Medicinal cannabis
Cannabis is at once a plant with a long medicinal and pharmacopoeial history, a set of compounds that act on the body's endocannabinoid system, a handful of approved medicines made from or modelled on those compounds, and an unregulated retail market whose products no agency has approved. Keeping these apart takes the chemistry of the compounds and what they act on, the medicines approved in the United States and Europe, how far the evidence reaches for each indication and what the harms are, what the law allows and what a medicine needs to reach the European market, how the compounds are made, and what legal recreational use asked of public health messaging.
The plant
The term cannabis covers all plants of the genus Cannabis. The genus has three species that differ in chemical composition, Cannabis sativa, C indica and C ruderalis. The word marijuana refers to a cannabis plant, mostly of C sativa, that gives a "high", euphoric or psychoactive effect and is cultivated for recreational use, while hemp or industrial hemp is a non-psychoactive form that was grown for its stalks and seeds to make textile fibre, paper, ropes, sailcloth and cellulose for plastic, and was an important source of essential oils, fatty acids and protein for humans and animals. In 2023 Cannabis sativa L. was the sixth most important crop in the United States, and besides recreational and medicinal use it can be used to make clothing and nutrition products such as seed oil and protein powders.
History of medicinal use
Cannabis use has been documented since 4000 BC, with plants cultivated either for their fibres, so-called hemp, or for therapeutic purposes. The botanical form of cannabis is thought to have originated in parts of Western and Central Asia, where it was cultivated for thousands of years for spiritual, health and psychoactive effects, and texts from ancient Hindu, Greek and Chinese cultures attest to its successful use against a wide range of ailments. It was introduced to the United States in the colonial period and cultivated there until the turn of the twentieth century.
In the United States cannabis was used as a medicine through the nineteenth and early twentieth centuries and was added to the United States Pharmacopeia and National Formulary in 1850. In the late nineteenth and early twentieth centuries it was included in Western pharmacopoeias, such as the British and American ones, and several pharmaceutical companies marketed cannabis extracts or tinctures.
The use of cannabis in the United States came to a progressively rapid halt because of socioeconomic factors that led to the federal Marihuana Tax Act of 1937, which prohibited its possession and cultivation. Further regulation culminated in the federal Controlled Substances Act of 1970, which placed further limits on cannabis research, and in recent US memory cannabis is associated negatively with the psychedelic hippie movement of the 1960s and 1970s. Cannabis was excluded from the American pharmacopoeia in 1941 because different samples of the plant had highly variable effects and more effective medications, such as vaccines, aspirin and barbiturates, had been developed. Most European countries followed the US lead in 1971. A strong stigma around its use, associated with cultural, historical and political connotations, remained in 2018.
In the 1960s, while recreational use was soaring, the chemical structure of the main psychoactive ingredient, delta-9-tetrahydrocannabinol, was revealed, and the finding sparked new interest in the therapeutic effects of the plant's constituents and a spike in related publications. That spike was small beside the one that followed the discovery in 1988 of the endocannabinoid system, composed of specific receptors in the nervous system sensitive to cannabis components and a naturally occurring agonist, anandamide. The discovery of the human endocannabinoid system and its relation to the plant's compounds was a breakthrough in cannabis-related research.
Cannabinoids and other compounds
By 2018 more than 460 compounds had been identified in cannabis, and only a handful were considered of therapeutic interest. Cannabinoids are the major group of compounds in the plant, and they show various health benefits, such as anti-cancer, painkilling and muscle- and nerve-relaxing effects, while some of them are psychoactive. By 2018 about 104 phytocannabinoids, the cannabinoids of the plant, had been identified alongside terpenes, flavonoids and other compounds, and the most researched are delta-9-tetrahydrocannabinol, cannabidiol and cannabinol. Tetrahydrocannabinol and cannabidiol are the phytocannabinoids most relevant in medicine. These substances vary in composition with cannabis strain, soil, weather and cultivation methods, and different varieties of the plant have different absolute and relative concentrations of cannabidiol and tetrahydrocannabinol.
Tetrahydrocannabinol is responsible for most of the hallucinogenic or psychotropic effects of cannabis, and produces the "high" by binding and activating the cannabinoid type 1 (CB1) receptor. Cannabidiol has very weak affinity for the cannabinoid receptors; instead it influences intracellular neurotransmitter release and triggers chemical cascades believed to produce anti-inflammatory, analgesic, anxiolytic, antinausea and antiepileptic effects, without the "high", and it counteracts the psychoactive effect of tetrahydrocannabinol by reducing its anxiety and other negative effects. Cannabidiol is structurally related to tetrahydrocannabinol and is the main non-psychotropic constituent of Cannabis sativa.
Delta-9-tetrahydrocannabinol, isolated in 1964, is psychotropic, and cannabidiol, isolated in 1940, is not. Other cannabinoids are cannabidiolic acid, cannabigerol, cannabinol, cannabichromene and the tetrahydrocannabinolic acid derivatives tetrahydrocannabutol, tetrahydrocannabivarin and delta-8-tetrahydrocannabinol, and research in 2023 confirmed that only tetrahydrocannabinol, tetrahydrocannabivarin and tetrahydrocannabutol are psychotropic. Tetrahydrocannabinol and cannabidiol share a precursor, cannabigerolic acid, produced in the glandular trichomes, hair-like growths on the leaves, stems and flowers that secrete various secondary metabolites. The highest cannabidiol concentration is in the glandular trichomes of the flowers, which are used for cannabidiol isolation at industrial scale.
The endocannabinoid system
The endocannabinoid system is a signalling system present in all vertebrates with important regulatory functions: it plays a role in neural development, inflammation, appetite and metabolism, immune function, pain, memory, learning, the regulation of stress and emotions, psychiatric disease, reproduction and many other physiological and pathophysiological processes. Because of its importance in regulating homeostasis it has been described as an "eat, sleep, relax, forget, and protect" system. It consists of the cannabinoid receptors, their endogenous ligands anandamide and 2-arachidonoylglycerol, and the enzymes that metabolise them. CB1 receptors are the most abundant G-protein–coupled receptors in the body and densely populate brain cells and the nervous system, connective tissue, musculoskeletal cells and virtually every organ; CB2 receptors are concentrated in peripheral organs, especially on immune cells, and to a lesser extent in bone, liver and nerve cells.
Endocannabinoids are naturally occurring substances that exert cannabis-like effects by binding and activating the CB1 and CB2 receptors, and cannabinoids are compounds isolated from the cannabis plant that elicit responses in the human body. The endocannabinoid system uses a network of cannabis-like substances produced by the body, which interact with the cannabinoid receptors, influence neurotransmitter release and so produce physiological effects. Anandamide and 2-arachidonoylglycerol are synthesised in postsynaptic cells and diffuse backwards to cannabinoid receptors on the presynaptic side, where CB1 activity suppresses the release from intracellular vesicles of neurotransmitters such as dopamine, serotonin, glutamate, acetylcholine, GABA, D-aspartate and cholecystokinin. Endocannabinoids and cannabis compounds also affect non-cannabinoid receptors, including opioid, noradrenaline, serotonin and dopamine receptors. Within the system, cannabis effects are enhanced or suppressed by surrounding chemical compounds and metabolised by degrading enzymes, and on immune cells CB2 activation inhibits inflammatory cytokine production and cell migration, affecting the immune response. Dysregulation or deficiency of the system has been implicated in migraine, fibromyalgia, irritable bowel syndrome and possibly depression. These interactions produce various physiological and pathological responses, many of them still being studied in 2018.
Released from postsynaptic cells, endocannabinoids bind and activate CB1 receptors on presynaptic neurons in the brain and nervous system and so suppress neurotransmitter release from presynaptic vesicles, a modulation thought to produce physiological responses. The synthetic CB1 agonists dronabinol and nabilone bind and activate the same receptor. Cannabidiol influences CB1 receptors without binding or activating them, and may raise synaptic endocannabinoid levels, and so their physiological actions, by inhibiting their breakdown.
Approved cannabis-derived medicines
Until 2018 the FDA had approved only two drugs derived from cannabis, and both were chemically synthesised. Dronabinol, a synthetic form of tetrahydrocannabinol, was licensed in 1985 as an appetite stimulant for people with AIDS and as an antiemetic for patients receiving chemotherapy. Nabilone, a synthetic derivative of tetrahydrocannabinol, was also approved in 1985 but not marketed until 2006, and is indicated for chemotherapy-induced nausea and vomiting; further studies have revealed a potential for it to treat chronic pain, for example in multiple sclerosis. In 2018 both were approved by the FDA for chemotherapy-induced nausea and vomiting in patients who do not respond to conventional treatments, and dronabinol also for patients who have lost weight because of AIDS-related anorexia. In 2018 the FDA had also approved further formulations for inclusion in clinical trials.
Nabiximols (Sativex) is an extract of cannabis containing tetrahydrocannabinol and cannabidiol, which in 2018 was available in the UK and other Western countries for treating symptoms of multiple sclerosis and approved for the relief of muscle spasticity in multiple sclerosis in Europe, the United Kingdom and Canada, but not yet in the United States. It is a whole-plant extract of two strains of cannabis at a 1:1 ratio of cannabidiol to tetrahydrocannabinol, given as an oromucosal spray. Health Canada has approved it for the adjunct treatment of neuropathic pain in multiple sclerosis and of moderate to severe cancer pain resistant to the highest opioid doses, and the FDA has granted it fast-track designation for pain in advanced cancer and for spasticity in multiple sclerosis. Sativex, developed by Jazz Pharmaceuticals (GW Pharmaceuticals), is a herbal preparation whose standardised cannabis extract contains 27 mg/mL tetrahydrocannabinol and 25 mg/mL cannabidiol.
In June 2018 the FDA approved an oral solution of cannabidiol, the first drug containing a substance purified from cannabis. Clinical trials showed that cannabidiol reduces seizures in Dravet and Lennox-Gastaut syndromes, two rare forms of epilepsy affecting children and infants, and it was approved as the first treatment for Dravet syndrome and as a complementary treatment for Lennox-Gastaut syndrome. A 2018 account describes Epidiolex, an oral formulation of pure cannabidiol (more than 98% cannabidiol oil), as approved in the United Kingdom and undergoing last-phase clinical trials in the United States for rare and drug-resistant epilepsy syndromes.
In 2023 four cannabis-derived medicinal products were authorised for the European market:
| Brand name | Active compound(s) | Authorised in | Indication | Route of administration |
|---|---|---|---|---|
| Epidyolex | CBD | EU (not available in every country), US (named Epidiolex) | Lennox-Gastaut syndrome, Dravet syndrome, adjunctive therapy of seizures associated with tuberous sclerosis complex | Oral |
| Marinol (dronabinol) | (-)-trans-delta-9-tetrahydrocannabinol isolated from the plant | EU (not available in every country), US, Australia | Cancer treatment, AIDS, multiple sclerosis | Oral |
| Cesamet (nabilone) | Synthetic (-)-trans-delta-9-tetrahydrocannabinol | EU (not available in every country), US, Australia | Cancer treatment | Oral |
| Sativex (nabiximols) | Cannabis herbal preparation (extract of cannabis) (oil), THC and CBD | EU (not available in every country) | Multiple sclerosis | Oral |
As of 2023 the FDA had approved no medicine containing cannabis but had authorised a cannabis-derived substance, cannabidiol in Epidiolex, and synthetic cannabis substances, dronabinol in Marinol and Syndros and nabilone in Cesamet, and it supported cannabis-derived medicine only where the benefits greatly outweigh the risks. The table gives the dronabinol in Marinol as isolated from the plant, while the same source lists it among the synthetic cannabis substances the FDA authorised.
Evidence for each indication
The best-studied medicinal properties of cannabis include antiemetic, analgesic, anticonvulsant and antimigraine effects. In 2018 anecdotal evidence of the benefits of cannabis abounded, while clinical studies of them were very limited though steadily increasing, and many tested recreational cannabis in its commonest form, smoked. Smoking produces the fastest effect, as tetrahydrocannabinol reaches the brain within minutes, causing a euphoric or psychotropic effect; vaporisers deliver cannabis substances effectively while reducing lung irritation from smoke toxins and possible carcinogens. The National Academies of Sciences, Engineering, and Medicine's 2017 report on the health effects of cannabis and cannabinoids gave a consensus on the efficacy of cannabis in various medical conditions, and concluded with its highest strength of recommendation that cannabis or cannabinoids are effective in treating chronic pain and chemotherapy-induced nausea and in improving muscle spasticity in multiple sclerosis. Health Canada's information for health care professionals is an in-depth report on the medical benefits and side effects of cannabis, its modes of administration and dosing suggestions for the clinical setting. In 2018 many scientific societies and associations acknowledged the beneficial effects of cannabinoids on health.
One of the best-substantiated medical uses of cannabis is relieving chronic pain, including neuropathic pain and pain from rheumatoid arthritis or musculoskeletal conditions, cancer and chemotherapy, and multiple sclerosis. Endocannabinoids, cannabidiol and tetrahydrocannabinol all play a role in producing analgesia, yet the psychoactive effects of tetrahydrocannabinol limit its use, and questions remain about the proper type of cannabis, the dose, the route of administration and the side effects in chronic pain. The endocannabinoid system modulates motor function, tremor, spasticity and the neuroinflammatory response, and oral cannabis has shown efficacy in relieving patient-reported muscle spasticity in multiple sclerosis. CB1 receptors are found in the areas of the brain that control nausea and vomiting. The CB1-mediated suppression of glutamate and GABA suggests a role in seizure activity, but studies of cannabis in epilepsy had been inconclusive, with newer efficacy studies awaiting publication in 2018. For irritable bowel syndrome, Tourette syndrome, amyotrophic lateral sclerosis, Huntington and Parkinson diseases, dementia, glaucoma, addiction, anxiety, depression, sleep disorders, post-traumatic stress disorder, and schizophrenia and other psychoses, all commonly discussed in relation to medical cannabis, the clinical trial evidence is limited and medical cannabis is not warranted. There is evidence of benefit from medicinal cannabis for chronic pain and for the palliative care of terminally ill patients.
A 2018 review concluded that the beneficial effects of cannabis on chronic pain, nausea and vomiting, muscle spasticity and other conditions have been clearly demonstrated by evidence-based research and published in official reports. It holds that medical cannabis used under medical supervision has proven beneficial and safe in several conditions. The properties of cannabis have been extensively reported and increasingly studied, and more studies are needed.
Systematic reviews of randomised controlled trials by the presenters of a primary-care evidence podcast, presented in 2018, found medical cannabinoids promoted for a variety of conditions despite a lack of high-level research to support their use, and because of the quality of the evidence available they concentrated on pain, spasticity, nausea and vomiting, and adverse effects. They concluded that medical marijuana is not supported by the evidence, and recommended only very limited use of pharmaceutical cannabinoids in general: for palliative and end-of-life pain, neuropathic pain, chemotherapy-induced nausea and vomiting, and spasticity from multiple sclerosis or spinal cord injury, and almost never as first- or second-line treatment. Adverse events were significantly more frequent with cannabinoids than with placebo, and the presenters hold that because many studies enrolled patients with a history of cannabinoid use, the benefit may be exaggerated and the adverse events are almost certainly more frequent than the data suggest.
A systematic review of clinical trials of cannabis for therapeutic purposes reported in 2023 that most of them were performed in the United States, Brazil, Australia, the Netherlands, Israel, Switzerland and the UK. As of October 2023 the EU Clinical Trials Register listed 73 trials involving cannabis, 17 of them testing the efficacy of cannabidiol against pain, with cannabis use disorder, the effects and toxicity of tetrahydrocannabinol, cancer, multiple sclerosis, pain and fibromyalgia the commonest indications, and the Clinical Trials Information System listed six trials with cannabis. In 2023 ClinicalTrials.gov listed many interventional trials using cannabis, most commonly in depression, marijuana abuse, pain, cannabis dependence and multiple sclerosis. By 2023 several safety studies of Sativex had been conducted, especially for pain management in patients with cancer, and the latest studies did not show it superior to placebo.
Health associations' position statements on cannabis vary. In 2023 the American Psychiatric Association saw no benefit in treating psychiatric disorders with cannabis and opposed its use in children, adolescents and young adults up to the age of 25; the American Nurses Society regarded cannabis as beneficial only for patients who really need it and where the treatment has been proved effective; and the UK's National Health Service guidance on prescribing cannabis-derived products did not recommend medicinal use for chronic pain except in clinical trials. By 2023 psychotropic drugs had shown promising results in treating symptoms of mental health disorders and in pain management, and one author held that their potential to improve patients' wellbeing should not be neglected. If effective, psychotropics could be used to treat neurological diseases, especially in patients with recurring depression or with terminal cancer.
Cannabinoids and opioids
Cannabinoids mediate their analgesic effects through activation of CB1 receptors. Evidence suggests that cannabinoid receptors and mu opioid receptors overlap or co-locate in presynaptic membranes in the brain and spinal cord, sharing pathways that process pain stimuli and perception, and acute and chronic use of tetrahydrocannabinol has been shown to increase the release of endogenous opioids, the body's naturally occurring substances with opioid-like effects, and the expression of opioid precursor genes. Preclinical studies have shown that vaporised tetrahydrocannabinol-rich cannabis given with stable doses of opioids increases the potency of the opioids and enhances overall analgesia persistently. A possible cannabinoid–opioid synergy has been hypothesised that could allow lower opioid doses, an opioid-sparing effect that avoids the negative effects of opioids, especially tolerance and addiction, though more studies are needed. Tetrahydrocannabinol has been shown to modulate reward pathways and addictive drug-seeking behaviour, and cannabidiol to limit these actions; patients with substance use disorders often have anxiety, insomnia and pain that cannabidiol may relieve, suggesting a role for cannabidiol in treating addiction and in opioid-related behaviour. The 2018 review that sets out this evidence also calls the synergy between cannabis and opioids observed, raising the possibility of using cannabis to lower opioid doses and avoid their undesirable effects. It calls the association between cannabis and opioids, and the potentiation of opioid analgesia by cannabis, proven, and "a golden opportunity" to discontinue or reduce opioids in favour of safer cannabis.
Side effects and risks
Much of the information about the side effects of cannabis comes from studies of recreational smoked cannabis. Acute recreational use causes euphoria, relaxation, intensified ordinary sensory experience, short-term memory loss, impaired motor coordination and paranoia or psychosis, and chronic heavy users are at increased risk of addiction, cognitive impairment, psychiatric manifestations such as schizophrenia and depression, and chronic bronchitis. Recreational and medical cannabis should be avoided in patients with a history of psychiatric and personality disorders. A risk of overdose exists in patients taking different forms of cannabis together, such as vaporised cannabis with prescription cannabinoids or with edible forms such as teas and baked goods, and the combination of cannabis with alcohol or other depressant medications is contraindicated and should be avoided at all costs. The public in 2018 was divided between acknowledging the medicinal benefits of cannabis and concern over its side effects and unknown risks, given the lack of rigorous testing, product standardisation and purity levels.
In in vitro and animal studies, cannabidiol has shown anti-anxiety, anti-nausea, anti-arthritic, anti-inflammatory and immunomodulatory properties, preclinical studies have shown that it can work synergistically with anti-cancer agents and improve their efficacy, and toxicity studies have found it generally well tolerated except at very high doses. Tetrahydrocannabinol, by contrast, interferes with the regulation of cancer development, promoting cancer and inflammation; it carries a high risk of abuse in chronic therapy, and in animal studies it caused high mortality and reproductive atrophy and hyperplasia. The US Centers for Disease Control and Prevention reported that cannabis-induced disorder is most common in people who use cannabis in youth or adolescence and use it frequently.
Isolated compounds and whole-plant products
Given the controversy over smoked medicinal cannabis, the trend has been away from natural preparations of unknown content and potency and towards drugs developed from isolated components with verifiable composition, stability, dosage and pharmacology; when cannabidiol interacts with tetrahydrocannabinol, for instance, they produce variable outcomes. Smoking cannabis or whole-plant extracts carries a risk of pulmonary damage or dependence, among other adverse effects. Despite the evidence of benefit for chronic pain and palliative care, smoked cannabis is generally discouraged because of safety concerns, variable effects from preparation and interpersonal variability, and a lack of quality control.
The use of cannabidiol oil is also controversial. Its products have variable content of the active ingredient and are not approved by any regulatory agency, yet they have been used for epilepsy, cannabis dependence, epidermolysis bullosa, anxiety and insomnia, among other conditions.
Legal status
In 2018 medical cannabis was legal in 28 US states, the District of Columbia, Guam and Puerto Rico, whose laws define its sale and distribution, and 8 states had legalised both medical and recreational use. California was the first, with the Compassionate Use Act of 1996, which allowed patients and their caregivers to use cannabis for anorexia, cancer, AIDS, spasticity, chronic pain, arthritis, migraine, nausea and glaucoma. States that have legalised cannabis run marijuana programmes that allow certified physicians to recommend cannabis to eligible patients, who obtain it from dispensaries with a state-issued marijuana identification card. In 2018 physicians in clinics and hospitals were reluctant to prescribe cannabis because of federal restrictions and registration requirements, and medical cannabis was not reimbursed by private or government insurance, making it harder to access. State legislatures were improving patient access to medical cannabis through these structured programmes, and the regulation of cannabis was evolving at a fast pace.
The Controlled Substances Act, the Comprehensive Drug Abuse Prevention and Control Act enacted in 1970 and enforced by the Drug Enforcement Administration of the Department of Justice, controls the distribution of all depressant and stimulant drugs with potential for abuse and classifies substances and prescription drugs into schedules I to V in decreasing order of potential for abuse and dependence. It classifies tetrahydrocannabinols in schedule I, as having "no acceptable medicinal use" and "the highest potential of abuse and dependence", a major hurdle for scientists trying to obtain cannabis for study: it impedes federal funding, limits large-scale trials and imposes a complicated application process at state and federal levels. In 2018 only one agency could approve cannabis research, and only in the context of addiction, a source of bias that impedes other avenues of clinical research. Obtaining cannabis in the quantity, quality and purity research requires is also difficult. In 2018 medical cannabis research faced important legal, administrative and logistical barriers.
In 2023 some countries in Europe had legalised medicinal and scientific cannabis use while only tolerating recreational use. A German draft published in September 2023 would allow possession of 25 grams of cannabis and cultivation of up to three plants for individual purposes. In the Netherlands recreational use is very restricted, tolerated only in licensed coffee shops, which may sell only small quantities, less than five grams and no more than five plants, to residents. Medicinal use is allowed, with slight differences in regulatory requirements, in most EU countries, the UK and other countries. Travelling with psychotropics may be challenging but possible, depending on each country's requirements, most of which the International Narcotics Control Board publishes with the advice to contact the embassy or consulate of the country before travelling.
Regulation of cannabis-derived medicines in Europe
With the United States and Canada pioneering cannabis legalisation and therapeutic demand for cannabis products rising in Europe, the pressure to regulate cannabis products in Europe was rising in 2023. In 2023 research on psychotropics such as cannabinoids and psilocybin was gaining popularity worldwide and support from drug regulators, who recognise the unmet medical needs of patients with mental disorders and of patients with cancer who experience depression. Cannabinoids and psilocybin had shown promising results in preclinical studies and clinical trials, but the clinical evidence was scarce and the regulatory requirements strict because of the high potential for abuse, and Europe was falling behind the United States and Canada in regulating psychotropic substances.
The EMA has published guidance on cannabis-derived medicinal products, under which they are marketed no differently from other medicines: the marketing authorisation holder should comply with the definition of a medicinal product in Article 1(2) of Directive 2001/83/EC. The application is a Common Technical Document that must include the results of preclinical research and clinical trials. A herbal product that meets neither the well-established use requirements of Article 10a nor the traditional use requirements of Article 16a(1) must comply with the general requirements of a marketing authorisation application. In October 2022 the European Pharmacopoeia published monographs on Cannabis flos (flowers) and on cannabis extracts, to be published in Supplement 11.5 in January 2024 and to take effect from July 2024.
Psychotropic substances are regulated globally and at EU level to prevent abuse. The UN classifies them into four schedules, in the annex of the 1971 UN Convention on Psychotropic Substances, and EU regulations govern drug precursors. Plant extracts can be used in a clinical trial but must comply with the general requirements of the European Pharmacopoeia, national pharmacopoeias and the EMA's guidance, and any country can tighten the requirements further. In 2023 the EMA had published no therapeutic guideline on developing and authorising psychotropic substances, though the EMA and the FDA had published general guidelines on conducting clinical trials with them. Cannabis-derived medicinal products have the same conditions as every marketing authorisation application: the therapeutic benefits must outweigh the potential risks. In 2023 the European Federation of Pharmaceutical Industries and Associations had no position statement on cannabis-derived products or psilocybin, but acknowledged the importance of psychotropics in its August 2022 pipeline innovation review.
Through the International Council for Harmonisation, approval of cannabinoids in one country may lead to more widespread approval, so extraction or synthesis of molecules from the plant may lead to a new approach to medicinal cannabis. One 2023 article names the main challenges in using psychotropics as therapy as managing their side effects, carefully considering the patient population and regulating the setting in which they are used, such as a hospital or doctor's office, and holds that patient safety is the highest priority and can be ensured by regulatory guidance, risk mitigation and worldwide regulation to prevent the drug abuse of the 1960s. With so much contradictory scientific data, regulators, especially in Europe, were in 2023 delaying mandatory guidance on research with psychoactive substances and their marketing authorisation, while acknowledging the unmet medical needs and working towards solutions.
How cannabinoids are produced
Cannabinoids can be produced by direct extraction from plants, by chemical synthesis or in microbial cells by fermentation. The commonest way to produce cannabidiol industrially is to grow Cannabis sativa in greenhouses or outdoors and extract cannabidiol and tetrahydrocannabinol chemically, and in recent years CRISPR-Cas9 gene editing has enabled the industry to produce plants more resistant to climatic hazards and diseases, yielding more cannabinoids or more or less of specific metabolites. The industry claims that the main benefit of extraction is that it co-isolates terpenes and flavonoids at very low concentrations, which could improve the therapeutic effect. This entourage effect is defined as a synergistic cooperation of compounds in Cannabis sativa that increases its efficacy, but the regulatory and public data on it are scarce. Chemical synthesis of cannabinoids is less efficient than extraction.
Increased interest and investment in psychotropics means higher market demand. Traditional manufacturing by chemical synthesis and extraction works well, with minor downsides: impurities, racemic mixtures and highly expensive purification, and biotechnologists are looking for efficient ways to maximise production using the cellular metabolic pathways of various hosts. Research on psychotropics has created opportunities to develop new biotechnological methods, such as cell culture.
Microbial fermentation, developed for cannabinoids in 2019, produces a single compound in a single-celled organism such as yeast, bacteria or algae. Cannabis genes introduced into yeast (Saccharomyces cerevisiae) enabled it to metabolise sugars into cannabigerolic acid, the precursor of tetrahydrocannabinol and cannabidiol, though at low milligram and microgram yields. The yeast Pichia pastoris has produced the enzyme tetrahydrocannabinolic acid synthase, which converts cannabigerolic acid into tetrahydrocannabinolic acid, the precursor of tetrahydrocannabinol, and tetrahydrocannabinol production has been tested in other organisms such as E. coli, S. cerevisiae and K. phaff. Biosynthesis in algal chloroplasts is still at an early start-up stage because it has proven very expensive, as algae have thick cell walls that need complex and expensive techniques to break. Patents for cannabinoid biosynthesis by microbial fermentation had been filed by 2014, and the latest, from 2020 to October 2023, use yeast or bacteria to produce cannabinoids via the geranyl pyrophosphate pathway by introducing Cannabis sativa genes or enzymes, while two US companies have patented cannabinoid synthesis in microalgae. In one demonstrated method, yeast strains ferment sugars into cannabigerolic acid, and chemical techniques then yield pure tetrahydrocannabinol and cannabidiol. In 2023 biotechnological production of cannabinoids was still in its infancy.
Public health after recreational legalisation
Colorado voters approved a state constitutional amendment in 2012 that paved the way for the legal sale and use of marijuana by adults aged 21 and over. By 2016 one resident whom legalisation had not affected personally had seen new kinds of content in her local newspaper, such as articles on trends like "pot coffee" and advertisements for marijuana products. The Colorado Department of Public Health and Environment's Retail Marijuana Public Health Advisory Committee is a working group focused on understanding the science and developing messaging to the public and to health care providers.
Inside the health department, legalisation was a huge paradigm shift: overnight, marijuana went from being treated like all other illicit drugs to being dealt with in the public health realm of education, prevention and monitoring. A scientific advisory panel of professionals with expertise in cannabinoid physiology was assembled for the committee to review the scientific literature systematically, review public surveillance data, recommend public health policies and surveillance activities, and identify research gaps important to public health, with the goal of translating science into public health. The department monitors use patterns through population surveys and looks at trends after legalisation. The Healthy Kids Colorado Survey for 2005 to 2015 showed marijuana use by high-school-age adolescents relatively flat in Colorado and similar to the national average, and in the middle between the prevalence of alcohol and of tobacco use; despite their limitations, the chief of the department's epidemiology branch considered these data reliable indications of trends. Marijuana-related emergency department visits had increased since recreational legalisation, which all the 2016 panellists attributed at least in part to increased availability, and the increase in accidental exposure of young children was being addressed through public health education on proper storage at home and changes to packaging regulation.
By 2016 a family medicine team in Colorado had met unexpected patient attitudes to marijuana use during pregnancy and breastfeeding. A study after legalisation found 8% to 14% of pregnant women testing positive for marijuana, results then in review showed use by pregnant women increasing since legalisation, following the general trend of increased use with increased availability, and research was under way on use among breastfeeding women and their infants. According to a clinical pharmacist on that team, there are public health concerns about both recreational and medical use, and moderate evidence associates maternal use during pregnancy with negative effects on cognitive function and attention that may not appear until adolescence. In her view, counselling pregnant and breastfeeding women about cannabis requires key messages that communicate the potential risks appropriately, and determining appropriate use requires evaluating drug interactions and certain health conditions. Resources are available to help health care professionals and patients understand the benefits and risks of cannabis.
In 2016 an emergency physician and toxicologist in Colorado reported that cannabis products were much different from earlier ones, and that many edible products had been packaged to look like other sweets, so that children were bound to get into them. New labelling regulations use a uniform symbol to identify all products containing THC. He held that increased availability of any drug causes more emergency visits and hospitalisations, that marijuana has had a number of negative unintended consequences, and that the risks of use must be communicated consistently, especially for edible products. Emergency departments were seeing disproportionate risk from edible ingestion compared with other forms of use. One syndrome associated with marijuana use is cannabinoid hyperemesis: THC seems to be a potent antiemetic at lower doses, but chronic use at higher concentrations is associated with a cyclic vomiting syndrome that conventional therapies cannot always manage.
The 2016 panellists held that medical writers can play a major role in getting messages out and should avoid overinterpreting data and err on the side of safety, and that on a politically polarising topic staying close to the facts is important. The emergency physician also recommended involving collaborators with a stake in the repercussions, people in the cannabis industry, with whom he had had very productive interactions. Article topics he suggested for writers include pesticide use, the financial implications for patients using cannabis for medical indications, effectiveness and safety for specific conditions, use as an over-the-counter therapeutic, and the effect of public health educational interventions. More information was becoming available every day, writers can get it from front-line health care providers, public health officials and the literature, and the department's online resources are a great place to learn about the topic. The state government's Good to Know initiative provides information for the public, and the advisory committee publishes its own information.
Public comments to the FDA on cannabis products
The legal status of cannabis continues to evolve, raising challenges for medical writers in population health and drug safety, and research on how the public perceives cannabis, to guide messaging, has often relied on surveys or on "big data" analyses of social media, which can be costly. In the United States the legal cannabis industry may exceed $43 billion in sales by mid-decade, in the decade to 2023 the share of adults opposing legalisation fell from 52% to 32%, and in 2023 9 in 10 adults supported legalising cannabis for medical or recreational use, raising numerous questions for public health. The FDA held a hearing on 31 May 2019 to "obtain scientific data and information about the safety, manufacturing, product quality, marketing, labeling, and sale of products containing cannabis or cannabis-derived compounds", and the discussion continued in the comments posted to its docket, 2019-N-1482, which are broadly accessible except for proprietary and other sensitive information. The docket held 4,300 comments by January 2021, and commenters could choose whether to give a geolocation and a demographic category.
A content analysis of the comments suggests that the commenters were less concerned with cannabis in the abstract than with specific products and symptoms, above all cannabidiol and hemp and the treatment of pain, anxiety and sleep problems. Of the ten themes it found, the commonest was cannabidiol (10,954 occurrences), its concept co-occurring with oil, use, take, helped, relief, milligrams, daily, doctor and dose, followed by pain (8,138), co-occurring with chronic, anxiety, life, sleep, work and arthritis among others, and then medical, products (co-occurring with hemp, consumer, testing, benefits, supplement and extract among others), health, cannabis, drug, time, marijuana and months. On sentiment scores normalised between −1.0 and 1.0, the comments had a mean subjectivity of 0.418 and a mean polarity of 0.121. The polarity suggests that commenters generally held neutral or favourable views of cannabis, which needs confirming, and the subjectivity that they tended to express personal feelings, opinions and preferences; whether FDA officials will consider these "sound grounds" for decisions is unknown. Only 467 commenters, 10.9% of the comments, chose a demographic category; more than half of these were other organisations (157) or associations (103), slightly less than a fifth were individual consumers (81), and 8 were health professionals. Slightly more than two-fifths of the comments (1,821) were geolocated, from all 50 states, the District of Columbia and six other countries, and about a third of the geolocated ones came from California, Texas, Florida, Missouri and New York. Because most comments were not geolocated, their representativeness cannot be determined, and they may not represent public opinion on cannabis at large.
The findings suggest that broad messaging on cannabis may have limited effectiveness, and that messages about the risks of particular products, or expressing empathy for consumers with particular symptoms or conditions, may be more effective. "Use" and "take" appeared frequently, which fits the large share of self-identified commenters who were individual consumers; at first glance "take" may be more associated with health and medical discourse and "use" with illicit or recreational activity, so future messages should vary the two verbs deliberately so that their effects can be evaluated. "Cannabis" co-occurred with concepts that seem regulatory and scientific, such as safety, public, regulations, compounds, industry, cannabinoids and data, while "marijuana" may have a more legalistic or punitive orientation, co-occurring with substance, law and money, so medical writers should use the two terms intentionally, considering the implications of each; though common in everyday speech, "marijuana" may carry more stigma. Future research should segment drug consumers further, demographically and psychographically, which could inform messaging, regulatory communication and state drug policy.