safe storage of all cannabis products with their patients who live with children. 54  Under the Child Abuse Prevention and Treatment Act (CAPTA), physicians are mandated reporters of suspected child abuse and neglect. 55  The 2010 law requires states to enact laws for reporting substance use-exposed infants to child protective services. 55

Family physicians play a key role in addressing marijuana, cannabinoid, and cannabis product use; reducing barriers to research; and advocating for appropriate policy to protect the health of patients and the public.

Family physicians can address the inappropriate use of marijuana, cannabinoid, and cannabis products. Family physicians should discuss safe storage of all cannabis products with patients who live with or serve as primary caregivers for children to prevent unintended exposure. 56  It is important to discuss the developmental and negative impacts of marijuana and cannabis products with individuals who are or can become pregnant, children, and adolescents. Family physicians should also emphasize the serious consequences of impaired driving and marijuana intoxication.

It is essential to decrease barriers to research all forms of marijuana, cannabis, and cannabinoids, including a reclassification of cannabis as a Schedule I drug. High-quality research regarding the impact on patients, public health, society, and health policy are essential to providing patient-centered care and promoting evidence-based public health practices. Immediate regulations for marijuana and cannabinoid products, including CBD, like product safety and consistency safeguards, child-proof packaging, labeling, marketing claims and advertising, and impairment standards are vital for consumer safety and injury prevention. Regulatory measures focused on preventing youth initiation of marijuana and cannabinoid product use must be prioritized to prevent a public health epidemic.

The health benefits associated with intervention and treatment of recreational marijuana and cannabinoid use, in lieu of incarceration, is an important policy consideration.

Utilizing an interdisciplinary, evidence-based approach to addressing both medical and recreational marijuana and cannabis use is essential to promote public health, inform policy, and provide patient-centered care. Family physicians, in partnership with public health and policy professionals, can play an imperative role in addressing the changing landscape of marijuana and cannabis products.

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(July 2019 BOD)

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74% Of Americans Live In A Legal Marijuana State, Research Finds

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Seattle, USA - July 14, 2016: People passing a State Legal Marijuana shop sign on 2nd avenue late in ... [+] the day in downtown.

Although marijuana is still illegal at the federal level, most Americans live in a state where marijuana is legal for medical or recreational purposes.

In its latest analysis on the status of marijuana in the United States, the American think-tank Pew Research Center has found that 74% of Americans live in a state where marijuana is legal for either recreational or medical use, while 54% of Americans live in a state where the recreational use of marijuana is legal.

After Colorado and Washington passed legislation in 2012, a total of 24 states (along with the District of Columbia) have legalized the recreational use of marijuana as of February 2024. Additionally, 14 states legalized marijuana for medical purposes only, while the remaining 12 states have enacted laws allowing restricted access to marijuana products with minimal or no THC.

The findings of this research demonstrate the increasing spread of marijuana legality throughout the country, following the state-level model. This trend is further supported by a recent Gallup poll indicating that 70% of Americans support marijuana legalization .

The Pew Research Center’s analysis also focuses on the distribution of marijuana dispensaries across the country and found that three-quarters of all dispensaries in the country (76%) are located in states where recreational marijuana use is legal, while 23% of them have opened in states that allow only medical marijuana.

The remaining 1% of dispensaries are located in states with regulations for low-THC or CBD-only products, and half of the residents in these states live in a county with at least one dispensary.

This trend is mainly attributed to the outcome of the 2018 Farm Bill, which legalized hemp with a THC level below 0.3% and contributed to the production of non-intoxicating marijuana compounds like CBD products, as well as products with milder intoxicating effects like marijuana, such as delta-8 THC products , which exist in a gray market area as they are neither federally legal nor illegal. However, it’s worth noting that states have started to regulate or even ban these latter products despite their growing popularity, especially in those states that have not yet legalized marijuana.

Among the legal marijuana states, California leads with 3,659 dispensaries, comprising a quarter of all dispensaries in the U.S. However, when we examine it closely, Oklahoma stands out, boasting the highest number of marijuana dispensaries per capita of any state: 36 dispensaries for every 100,000 residents. Overall, 79% of Americans live in a county with at least one of the nearly 15,000 marijuana dispensaries across the nation.

Interestingly, The Pew Research Center’s analysis reveals concentrations of dispensaries near borders between states with differing levels of permissiveness regarding marijuana.

“Overall, one in every five dispensaries in the U.S. is located within 20 miles of a state border. And 29% of these border dispensaries adjoin a neighboring state with less permissive cannabis laws,” the research reads.

The legalization of both medical and recreational marijuana also has implications for the real estate market.

The analysis further reveals that in four states where marijuana is legalized for both recreational and medical use – Colorado, Connecticut, Maryland, and Virginia – areas with high concentrations of dispensaries have median annual household incomes at least $20,000 lower compared to areas with low concentrations of dispensaries. However, the situation is different in New Hampshire and New York, as areas with many dispensaries have median household incomes around $20,000 or more higher than those with few dispensaries.

Dario Sabaghi

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Published on 14.3.2024 in Vol 26 (2024)

Quality and Dependability of ChatGPT and DingXiangYuan Forums for Remote Orthopedic Consultations: Comparative Analysis

Authors of this article:

Author Orcid Image

Original Paper

  • Zhaowen Xue * , PhD   ; 
  • Yiming Zhang * , PhD   ; 
  • Wenyi Gan * , PhD   ; 
  • Huajun Wang * , PhD   ; 
  • Guorong She * , PhD   ; 
  • Xiaofei Zheng, PhD  

Department of Bone and Joint Surgery and Sports Medicine Center, The First Affiliated Hospital, The First Affiliated Hospital of Jinan University, Guangzhou, China

*these authors contributed equally

Corresponding Author:

Xiaofei Zheng, PhD

Department of Bone and Joint Surgery and Sports Medicine Center, The First Affiliated Hospital, The First Affiliated Hospital of Jinan University

No. 613, Huangpu Avenue West

Tianhe District

Guangzhou, 510630

Phone: 86 13076855735

Email: [email protected]

Background: The widespread use of artificial intelligence, such as ChatGPT (OpenAI), is transforming sectors, including health care, while separate advancements of the internet have enabled platforms such as China’s DingXiangYuan to offer remote medical services.

Objective: This study evaluates ChatGPT-4’s responses against those of professional health care providers in telemedicine, assessing artificial intelligence’s capability to support the surge in remote medical consultations and its impact on health care delivery.

Methods: We sourced remote orthopedic consultations from “Doctor DingXiang,” with responses from its certified physicians as the control and ChatGPT’s responses as the experimental group. In all, 3 blindfolded, experienced orthopedic surgeons assessed responses against 7 criteria: “logical reasoning,” “internal information,” “external information,” “guiding function,” “therapeutic effect,” “medical knowledge popularization education,” and “overall satisfaction.” We used Fleiss κ to measure agreement among multiple raters.

Results: Initially, consultation records for a cumulative count of 8 maladies (equivalent to 800 cases) were gathered. We ultimately included 73 consultation records by May 2023, following primary and rescreening, in which no communication records containing private information, images, or voice messages were transmitted. After statistical scoring, we discovered that ChatGPT’s “internal information” score (mean 4.61, SD 0.52 points vs mean 4.66, SD 0.49 points; P =.43) and “therapeutic effect” score (mean 4.43, SD 0.75 points vs mean 4.55, SD 0.62 points; P =.32) were lower than those of the control group, but the differences were not statistically significant. ChatGPT showed better performance with a higher “logical reasoning” score (mean 4.81, SD 0.36 points vs mean 4.75, SD 0.39 points; P =.38), “external information” score (mean 4.06, SD 0.72 points vs mean 3.92, SD 0.77 points; P =.25), and “guiding function” score (mean 4.73, SD 0.51 points vs mean 4.72, SD 0.54 points; P =.96), although the differences were not statistically significant. Meanwhile, the “medical knowledge popularization education” score of ChatGPT was better than that of the control group (mean 4.49, SD 0.67 points vs mean 3.87, SD 1.01 points; P <.001), and the difference was statistically significant. In terms of “overall satisfaction,” the difference was not statistically significant between the groups (mean 8.35, SD 1.38 points vs mean 8.37, SD 1.24 points; P =.92). According to how Fleiss κ values were interpreted, 6 of the control group’s score points were classified as displaying “fair agreement” ( P <.001), and 1 was classified as showing “substantial agreement” ( P <.001). In the experimental group, 3 points were classified as indicating “fair agreement,” while 4 suggested “moderate agreement” ( P <.001).

Conclusions: ChatGPT-4 matches the expertise found in DingXiangYuan forums’ paid consultations, excelling particularly in scientific education. It presents a promising alternative for remote health advice. For health care professionals, it could act as an aid in patient education, while patients may use it as a convenient tool for health inquiries.

Introduction

The fast growth of artificial intelligence (AI) in recent years has brought tremendous changes to different professions and businesses, altering the way people live and work. The application of AI in medicine is expanding in several areas, including medical image analysis, medication-interaction detection, the identification of high-risk patients, and medical record coding [ 1 , 2 ]. As technology advances, OpenAI introduced ChatGPT on November 30, 2022, as a new kind of natural language model capable of communicating with people through text-to-text, human-like dialogues [ 3 , 4 ]. The more powerful GPT-4 subsequently became accessible through a paid ChatGPT Plus membership on March 13, 2023. It has attracted a lot of interest since its release and has the potential to be widely used in the health care system [ 5 , 6 ]. Most medical AI research has targeted medical workers as software users, which requires medical knowledge reserves [ 7 ]. ChatGPT and other conversation question-and-answer AI software programs do not establish a user threshold, and their strong function makes them an essential auxiliary tool to increase finance and management job efficiency [ 8 ]. Health is a natural component of humans and should be explored and used in ChatGPT, particularly in the context of situational conversations between patients and physicians.

As human civilization advances, the quest for more convenient, professional, and precise medical services intensifies, with patients expecting increasingly high standards of care. The internet era has spurred hospitals to offer remote diagnostic and treatment services, facilitating doctor-patient interactions beyond physical boundaries and enhancing an understanding of medical issues through remote health care, particularly for those far from medical centers [ 1 ]. The recent COVID-19 pandemic has accelerated this digital shift in medicine [ 2 , 9 , 10 ]. However, the complexity of medical information can reduce physician efficiency and patient comprehension, highlighting the need for patient navigation services, especially in countries with evolving medical systems such as China [ 11 - 13 ]. Amid this backdrop, the rapid advancement of AI technologies such as ChatGPT offers promising support in navigating medical systems, aiding patients in understanding their disease, and selecting a health care facility [ 14 ].

“DingXiangYuan” is a leading digital health technology enterprise in China that seeks to unite physicians, researchers, patients, and hospitals through expert and authoritative knowledge exchange, extensive and thorough medical data collection, and top-notch digital medical services [ 15 ]. Its remote diagnosis and treatment application has been widely used in China. In the application forums, users may seek the assistance of physicians who are qualified and accredited by the site. At the same time, the information provided by doctors is public, and supervision by the platform leads to a high level of quality for the questions and answers listed in these forums. However, consultations on DingXiangYuan are costly and restrict the number of conversations patients can have with their physicians. In addition, websites offering remote consultations, such as DingXiangYuan, still require physicians to respond on the web, which does not reduce the burden on clinicians.

Nevertheless, a comparative analysis of the quality of responses obtained from paid remote health consultations and ChatGPT-4 has yet to occur. This analysis was based on 82 orthopedic surgery–related consultations sourced from the Doctor DingXiang section of the DingXiangYuan platform. Responses from physicians on the web served as the control group, while those from ChatGPT-4 made up the experimental group. To determine the efficacy of ChatGPT-4 as a reliable remote health consultation resource, we conducted a comparative analysis of its logical response structure, diagnostic accuracy, the viability of its treatment recommendations, and the ability to effectively disseminate medical knowledge pertaining to various conditions. The goal is to provide a workable foundation for the development of ChatGPT-4 in the medical domain.

Data Set of Orthopedic-Related Remote Consultation

The “Doctor DingXiang” website is a remote network that houses a collection of orthopedic-related medical dialogues and is one of China’s largest remote-paid consultation platforms ( Figure 1 A and Figure 2 ). To protect patients, the website blocks access to all content that may compromise their privacy, including the patient’s username, images provided in the question, imaging data, and biochemical examination results, from all other website visitors, allowing only the questioner and the target doctor to access it. In addition, there are categories of diseases on the site, and only about 100 consultation results are displayed for each type of disease. Each doctor’s response can be either spoken or written; however, since the spoken answers are not as accurate as the written answers and contain many spoken words, only the written answers were adopted ( Multimedia Appendix 1 ). From May 20, 2023, to May 30, 2023, a total of 8 types of illness (with a total of 800 cases) were identified, namely gout, osteoarthritis, plantar fasciitis, fracture, osteoporosis, lumbar disc herniation, tendon sheath cyst, and osteoporosis. Of these, 82 patients originally met the screening criteria according to the above requirements. The 82 issues ( Figure 1 ) we collected from this website are compliant with the HIPAA (Health Insurance Portability and Accountability Act) of 1996, given the information provided above [ 16 ]. “Doctor answers” refers to the website’s collection of responses from board-certified physicians ( Figure 2 A). Multimedia Appendix 2 contains all queries obtained from the Doctor DingXiang website, as well as the doctors’ responses.

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ChatGPT’s Answers

ChatGPT exhibits robust learning capabilities within the same dialogue window, enhancing responses to subsequent questions based on previous answers. However, this ability also introduces the potential for systematic error. To elaborate, this interconnectedness of responses does not allow for the maintenance of independence in ChatGPT-4’s answers to each question. Therefore, when 73 patients’ questions from the included consultations were entered into ChatGPT as questions ( Figure 1 B), a “new chat” was created for each question-and-answer set to minimize systematic errors. This process took place from June 1, 2023, to June 10, 2023. The use of a “new chat” for each inquiry ensured the independence of each response by preventing the AI from using context from previous interactions, thereby eliminating any learning or bias that may have been carried over from earlier questions. In addition, no plug-ins were used with ChatGPT-4, and the “chat history and training” option was deactivated to preserve the objectivity of each response. All ChatGPT-4 answers can be found in Multimedia Appendix 4 .

Response Qualification

The “data set of orthopedic-related remote consultation” was compiled by a professional orthopedic doctor on the Doctor DingXiang website, and 3 professional orthopedic physicians evaluated the ChatGPT and doctor response quality scores. To reduce systematic error resulting from human factors, the orthopedic surgeon who assessed the answers did not know how the answers were grouped. Specific scoring criteria were separated into “properties of natural coherence,” “clinical effect,” and “overall satisfaction” ( Multimedia Appendix 5 ). The 3 orthopedic physicians convened initially to calibrate their scoring criteria using 2 examples provided by the author ( Multimedia Appendix 6 ). After individual scoring, the Fleiss κ method was used to test the interrater consistency among the 3 physicians’ scores. The final statistical data were derived from the mean value of the scores given by the 3 physicians.

Dependability of Comparative Analysis of Responses

When discussing the dependability of comparative analysis of responses, it is essential to consider 3 critical aspects: logical reasoning, internal information, and external information. These components collectively form the foundation for assessing the dependability of answers.

  • Logical reasoning: The answer uses logic and stepwise thinking to produce a response with the given information in the question stem.
  • Internal information: The answer uses information present within the question stem to procure a response.
  • External information: The answer uses external information to produce a response.

Usability of Comparative Analysis of Responses

When assessing the usability of comparative analysis of responses in the medical field, it is crucial to focus on how effectively these analyses can guide diagnosis and treatment, provide therapeutic insights, and educate patients on their conditions.

  • Guiding function: To evaluate the accuracy of the provided diagnosis and differential diagnosis as well as the accuracy of the clinical treatment direction judgement and guidance.
  • Therapeutic effect: To determine whether the treatment suggestions provided in response to the consultation are accurate and if they can alleviate or treat the diseases proposed by the patients.
  • Medical knowledge popularization education: To evaluate whether the response introduces the cause and course of the disease and whether it can enhance patients’ understanding of the illness.

Overall Satisfaction

On a scale of 1-10 points, the rater assigned a general rating to the replies. A score of 1-3 points indicated that the responses are biased and that they do not include contents that could call for differential diagnosis and certain auxiliary exams that need to be improved. A score of 4-6 points suggests that there is a possible danger of misdiagnosis or a delay in treatment. Scores of 7-9 points indicate consultation services that can practically replace licensed medical professionals. Finally, a score of 10 points indicates a full replacement for a licensed medical professional’s consultation service.

For statistical analysis, SPSS (version 26.0; IBM Corporation) was used. Chi-square analysis was used to analyze scoring differences between different groups. The Kolmogorov-Smirnov technique was used to determine whether the data exhibited a normal distribution; ultimately, it indicated that none of the data in this investigation were normally distributed. Consequently, the Mann-Whitney U test of independent samples was used to assess the disparity in scoring performance between the experimental and control groups [ 17 ]. When P <.05, the difference was considered statistically significant. Scott π statistic is a statistical measure of interrater reliability. Fleiss κ is a generalization of this statistic. SPSS was used to examine the consistency of the 3 raters for each item. Finally, GraphPad Prism 8 (GraphPad Software) was used to construct bar charts to display the comparison of dependability and usability between 2 types of responses, as well as the overall satisfaction outcomes.

Orthopedic Case Selection and Comparative Assessment

We selected 8 orthopedic diseases from the Doctor DingXiang website and consulted 800 cases in total, namely fracture, osteoarthritis, cervical spondylosis, lumbar disc herniation, tendon sheath cyst, plantar fasciitis, osteoporosis, and gout. In the initial screening, we excluded 717 cases in which patients provided information that visitors could not view or where doctors used voice responses. The second screening process excluded patients who provided information that the visitor could not view in the follow-up questions (a total of 9 cases). Finally, 73 eligible cases were included. Without being aware of the replies’ origin, 3 orthopedic physicians in practice assessed the responses. The authors concluded by summarizing the statistical findings and designating the response assessment of Doctor DingXiang as the control group and the response evaluation of ChatGPT-4 as the experimental group.

Evaluation Results for Dependability and Usability

After statistical scoring, we discovered that ChatGPT’s “internal information” score (mean 4.61, SD 0.52 points vs mean 4.66, SD 0.49 points; P =.43) and “therapeutic effect” score (mean 4.43, SD 0.75 points vs mean 4.55, SD 0.62 points, P =.32) were lower than those of the control group, but the differences were not statistically significant ( P >.05; Figures 3 E and 4E). ChatGPT showed better performance in the “logical reasoning” score (mean 4.81, SD 0.36 points vs mean 4.75, SD 0.39 points; P =.38), “external information” score (mean 4.06, SD 0.72 points vs mean 3.92, SD 0.77 points; P =.25), and “guiding function” score (mean 4.73, SD 0.51 points vs mean 4.72, SD 0.54 points; P =.96), although the changes were not statistically significant ( Figures 3 D, 3F, and 4D). However, we were glad to see that, in terms of remote diagnosis and treatment, ChatGPT’s “medical knowledge popularization education” scores were better than those of the control group (mean 4.49, SD 0.67 points vs mean 3.87, SD 1.01 points; P <.001), and the difference was statistically significant ( Figure 4 F). Figure 3 A depicts the score distribution of ChatGPT and the control group in terms of “logical reasoning.”

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The figures show the distributions of “logical reasoning” ( Figure 3 A), “internal information” ( Figure 3 B), “external information” ( Figure 3 C), “guiding function” ( Figure 4 A), “therapeutic effect” ( Figure 4 B), and “medical knowledge popularization education” ( Figure 4 C). Other than that for “medical knowledge popularization education,” the score distribution for the remaining elements was roughly comparable.

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In terms of “overall satisfaction,” we see that ChatGPT had slightly higher overall satisfaction scores of <5 points compared with the control group ( Figures 5 A and 5B), but the difference was not statistically significant (mean 8.35, SD 1.38 points vs mean 8.37, SD 1.24 points; P =.92; Figure 5 C).

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Consistency Testing Among the 3 Orthopedic Physicians’ Evaluations

Using Fleiss κ, the consistency of the ratings among 3 physicians was determined ( Multimedia Appendix 5 ). The Fleiss κ evaluations for “logical reasoning,” “internal information,” “external information,” “therapeutic effect,” “medical knowledge popularization education,” and “overall satisfaction” were rated as showing “fair agreement” for the control group, while “guiding function” was rated as showing “substantial agreement” ( Multimedia Appendix 5 ; P <.001). According to Fleiss κ values, “internal information,” “external information,” and “overall satisfaction” were rated as displaying “fair agreement” in the ChatGPT responses, whereas “logical reasoning,” “guiding function,” “therapeutic effect,” and “medical knowledge popularization education” were rated as showing “moderate agreement” ( Multimedia Appendix 5 ; P <.001).

Main Findings of This Study

This cross-sectional research gathered 73 frequently asked clinical questions from patients and excellent responses given by licensed, qualified physicians on a reputable remote medical service website. After using ChatGPT to get the answers to these queries and seeking the evaluation of professional doctors, we discovered that, when compared with the responses of qualified clinicians, ChatGPT’s answers also showed strong logic and the capacity to extract and analyze key information, and they could help physicians respond to patients’ questions in a manner that reflects professionalism. Overall, ChatGPT’s responses received generally positive feedback from doctors. Professional responses from ChatGPT were able to assess and address queries in light of a large database, and the service even suggested literature on diseases for interested customers. With the help of ChatGPT, this method may unleash latent productivity, allowing health care personnel to use the time saved on more difficult duties. However, ChatGPT still has a lot of drawbacks. Although ChatGPT can analyze photographs, the procedure to do so is very complicated: medical images must be submitted to a public site to establish links for analysis, and the success rate of analysis is not very high. In addition, ChatGPT is not yet able to accurately diagnose a patient’s illness; this task must be left to expert physicians, whose assessment and oversight are crucial to the process [ 18 ]. Therefore, we believe that ChatGPT may successfully help doctors with remote diagnosis and treatment services, significantly increase clinicians’ job efficiency, and save more time, but it still cannot take over from the doctor entirely.

Comparison With Previous Research

As the internet has grown, many hospitals have established remote medical services. Doctor-patient contact is no longer hampered by distance thanks to the internet, which makes it easier for both parties to interact. Remote medical services have expanded quickly over the last 3 years as a result of the COVID-19 pandemic, and, to some degree, they have even altered the conventional medical model. Remote diagnosis and therapy, nevertheless, are not yet flawless. Patients must pay additional costs for remote diagnostic and therapy services, and their communications may be ignored or they may receive pointless answers [ 2 ]. More crucially, in certain fields, including orthopedics, textual communication alone may be unable to provide clinicians with a whole picture of the patient’s condition. There is still no replacement for a physical examination, imaging examination, or biochemical test. In addition, physicians must expend a great deal of additional time and effort to decide how to respond to patients, which adds significantly to their burden and may not have the intended outcome [ 19 ].

Previous studies have indicated that ChatGPT-3.5 demonstrated strong performance in addressing public health inquiries on Reddit’s r/AskDocs, showcasing its considerable promise for offering remote medical consultation services [ 20 ]. This is noteworthy given the hesitancy of some patients to discuss their health issues publicly, coupled with the challenge of ensuring the reliability of unpaid responses on such platforms [ 20 ]. Contrasting with this, this study compares ChatGPT-4 with paid professional responses on the Doctor DingXiang forums, revealing that ChatGPT-4’s overall performance is comparable to that of paid medical professionals, with the added benefit of more effective dissemination of medical knowledge. In addition, ChatGPT’s low barrier to entry means this real-time, AI-driven, question-and-answer software better addresses the immediate health consultation needs of users, making it more significant for widespread application.

Interactive AI software that offers immediate feedback has an advantage over traditional AI analytical output software in that it allows users to inquire not only about the answers to “what” but also about the underlying “why” [ 21 ]. In the context of clinical scenarios, users have the ability to request critical information and foundations for diagnosis and treatment through ChatGPT. This functionality aids in the clarification of the operational logic behind their decisions, fostering greater transparency in the use of ChatGPT software and the comprehension of users. In relation to personal privacy, users have the ability to configure ChatGPT’s personal settings to “chat history and training” and enable a personalized input mode to proactively minimize the exposure of sensitive data.

Significance for Hierarchical Diagnosis and Treatment as Well as Triage

A major worldwide problem is the scarcity and unequal distribution of medical resources. The issue is made worse in certain nations with high population densities, such as China, by the abundance of people who require medical treatment [ 22 ]. In addition, China is unable to guarantee the effectiveness of medical resource allocation, as other high-income countries can, due to ineffective rules and legislation and a lack of rigorously educated general practitioners [ 23 ]. To address this issue, the hierarchical medical system was created, and it has steadily replaced other medical systems to provide basic health care in the majority of high-income countries [ 24 ]. According to the severity and urgency of their sickness, patients must be sent to medical facilities of the appropriate level, such as primary medical institutions or specialized medical institutions [ 25 ]. This is a perfect medical paradigm, but patients’ treatment decisions are significantly influenced by their self-rated health state, chronic illnesses, socioeconomic situation, and educational level, particularly since the majority of patients lack an objective grasp of their ailment and pertinent medical expertise [ 26 , 27 ]. The hierarchical medical system has not had the desired impact in China as a consequence of its deployment. Some medical facilities are suffering from severe work pressure overload due to a lack of medical resources and patients’ unrealistic treatment preferences [ 23 ]. To enhance patients’ medical behavior and help them choose the best medical facilities, high-quality guiding services are thus necessary to assist patients in understanding their disease-related information before treatment [ 28 ]. This may somewhat mitigate the issues brought on by a lack of medical resources and assist patients in receiving more focused and appropriate medical care.

Patient navigation services, a patient-centered intervention, are becoming more and more popular. These services use trained personnel to identify patient-level barriers to care, such as cultural, logistical, and educational ones, and then remove them to encourage full and prompt access to care [ 29 , 30 ]. A growing body of research demonstrates the beneficial effects that patient guide services have on illness prevention, the spread of health information, medical decision-making, and communication promotion. Patient navigation can help remove barriers brought on by language, cultural differences, a lack of relevant medical knowledge, and other factors, especially for some patients with a lack of medical knowledge or a relatively low level of education, in the face of a more complex but hierarchical medical center or sociomedical system. This will lead to a more effective patient path and fewer delays in diagnosis and treatment [ 31 ]. More crucially, research has demonstrated that patient guiding services have benefited people with chronic illnesses such as diabetes and cardiovascular disease and have somewhat decreased the likelihood of rehospitalization [ 32 ]. Patient guidance services may not only aid in the patient’s healing process but also assist them with developing a more thorough and expert understanding of the causes, symptoms, and other facets of associated diseases, enabling them to treat, care for, and monitor their disease more skillfully and effectively [ 33 ]. However, previous research discovered that some issues remain with the present patient guidance service, such as navigators’ potential lack of expertise. In addition, some patient navigators, although trained on how to perform their job, lack a history of medical education, making it difficult for them to respond to the patient’s consultation [ 11 ]. Even if it may be a little harsh to demand that patient navigators be all-knowing, finding practical and trustworthy approaches to boost the effectiveness and caliber of patient navigation services is still necessary.

The Challenges of Promoting ChatGPT in the Medical Field

While using AI is the general trend in science and technology development, individuals must also understand that the tool can only work optimally in the ideal regulatory environment, which often has some lag. To ensure the rational use of ChatGPT in the medical field, hospitals need to organize training on the use of ChatGPT and uniformly manage the accounts used by doctors during working hours. Doctors must also take responsibility for assessing the quality of ChatGPT’s responses and ensuring that the patient’s right to be informed of the use of ChatGPT is met. Specifically, physicians are required to assign a unique account when using ChatGPT in clinical practice, and they must also have the corresponding patient present. The physician has the authority not only to assess the quality of ChatGPT’s responses before presenting them to the patient but also to provide the patient with the final interpretation of said responses. Conversely, individuals who use ChatGPT but do not identify as medical professionals should refrain from relying exclusively on it for health-related information.

ChatGPT can assist clinicians in better organizing clinical data, analyzing imaging results, and providing personalized support for clinical decision-making regarding cancer patients, according to recent studies [ 34 - 36 ]. As previously stated, physicians, in their capacity as users of ChatGPT, are additionally obligated to oversee its use. In this regard, ChatGPT functions as a supplementary tool. Should ChatGPT outputs be incorporated into the physician-patient communication and clinical decision-making process, the physician must disclose the information source to the patients to guarantee that they are well-informed. Simultaneously, the hospital must oversee the ChatGPT accounts used by physicians and coordinate training courses on ChatGPT usage to guarantee that physicians who use ChatGPT in their clinical practice possess a certain level of proficiency in its operation. By implementing these management tasks, certain potential hazards and medical disputes can be circumvented, and the application of AI software in the medical field can be promoted more effectively.

Although this study establishes a sound theoretical foundation for the clinical implementation of ChatGPT, there are numerous areas still requiring further refinement. As one example, there is a need for further refinement of cross-sectional experiments in the future to compare the following: the quality of answers provided by AI software in various clinical disciplines, variations in the quality of answers generated by different AI software programs (ChatGPT, Google Board, Claude, and so forth), and disparities between different language inputs used by AI software. Alternatively, a randomized controlled trial could assess the efficacy of ChatGPT as a supplementary tool for clinicians to use while interacting with patients. Further development is required to ensure the full functionality, safety, and dependability of ChatGPT as a medical AI.

Limitations

Initially, we intended to investigate the viability of using the ChatGPT app for medical guidance. This study solely included orthopedic cases as the research object and did not gather multidisciplinary clinical cases to rule out variations in the difficulty levels of working in other clinical specialties, which may produce different findings. In the future, it will be possible to aggregate challenges from many disciplines and examine how AI performance differs between fields in solving difficulties. Furthermore, neither machine translation nor manual translation can preserve the flaws and precision of the original sentence content. Users are unable to ascertain the processing logic of AI when using ChatGPT as a research tool across different language types. Consequently, they are limited to inputting ChatGPT data in accordance with the language type used in the control content and assessing the output quality of ChatGPT content in the same language. Medical personnel are required to use ChatGPT under a special number with a real-name system for supervision purposes. As an auxiliary tool, ChatGPT users are not only tasked with assessing the quality of responses but also possess the authority to make the ultimate interpretation of the content. Ultimately, further randomized controlled trials are required in the future to validate the use of AI in medicine while controlling for confounding variables, as this study was cross-sectional in nature.

This study demonstrates that ChatGPT-4 responses match the expertise found among health care practitioners on DingXiangYuan, a leading remote medical consultation platform in China, across various metrics such as logical reasoning and diagnostic accuracy. Notably, it excels at providing scientific education. ChatGPT-4 is thus recommended as an alternative to traditional remote health consultations. It can assist physicians in educating patients, thereby enhancing medical knowledge dissemination. For patients, it offers accessible, reliable health advice, improving information accessibility and decision-making support. These findings suggest a transformative potential for ChatGPT-4 in health care, notably in enhancing access to medical advice and patient education. It implies the need for advancing medical AI with a focus on ethical and transparent applications, highlighting its role in improving health care delivery and patient empowerment.

Acknowledgments

The authors would like to thank DingXiangYuan and the Doctor DingXiang website’s public display of orthopedic-related remote consultation cases. We thank the LetPub website for its linguistic assistance during the preparation of this manuscript.

Authors' Contributions

ZX was responsible for conceptualization, investigation, visualization, and writing of the original draft, as well as writing, reviewing, and editing. YZ was responsible for data curation, formal analysis, and writing the original draft. WG was responsible for data curation and formal analysis. HW, GS, and XZ were responsible for grading the responses, writing—reviewing and editing, and supervising the entire study. All authors read and approved the final manuscript.

Conflicts of Interest

None declared.

Select inclusion criteria and exclusion criteria for website consultation dialogue information.

The 82 patient questions and online responses from doctors on the Doctor DingXiang website (translated from Chinese to English using ChatGPT-3.5).

High-resolution version Figure 1.

ChatGPT-4 responses after asking questions from 82 patients in Chinese (translated from Chinese to English using ChatGPT-3.5).

Consistent evaluation of Fleiss κ among the 3 raters.

Orthopaedic physicians’ initial criteria calibration.

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Abbreviations

Edited by A Castonguay; submitted 15.07.23; peer-reviewed by M Chatzimina, F Tang, J Li; comments to author 27.10.23; revised version received 04.11.23; accepted 30.01.24; published 14.03.24.

©Zhaowen Xue, Yiming Zhang, Wenyi Gan, Huajun Wang, Guorong She, Xiaofei Zheng. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 14.03.2024.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in the Journal of Medical Internet Research, is properly cited. The complete bibliographic information, a link to the original publication on https://www.jmir.org/, as well as this copyright and license information must be included.

Review of medical image recognition technologies to detect melanomas using neural networks

Affiliations.

  • 1 Digital Health Institute, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia.
  • 2 Moscow Scientific and Practical Center of Dermatology, Venereology and Cosmetology of Moscow City Health Department, Moscow, Russia.
  • 3 Digital Health Institute, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia. [email protected].
  • 4 Information Technology Department, Federal State Budgetary Institution Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation, Moscow, Russia. [email protected].
  • PMID: 32921304
  • PMCID: PMC7488698
  • DOI: 10.1186/s12859-020-03615-1

Background: Melanoma is one of the most aggressive types of cancer that has become a world-class problem. According to the World Health Organization estimates, 132,000 cases of the disease and 66,000 deaths from malignant melanoma and other forms of skin cancer are reported annually worldwide ( https://apps.who.int/gho/data/?theme=main ) and those numbers continue to grow. In our opinion, due to the increasing incidence of the disease, it is necessary to find new, easy to use and sensitive methods for the early diagnosis of melanoma in a large number of people around the world. Over the last decade, neural networks show highly sensitive, specific, and accurate results.

Objective: This study presents a review of PubMed papers including requests «melanoma neural network» and «melanoma neural network dermatoscopy». We review recent researches and discuss their opportunities acceptable in clinical practice.

Methods: We searched the PubMed database for systematic reviews and original research papers on the requests «melanoma neural network» and «melanoma neural network dermatoscopy» published in English. Only papers that reported results, progress and outcomes are included in this review.

Results: We found 11 papers that match our requests that observed convolutional and deep-learning neural networks combined with fuzzy clustering or World Cup Optimization algorithms in analyzing dermatoscopic images. All of them require an ABCD (asymmetry, border, color, and differential structures) algorithm and its derivates (in combination with ABCD algorithm or separately). Also, they require a large dataset of dermatoscopic images and optimized estimation parameters to provide high specificity, accuracy and sensitivity.

Conclusions: According to the analyzed papers, neural networks show higher specificity, accuracy and sensitivity than dermatologists. Neural networks are able to evaluate features that might be unavailable to the naked human eye. Despite that, we need more datasets to confirm those statements. Nowadays machine learning becomes a helpful tool in early diagnosing skin diseases, especially melanoma.

Keywords: Convolutional neural network; Deep learning neural network; Fuzzy clustering algorithm; Melanoma classification; Skin cancer.

Publication types

  • Data Accuracy
  • Deep Learning*
  • Early Detection of Cancer*
  • Image Interpretation, Computer-Assisted / methods*
  • Melanoma / diagnostic imaging*
  • Melanoma, Cutaneous Malignant
  • Sensitivity and Specificity
  • Skin Neoplasms / diagnostic imaging*

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Department of Defense Announces Fiscal Year 2024 University Research Funding Awards

The Department of Defense today announced $221 million in awards for basic defense-related research projects as part of the Multidisciplinary University Research Initiative (MURI) program. At an average award amount of $7.5 million over five years, these competitive grants will support 30 teams located at 73 U.S. academic institutions, subject to satisfactory research progress and the availability of funds.

"The science and engineering challenges we face today are highly complex and cross disciplinary," said Dr. Bindu Nair, director of the Basic Research Office in the Office of the Under Secretary of Defense for Research and Engineering. "The MURI program acknowledges these complexities by supporting teams whose members have diverse sets of expertise as well as creative scientific approaches to tackling problems. 

"This cross-fertilization of ideas can accelerate research progress to enable more rapid scientific breakthroughs and hasten the transition of basic research funding to practical applications. The program is a cornerstone of DoD's basic research portfolio and a strong contributor to its legacy of scientific impact." 

Since its inception in 1985, the Department's MURI program has allowed teams of investigators from multiple disciplines to generate collective insights, facilitating the growth of cutting-edge technologies to address the Department's unique challenges. 

The highly competitive program, which complements the Department's single-investigator basic research grants, has made immense contributions to current and future military capabilities and produced numerous commercial sector applications. 

Notable MURI achievements include breakthroughs in cold-atom quantum methods with potential applications in quantum sensing and communication, as well as advances in pulsed magnetic field propagation and Doppler radar detection leading to new detection physics for landmines.

The Fiscal Year 2024 competition identified six topics that received an additional $1.5 million each over the five-year award term specifically to support the participation of historically Black colleges and universities and minority-serving institutions (HBCU/MIs). Seven proposals selected across the six topics will receive support for HBCU/MI participation on the MURI projects.

The Army Research Office, Air Force Office of Scientific Research, and Office of Naval Research solicited Fiscal Year 2024 proposals in 25 topic areas of strategic importance to the Department. After a merit-based review of 276 white papers, a panel of experts narrowed the pool to a subset of 102 full proposals, from which the 30 final awards were selected. The list of winning teams can be downloaded here .

About USD(R&E) 

The Under Secretary of Defense for Research and Engineering (USD(R&E)) is the Chief Technology Officer of the Department of Defense. The USD(R&E) champions research, science, technology, engineering, and innovation to maintain the U.S. military's technological advantage. Learn more at www.cto.mil, follow us on Twitter @DoDCTO, or visit us on LinkedIn at https://www.linkedin.com/company/ousdre .

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The hand of a person with a pulse oximeter on their finger, with an illustration of the coronavirus in the background

UK report reveals bias within medical tools and devices

Experts say action needed as report finds minority ethnic people, women and those from deprived backgrounds at risk of poorer healthcare

Minority ethnic people, women and people from deprived communities are at risk of poorer healthcare because of biases within medical tools and devices, a report has revealed.

Among other findings, the Equity in Medical Devices: Independent Review has raised concerns over devices that use artificial intelligence (AI), as well as those that measure oxygen levels. The team behind the review said urgent action was needed.

Prof Frank Kee, the director of the centre for public health at Queen’s University Belfast and a co-author of the review, said: “We’d like an equity lens on the entire lifecycle of medical devices, from the initial testing, to recruitment of patients either in hospital or in the community, into the early phase studies and the implementation in the field after they are licensed,.”

The junior health minister Andrew Stephenson said: “Making sure the healthcare system works for everyone, regardless of ethnicity, is paramount to our values as a nation. It supports our wider work to create a fairer and simpler NHS.”

The government-commissioned review was set up by Sajid Javid in 2022 when he was health secretary after concerns were raised over the accuracy of pulse oximeter readings in Black and minority ethnic people.

The widely used devices were thrown into the spotlight due to their importance in healthcare during the Covid pandemic, where low oxygen levels were an important sign of serious illness.

The report has confirmed concerns pulse oximeters overestimate the amount of oxygen in the blood of people with dark skin, noting that while there was no evidence of this affecting care in the NHS, harm has been found in the US with such biases leading to delayed diagnosis and treatment, as well as worse organ function and death, in Black patients.

The team members stress they are not calling for the devices to be avoided. Instead the review puts forward a number of measures to improve the use of pulse oximeters in people of different skin tones, including the need to look at changes in readings rather than single readings, while it also provides advice on how to develop and test new devices to ensure they work well for patients of all ethnicities.

Concerns over AI-based devices were also highlighted by the report, including the potential for such technology to exacerbate the under-diagnosis of cardiac conditions in women, lead to discrimination based on patients’ socioeconomic status, and result in under-diagnosis of skin cancers in people with darker skin tones. Concerns over the latter, they say, is down to the fact AI devices are largely trained on images of lighter skin tones.

The report also noted problems with polygenic risk scores – which are often used to provide a measure of an individual’s disease risk due to their genes.

“Major genetic datasets that polygenic risk scores use are overwhelmingly on people of European ancestry, which means that they may not be applicable to people of other ancestries,” said Enitan Carrol, professor of paediatric infection at the University of Liverpool and a co-author of the review.

However, attempts to correct biases can also be problematic. Among examples highlighted by the report are race-based corrections applied to measurements from devices known as spirometers that are used to assess lung function and diagnose respiratory conditions, have themselves been found to contain biases.

Prof Habib Naqvi, the chief executive of the NHS Race and Health Observatory, welcomed the findings, adding the review acknowledged the need for immediate modifications, equity assessments and tighter guidance and regulation around pulse oximeters and other medical devices.

“Access to better health should not be determined by your ethnicity nor by the colour of your skin; medical devices therefore need to be fit-for-purpose for all communities,” he said.

“It’s clear the lack of diverse representation in health research, the absence of robust equity considerations and the scarcity of co-production approaches, have led to racial bias in medical devices, clinical assessments and in other healthcare interventions.”

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Medical cannabis in the UK: From principle to practice

Anne katrin schlag.

1 Drug Science, London, UK

2 King’s College London, London, UK

David S Baldwin

3 Clinical and Experimental Sciences, University of Southampton, Southampton, UK

4 University of Cape Town, Cape Town, South Africa

Michael Barnes

5 University of Newcastle, Newcastle upon Tyne, UK

Steve Bazire

6 School of Pharmacy, University of East Anglia, Norwich, UK

Rachel Coathup

7 University of Manchester, Manchester, UK

H Valerie Curran

8 Clinical, Education and Health Psychology, University College London, London, UK

Rupert McShane

9 Interventional Psychiatry Service, Oxford Health NHS Foundation Trust, Oxford, UK

Lawrence D Phillips

10 Department of Management, London School of Economics & Political Science, London, UK

Ilina Singh

11 Department of Psychiatry, University of Oxford, Oxford, UK

David J Nutt

12 Department of Brain Sciences, Imperial College London, London, UK

Background:

In the UK, medical cannabis was approved in November 2018, leading many patients to believe that the medicine would now be available on the NHS. Yet, to date, there have been only 12 NHS prescriptions and less than 60 prescriptions in total. In marked contrast, a recent patient survey by the Centre for Medical Cannabis (Couch, 2020) found 1.4 m people are using illicit cannabis for medical problems.

Such a mismatch between demand and supply is rare in medicine. This article outlines some of the current controversies about medical cannabis that underpin this disparity, beginning by contrasting current medical evidence from research studies with patient-reported outcomes.

Although definite scientific evidence is scarce for most conditions, there is significant patient demand for access to medical cannabis. This disparity poses a challenge for prescribers, and there are many concerns of physicians when deciding if, and how, to prescribe medical cannabis which still need to be addressed. Potential solutions are outlined as to how the medical profession and regulators could respond to the strong demand from patients and families for access to medical cannabis to treat chronic illnesses when there is often a limited scientific evidence base on whether and how to use it in many of these conditions.

Conclusions:

There is a need to maximise both clinical research and patient benefit, in a safe, cautious and ethical manner, so that those patients for whom cannabis is shown to be effective can access it. We hope our discussion and outlines for future progress offer a contribution to this process.

Introduction

Cannabis is arguably the world’s oldest medicine. After a period of being banned for political reasons in the second half of the 20th century, cannabis has now been restored as a medicine in an ever-increasing number of countries. Interest in the therapeutic benefits of medical cannabis has grown rapidly in the past 20 years. This often has been the result of patient interest ( House of Commons Health and Social Care Committee (HSCC), 2019 ) in using cannabis and cannabinoids to treat a variety of conditions, from chronic and cancer pain, through depression, anxiety disorders and sleep disturbances to neurological disorders (amongst others) ( Couch, 2020 ). The scientific evidence in this field is still developing and has been summarised in various meta-analyses (e.g. National Academies of Science, Engineering, and Medicine (NASEM), 2017 ; Whiting et al., 2015 ). For some indications this evidence is substantial, for others it is only moderate or limited. Yet many countries (and the majority of US states) now allow or are considering allowing the medical use of cannabis in some form.

In the UK, cannabis was made a medicine on 1 November 2018, largely as a result of patient pressure, including high-profile media campaigns for children whose intractable epilepsy had been remarkably improved (such as Alfie Dingley) ( HSCC, 2019 ). Nevertheless, by March 2020, the medicine is still unavailable to most patients.

The current National Institute for Heath and Care Excellence (NICE) guidelines recommend the prescription of two cannabis-based medicinal products (CBMPs) for the treatment of four main conditions: Sativex for spasticity of adults with multiple sclerosis (MS), Nabilone for chemotherapy-induced nausea and vomiting, and Epidyolex for severe treatment-resistant epilepsy, i.e. Lennox-Gastaut syndrome and Dravet syndrome ( NICE, 2019 ).

Whilst welcomed by patients as a move in the right direction, these guidelines have been criticised by patients, campaigners and some doctors as too limiting ( Busby, 2019 ). Many question the narrow choice of recommended products and the lack of recommendation of medical cannabis for the treatment of chronic pain ( The Pharmaceutical Journal , 2019 ). Despite the lack of scientific evidence in many cases, there is significant patient demand for access to medical cannabis.

Definitions

There is often confusion about what exactly is cannabis, cannabinoid or tetrahydrocannabinol (THC), as well as the different formulations available. It is important to distinguish between cannabidiol (CBD; not a controlled drug in the UK) and CBD plus THC to ensure a clear understanding of the distinctions in active ingredients and in formulations as these relate to specific applications. Freeman et al. (2019) provide a useful overview, highlighting that cannabis is not one medicine but rather a whole family of medicines. We focus on CBMPs as defined by The Misuse of Drugs (Amendments) (Cannabis and Licence Fees) (England, Wales and Scotland) Regulations ( 2018 ):

[A] cannabis-based product for medicinal use in humans means a preparation or other product. . . which a) is or contains cannabis, cannabis resin, cannabinol or a cannabinol derivative (not being dronabinol or its stereoisomers); (b) is produced for medicinal use in humans; and (c) is (i) a medicinal product, or (ii) a substance or preparation for use as an ingredient of, or in the production of an ingredient of, a medicinal product.

Current evidence of medical value

The previous status of cannabis in Schedule 1 before 2018 severely restricted scientific research in the UK, resulting in a lack of essential information on the health implications of medical cannabis. Despite extensive changes in global policy on medical cannabis, there is still little definite evidence regarding its short- and long-term health effects (both harms and benefits) contributing to the discord between scientific and patient-reported evidence.

Research studies

The 2017 review by NASEM (2017) provides a wide range of research conclusions on the health effects of cannabis and cannabinoids which are presented in Box 1 with recent additions by Drug Science (2019) . The scientific evidence (or lack thereof) is controversial, emphasising the need for further research in most areas.

Box 1: Current evidence of the medical value

This panel summarises findings by NASEM (2017) and is kept within the style of their seminal review.

There is substantial evidence that cannabis or cannabinoids are effective:

  • For the treatment of chronic pain in adults (cannabis)
  • As antiemetics in the treatment of chemotherapy-induced nausea and vomiting (oral cannabinoids, THC specifically)
  • For improving patient-reported multiple sclerosis spasticity symptoms (oral cannabinoids, equal amounts of THC and CBD specifically)
  • Epilepsy (cannabinoids, CBD specifically) ( Drug Science, 2019 )

There is moderate evidence that cannabis or cannabinoids are effective for:

  • Improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnoea syndrome, fibromyalgia, chronic pain and multiple sclerosis (cannabinoids, primarily THC)

There is limited evidence that cannabis or cannabinoids are effective for:

  • Increasing appetite and decreasing weight loss associated with HIV/AIDS (cannabis and oral cannabinoids)
  • Improving clinician-measured multiple sclerosis spasticity symptoms (oral cannabinoids)
  • Improving symptoms of Tourette syndrome (THC capsules)
  • Improving anxiety symptoms, as assessed by a public speaking test, in individuals with social anxiety disorders (cannabidiol)
  • Improving symptoms of posttraumatic stress disorder (nabilone; a single, small fair-quality trial) and schizophrenia (cannabidiol add-on to current medications) and attention deficit hyperactivity disorder (ADHD) (nabiximols; one small-scale trial)
  • Reducing cravings and anxiety for people with opioid use disorder (cannabidiol)
  • Better outcomes (i.e. mortality, disability) after a traumatic brain injury or intracranial haemorrhage

Focusing on the effectiveness of cannabinoids in the treatment of psychiatric conditions, including depression, ADHD, Tourette’s syndrome, post-traumatic stress disorder (PTSD), psychosis and anxiety, a recent meta-analysis found the evidence to be limited and of a low standard, concluding that a prescription for mental health treatments cannot be justified ( Black et al., 2019 ). However, in that study the main focus was on pharmaceutical cannabinoids, rather than plant-derived medical cannabis for which the therapeutic potential may differ widely, and is broadly used in the USA, Canada and Germany.

Patient-reported evidence

Notwithstanding the lack of evidence in many cases, people are using medical cannabis for a broad variety of conditions, including many mental health indications. A survey by the United Patients Alliance (UPA; 2018 ), a UK patient-led medical cannabis support group, found that indications range from (in order of self-reported use) pain, depression, anxiety, insomnia, arthritis, fibromyalgia, muscle spasms, irritable bowel syndrome and migraines to headaches and more.

These findings were largely replicated with a representative sample, drawing attention to patient-reported outcomes (PROs). PROs emphasise the patient’s wellbeing and have been shown to be more sensitive to the effects of medical cannabis than traditional symptom-based measures. For example, a large recent naturalistic study on pain syndromes using PROs found adding a CBMP to ongoing medication significantly improved outcomes in patients with neuropathic pain ( Ueberall et al., 2019 ). Further real-world benefits from CBMPs using patient reports have been reported for Parkinson’s disease ( Balash et al., 2017 ), autism (Bar-Lev Schleider et al., 2019), pain, depression, and anxiety symptoms ( Gulbransen et al., 2020 ). Many patients experience therapeutic satisfaction when using medical cannabis and report improvements in or relief of a range of symptoms ( Gulbransen et al., 2020 ; Stith et al., 2018 ; Sexton et al., 2016 ). Others report using cannabis as an alternative to pharmaceutical prescriptions ( Sith et al., 2018 ) and this can lead to reduced use of opioids for example ( Ueberall et al., 2019 ). Many of these also report that the medical cannabis improves their quality of life ( Bar-Leve Schleider et al., 2019 ; Gulbransen et al., 2020 ; Sith et al., 2018 ).

Current barriers to prescribing

In the UK, despite the change in legislation there is ongoing controversy surrounding prescriptions. Medical cannabis is atypical in that its medical use preceded the demonstration of its efficacy in clinical trials, generally required for the marketing of modern pharmaceuticals D’Souza, 2019 ). Whilst on the one hand, there is strong patient demand for access to medical cannabis to treat chronic illnesses for which there are very few effective treatment alternatives, on the other hand there is only a limited placebo-controlled evidence base on whether and how to use cannabis for many of these conditions. Potential prescribers face a wide range of challenges, particularly as in the UK medical cannabis is regulated as an unlicensed medicine.

Lack of education

Doctors lack the knowledge of cannabis medicines to have the confidence to prescribe, especially off-license: they have not been trained in prescribing them and may not know the dosage etc. This barrier can be overcome by developing an educational programme, e.g. by Health Education England. A priority should be to provide a range of good quality teaching programmes. The Academy of Medical Cannabis ( http://taomc.org ) provides a free 12-module programme on the basics of cannabis which has now been used by about 1000 doctors. Drug Science launched a similar online resource ( https://mymedic.org.uk/ ), arranged a series of seminars for health-care professionals (HCPs), and developed a teaching module for medical students ( https://drugscience.org.uk/medical-cannabis-education-hub/ ). Further developments should include a diverse range of other teaching possibilities, especially accredited certificate course programmes.

Restrictive guidelines

In addition to the NICE guidelines, doctors are influenced by the guidelines produced by the Royal College of Physicians (2018) (for pain and nausea) and by the British Paediatric Neurology Association (2018) (for childhood epilepsy), which recommend the prescription of medical cannabis only as a last resort when conventional treatment has not been effective. In contrast, the Medical Cannabis Clinicians Society (MCCS) offer more balanced guidelines, proposing that for chronic pain for instance, cannabis medicine could be considered instead of opioids ( MCCS, 2019 ). The British Pain Society (2019) recently released a revised position statement considering the potential role of medical cannabis in pain management, while at the same time continuing to highlight the need for further high quality research, clinical surveillance and patient monitoring. By reference to all these guidelines a physician can now make a more informed decision on prescription in the best interests of their patient.

Fear of adverse effects, especially psychosis and dependence

Concerns about adverse mental health effects, especially psychosis and dependence, have been expressed ( Di Forti et al., 2009 ) but the recent data suggest that these are mainly the result of using street ‘skunk’ with high levels (>10%) of d9THC and negligible levels of CBD ( Di Forti et al., 2019 ). The large-scale database by Health Canada shows very few, if any, cases of psychosis with medicinal use. Surveys of people using medical cannabis revealed some patients with schizophrenia are using it to treat their symptoms and there are several studies providing experimental support for this application ( Leweke et al., 2012 ; McGuire et al., 2018 ).

Similarly, whilst the risk of dependence is around 9% for recreational users of street cannabis, it is more common with high potency THC strains with a low CBD content, large ‘doses’, high frequency use (heavy, daily) and starting use in adolescence ( Curran et al., 2016 ). Risk of dependence can therefore be mitigated with these factors in mind by giving harm-reduction advice. The Canadian database reveals that only about half of patients initiated on medical cannabis continue beyond six months, suggesting dependence liability is low. Moreover, the very easy access to street cannabis further argues that medical cannabis is unlikely to be sought for recreational purposes.

Still, regulations should mitigate against adolescent uptake and against the availability of high potency THC products lacking CBD. Additionally, in light of the recent outbreak in the USA of respiratory illness, including linked fatalities, associated with the vaping of black market (THC) cannabis oils ( Centres for Disease Control and Prevention (CDC), 2019 ), it is vital to further communicate with the public about related risks and to more effectively regulate products and routes of administration in order to limit illicit products.

It is a serious shortcoming of current research that adverse effects of cannabis have largely been studied in relation to recreational (i.e. non-medical) use, rather than medical use. This is complicated by recent findings indicating that a large proportion of medical cannabis users also report recreational use ( Han et al., 2018 ). Drug Science is currently reviewing existing research to discern if, how, and to what extent, adverse effects apply to prescribed medical use.

The cost of medical cannabis in the UK is currently high. Some families are forced to pay for private prescriptions, costing up to £40,000 a year, after their National Health Service (NHS) clinicians do not prescribe it ( Wickware, 2019 ). Yet medical cannabis is potentially cheap – saving money on conventional treatments as well as on opioid prescription costs ( Boehnke et al., 2016 ), anxiety prescriptions ( Baron et al., 2018 ) and hospital admissions, for example, epilepsy ( Bellnier et al., 2018 ). Medical cannabis could work out well economically, and a full health economics analysis is vital for conditions for which clinical efficacy has been shown.

Importation and supply chain issues

The high cost of private prescriptions is related to the import challenges of medical cannabis. It is difficult to get access to the right products in a timely manner. Licensing and imports generally are for one patient for one month at a time as bulk import is still limited ( Barnes, 2019 ). However, in March 2020, these restrictions were loosened and the UK government is now allowing bulk, non-patient specific, importation which should improve delivery time to the patient and begin to bring down costs. Current UK standards of regulation as well as of practice need to be fully developed and regularly revised, as is done, for example, by the Royal College of Physicians and Surgeons in Alberta/Canada in their ‘advice to the profession’ ( http://www.cpsa.ca/wp-content/uploads/2018/05/AP_Cannabis-for-Medical-Purposes.pdf ).

Ethical issues

The discordance between patient reports and prescribers’ confidence and reliance on clinical trial data supports the developing view that randomised controlled trials (RCTs) are not the only way to assess the efficacy of a spectrum of medical products that have subtly different effects and individual responses ( Barnes, 2018 ). Taking into account other evidence, such as observational trials, ‘experimental medicine’ studies and audits of patients already using the medicine would help to maximise research and patient benefit. Individual cases could be taken into account to build up to a pattern of evidence (indeed, in the case of childhood epilepsy, just two of these effectively changed UK law).

The concern that by using a broader evidence base for medical cannabis would lead to a lowering of scientific standards generally is understandable but misplaced. CBMPs are not the only medicine whereby non-RCT evidence was included – there are over 50 medicines or indications that have been licensed by FDA and/or EMA between 1999–2014 without RCT data ( Hatswell et al., 2016 ).

To include more ‘qualitative’ evidence is not to diminish the value of RCTs but rather to complement them and to serve as a precursor to later studies. If there is a sole focus on RCTs, it will take many years for results to be available and many disorders may never be studied – yet patients could benefit from the medicine now, making it essential to evaluate harm minimization against patient need.

Balancing patient need and potential for harm

Many patients who request cannabis have not responded to standard treatments and are desperate to find something that helps ease their symptoms. In such cases, the fact that other treatments might be statistically more effective may not be relevant as a contra-indication to use of cannabinoids ( Stockings et al., 2018 ). Now that cannabis substances have been legalised for medical uses, it is the duty of clinicians to assess the balance of legitimate patient need against potential harms as in any other area of medicine, particularly taking into account informed choice on behalf of the patient.

The ethical importance of autonomy interests in medical decision-making means that patients’ rights to information that enables them to properly weigh up potential goods and potential harms is paramount. When there is insufficient evidence and/or insufficient clinical understanding to adequately inform patients, patients are at risk of making bad decisions that can lead to harm. In the current context, most patients who use cannabis and their caregivers have decided to access cannabis without the benefit of clinical guidance or support. In so doing, patients are exercising autonomy and it would be excessively paternalistic to argue that such patients are intrinsically wrong in their actions. The desire for access to potentially beneficial treatments is certainly not wrong. Moreover, when a treatment is legally sanctioned by a national healthcare system for the application desired by the patient, then the patient has a right to access, within parameters. A healthcare system that legalises a treatment but then leaves patients to independently access and use those treatments because of a lack of evidence and clinical confidence, is arguably in danger of shirking its duty of care to vulnerable patients. At the same time, the challenges for prescribers have to be addressed as key gaps exist not only in the scientific evidence but also in the detailed information needed (but not yet available) about dosages, types, duration and formulations.

The development of the evidence base for medical cannabis needs to go hand in hand with the pursuit of clinicians’ education if the risk to patients of using cannabis from illicit sources is to be minimised. As evidence is being gathered, professional organisations must do what they can to educate clinicians. Given the problematics of clinical responsibility in an area where there is significant medical uncertainty and confusion ( Singh et al., 2017 ), the education process needs to engage explicitly with the ideal qualities of a practitioner. One such important quality is professional integrity, which may invite clinicians to acknowledge the limits of knowledge and confidence in this context, while still seeking to provide the best possible care and support for their patients. Physicians need to comply with the standards of practice, and develop a healthy physician-patient relationship, rather than simply being ‘prescribers employed by a cannabis clinic’. It is essential to develop the UK regulatory regime for medical cannabis so that it can allow for patient access while at the same time avoiding a ‘free for all’ scenario as in some US states ( Schlag, 2020 ).

Recommendations for best practice

Due to the scarcity of research, few clear and widely accepted standards exist to help guide patients and clinicians to make decisions of if, when and how to use cannabis safely and effectively. It is vital to develop strategies for best practice and ensure that global legislative changes are informed by neuroscience and public health.

Monitoring of prescriptions, patient outcomes and adverse effects

It is essential to monitor patient outcomes and adverse effects, as is already being done by Health Canada. In the UK, Drug Science launched Project Twenty21 in November 2019 to create Europe’s largest national medical cannabis database registry ( https://drugscience.org.uk/project-twenty21/ ). Continued monitoring and regulation can play a major role to mitigate risks and to collect and collate experimental and trial data. Efforts to collect valid ‘real world data’ in responsible and ethical ways need to be further improved. A ‘real world data’ approach, specifically promoting a digital solution to the multiple complexities of data, evidence, uses and formulations can offer a key resource. In the longer term, anonymous electronic patient records, such as Clinical Records Interactive Search (CRIS) can establish ‘real world’ data in large quantities.

When new compounds with misuse potential are licensed and deployed, the risks associated with misuse need to be mitigated so that patients are protected, but also so that the compound is not overused so widely that its use attracts stigma. A variety of elements to assure the safe use of such compounds can be instituted. In the UK, the packaging of opiates is to acquire warnings similar to those on cigarettes ( Gregory and Wheeler, 2019 ). In the USA, the use of Spravato, Janssen’s intranasal esketamine for depression, is conditional on patients confirming they understand the risks, and on doctors and pharmacies undergoing training ( Janssen Care Paths, 2019 ).

Registries, in which individual prescriptions or treatments are tracked, may offer a partial solution. At one end, the model of clozapine shows how a clear risk is mitigated by a pharmacist-operated algorithm based on a blood test result: no blood result, no dispensing. In some US and Australian jurisdictions, prescribers must check whether a patient is being prescribed an opiate elsewhere before writing the first prescription. In relation to medical cannabis, prescribers and regulators still need to develop and decide on the exact details of registry implementation.

Future progress – the next steps

Medical cannabis as a ‘last resort’ provision.

In the UK, medical cannabis at present is offered as a ‘last resort’, when other licensed medicines have been shown to be unsuccessful. It would be useful to develop a hierarchy of evidence to see where cannabis medicines sit, which likely would be indication-specific. However, this is a challenging task as cannabis is not one medicine but a whole family of medicines. They would come out poorly in a double-blind trial as, for example, in chronic pain some people might respond to a high CBD product, some to a high THC product and some to a product that combines both. As such, whilst the effect of a single cannabis product might lack statistical significance in a clinical trial, an analysis of different combinations of ‘cannabis’ could be statistically significant ( Namdar et al., 2019 ).

Comparing benefit-safety balances

Best-practice guidelines for prescribing medical cannabis could be informed by comparing its benefit-safety balance with those of drugs already in use. Multi-criteria decision analysis provides a well-demonstrated basis for making such comparisons based on available evidence and clinical practice ( Moore et al., 2017 ). For example, a multi-criteria decision analysis comparison of drugs for relapsing–remitting multiple sclerosis (RRMS) revealed very different benefit-safety profiles between drugs, which would enable prescribers to accurately select the most suitable drug for their patient ( Vermersch et al., 2019 ). Such an analysis could include options of alternative products, doses and timing in order to aid practitioners’ decision-making.

Coordinating a network for clinical studies

There is a need for collaboration between different stakeholders (including patients, prescribers, clinics and scientists), and to develop an overarching mechanism to convene different parties together. A network of clinical studies could report on clinical practice and monitor outcomes (both risks and benefits), to enable innovative use of medical cannabis with care, precaution and foresight. This network group could address particular diseases or more general controversies related to medical cannabis. All these concerns are part of society’s move towards increasingly personalised medicine.

Communicating with the public

The 2018 re-scheduling of medical cannabis has been rightly criticised by the public and media alike based on the misperception that these medicines would become freely available on the NHS. Public communication about medical cannabis needs to be much better. Whilst information is available on the NHS website for the public, communication efforts need to be increased. Accusing the public of not understanding is unhelpful and may lead to a lack of trust which is vital for the doctor-patient relationship. If a communication vacuum occurs, this will be filled by other interest groups, such as industry lobbying groups. Hereby, medical cannabis should not be presented as a panacea for all ailments – rather the public needs to understand that not all patients may benefit from the use of cannabis.

Conclusions

Today, medical cannabis policy and research is developing rapidly in line with shifting public attitudes. Yet the current UK procedures to access medical cannabis are not working. High hopes by patients have not been realised in practice.

The re-scheduling of cannabis from Schedule 1 to Schedule 2 should open up urgently needed research opportunities. For other drugs, research funding usually comes from the companies who will benefit financially, yet it remains to be seen if/what funding will be provided by the medical cannabis industry given the problems of patenting. Whilst awaiting RCTs, different methodologies can be applied to move the evidence base forward.

In addition to further scientific studies, the medical cannabis regulatory framework and its application in practice need to be clarified so that this framework can be responsive to patient need whilst adhering to medical practice and high ethical standards. Many questions remain unanswered: What medical cannabis products will be used exactly? How can governments permit the manufacturing and distribution of cannabis for medical purposes? Although these regulatory challenges highlight the complexity of decision-making about medical cannabis they have already been resolved in other jurisdictions, e.g. in the Netherlands.

Concerns by physicians when deciding if and how to prescribe medical cannabis need to be addressed. Because of concern about its recreational use and previous Schedule 1 status, there is still an emotional barrier to prescribing cannabis. It may take time to change doctors’ perceptions and to fill the knowledge gap. Hopefully, the various efforts to educate doctors and other HCPs will go some way in this task and the access to a standardised way of data collecting as in Project Twenty21 should help assuage prescribers’ anxieties. There is a need to maximise clinical research and patient benefit, in a safe, cautious and ethical manner, so that those patients for whom cannabis is shown to be effective can access it. We hope our discussion and outlines for future progress offer a contribution to this process.

Author contributions: AKS developed the initial draft, wrote the sections on definitions, scientific evidence, future progress and conclusions and compiled and revised all authors’ contributions. DJN wrote the introduction and revised the manuscript. HVC wrote the section on cannabis and mental health. IS contributed the ethical sections. RMS wrote the section on registries, MB on barriers to prescribing, LP on comparing benefit-safety balances, SB on how to aid prescribers and decision makers, RC and DB contributed further references and revised the manuscript. All authors reviewed and accepted the article before submission.

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AKS is head of research at the charity Drug Science. DJN is chair of Drug Science. MB is chief medical officer of ECH and Sol Global Investments, chair of the Medical Cannabis Clinicians Society, and director of Maple Tree Consultants. None are employed positions and MB would not benefit from broader prescription of cannabis in any role. All other authors declare no competing interests.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This article was produced with support from Drug Science (DrugScience.org.uk)

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    Background: The widespread use of artificial intelligence, such as ChatGPT (OpenAI), is transforming sectors, including health care, while separate advancements of the internet have enabled platforms such as China's DingXiangYuan to offer remote medical services. Objective: This study evaluates ChatGPT-4's responses against those of professional health care providers in telemedicine ...

  20. Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to

    The Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing - Clinical Research Department. Rodion Oseshnyuk. Medical Center "Eco-safety" Tatyana Soluyanova. Medical Center "Group of companies "MEDSI" JSC. Irina Shestakova. Medical Center "Group of companies "MEDSI" JSC. Adel Vafin. Medical Center "Group of companies ...

  21. Phase 3 trial of coronavir (favipiravir) in patients with mild to

    Favipiravir has demonstrated efficacy against the SARS-CoV-2 virus in several preliminary studies. This study aimed to evaluate the efficacy and safety of favipiravir for treatment of mild to moderate COVID-19 in outpatients and hospitalized patients. We conducted an open-label, randomized, active-c ….

  22. Medical Marijuana and Marijuana Legalization

    Abstract. State-level marijuana liberalization policies have been evolving for the past five decades, and yet the overall scientific evidence of the impact of these policies is widely believed to be inconclusive. In this review we summarize some of the key limitations of the studies evaluating the effects of decriminalization and medical ...

  23. Review of medical image recognition technologies to detect ...

    According to the analyzed papers, neural networks show higher specificity, accuracy and sensitivity than dermatologists. Neural networks are able to evaluate features that might be unavailable to the naked human eye. Despite that, we need more datasets to confirm those statements. Nowadays machine l …

  24. Department of Defense Announces Fiscal Year 2024 University Research

    The Army Research Office, Air Force Office of Scientific Research, and Office of Naval Research solicited Fiscal Year 2024 proposals in 25 topic areas of strategic importance to the Department.

  25. Therapeutic Benefits of Cannabis: A Patient Survey

    Whereas, 2) Cannabis has many well-known medical benefits (including efficacy for anorexia, nausea, vomiting, pain, muscle spasms, and glaucoma) and is currently recommended by thousands of physicians; and. Whereas 3) Cannabis has been used by millions of people for many centuries with no history of recorded fatalities and with no lethal dosage ...

  26. UK report reveals bias within medical tools and devices

    Last modified on Mon 11 Mar 2024 09.03 EDT. Minority ethnic people, women and people from deprived communities are at risk of poorer healthcare because of biases within medical tools and devices ...

  27. Medical cannabis in the UK: From principle to practice

    Background: In the UK, medical cannabis was approved in November 2018, leading many patients to believe that the medicine would now be available on the NHS. Yet, to date, there have been only 12 NHS prescriptions and less than 60 prescriptions in total. In marked contrast, a recent patient survey by the Centre for Medical Cannabis (Couch, 2020 ...