Medicinal use of cannabis based products and cannabinoids.

Cannabis based products for medicinal use contain cannabinoids derived from the cannabis plant, including ∆9-tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of THC and CBD. Synthetic cannabinoids for medicinal use typically mimic the effects of specific cannabinoids such as THC

THC is the constituent of cannabis that causes the “high,” whereas CBD is not intoxicating at typical doses. THC and CBD have contrasting mechanisms of action and therapeutic indications; THC carries a higher risk of adverse events compared with CBD

Rescheduling on 1 November 2018 permits some unlicensed cannabis based products to be prescribed for the first time in the UK, but only by doctors on the relevant Specialist Register of the General Medical Council

Indications for treatment, supported by evidence of low to moderate certainty, include chronic pain, some treatment resistant epilepsies, and nausea and vomiting caused by chemotherapy (table 2)

Table 2

Summary of evidence for medicinal use of cannabis based products and cannabinoids.

Indication	Number of studies (participants)	Primary products tested	Comparator	Outcome	Summary estimate (95% confidence interval)	GRADE certainty rating
Chronic pain23	9 (1734)	Sativex (THC+CBD)	Placebo	30% reduction in pain	Odds ratio: 1.46 (1.16 to 1.84).More effective than placebo	⨁⨁⨁◯ Moderate
Multiple sclerosis11	5 (1244)	Sativex (THC+CBD)	Placebo	Ashworth spasticity scale	Weighted mean difference:−0.12 (−0.24 to 0.01).Not more effective than placebo	⨁⨁⨁◯ Moderate
Treatment resistant epilepsy24	2 (291)	Epidiolex (CBD)	Placebo	50% reduction in seizure frequency	Relative risk:1.74 (1.24 to 2.43).More effective than placebo	⨁⨁◯◯Low
Nausea and vomiting due to chemotherapy11	3 (102)	Dronabinol (THC)	Placebo	Complete response in nausea and vomiting	Odds ratio: 3.82 (1.55 to 9.42).More effective than placebo	⨁⨁◯◯Low

Grading of recommendations, assessment, development, and evaluations (GRADE)25

⨁⨁⨁⨁ High, the authors have a lot of confidence that the true effect is similar to the estimated effect

⨁⨁⨁◯ Moderate, the authors believe that the true effect is probably close to the estimated effect

⨁⨁◯◯ Low, the true effect might be markedly different from the estimated effect

⨁◯◯◯ Very low, the true effect is probably markedly different from the estimated effect

Non-medicinal CBD products are legal and widely available on the internet and from health food retailers, but they lack quality standards and should not be used for medicinal purposes

Until recently, cannabis and its derivatives were widely restricted under legislation which stated they had no medical value and carried a substantial risk of misuse. Policy is rapidly changing, and cannabis can now be prescribed for medicinal use in many countries, including the UK. This provides important new opportunities for treating patients although these need to be weighed up against potential risks. Several different medicinal products exist, with contrasting mechanisms of action, efficacy, and safety. Use of these products may increase as new evidence arises and policy changes occur. Here we review this emerging field.

What are the latest developments in regulation, in the UK and internationally?

In the UK, drugs perceived by policy makers to have no medical value and a high risk of misuse, such as MDMA (3,4-methylenedioxy-methamphetamine, common street name “ecstasy”) are placed in Schedule 1 of the Misuse of Drugs Regulations 2001. These drugs cannot be prescribed, and research can only be conducted under a Home Office licence.

On 1 November 2018, unlicensed cannabis based products were moved from Schedule 1 to Schedule 2 in the UK, enabling them to be prescribed for the first time.1 This amendment of UK legislation affected some but not all products, as some were already listed in Schedule 2 or 4 (table 1). Non-medicinal synthetic cannabinoids (which are found in products such as “Spice”) were not rescheduled and remain in Schedule 1. Cannabidiol (CBD) has minimal risk of misuse5 and was never scheduled in the UK.

Table 1

An overview of cannabis based products and cannabinoids

	Medicinal products						Non-medicinal products
	Cannabis based products for medicinal use				Synthetic cannabinoids for medicinal use		Non-medicinal CBD products	Non-medicinal cannabis	Non-medicinal synthetic cannabinoids
Example	Bedrocan	Tilray	Sativex	Epidiolex	Dronabinol	Nabilone	CBD oil2	White Widow3	Spice4
Cannabinoid profile	THC +/−CBD	THC +/−CBD	THC:CBD ratio 1:1	CBD	THC	THC	High CBD, low THC	High THC, low CBD	Synthetic cannabinoid receptor agonists
Formulation	Herbal cannabis	Oil	Oromucosal spray	Oral solution	Capsule or liquid	Capsule	Varied; capsule and oil	Varied; herbal cannabis	Herbal, liquid, or powder
Licensed indications (UK)	None	None	Multiple sclerosis	None	None	Chemotherapy induced nausea and vomiting	Not medicinal products
Quality standards	Good manufacturing practice	Good manufacturing practice	Good manufacturing practice	Good manufacturing practice	Good manufacturing practice	Good manufacturing practice	No quality assurance
Affected by rescheduling (UK) on 1 November 2018?	Yes	Yes	No	No	No	No	No	No	No
Pre-amendment Schedule (UK)	1	1	4	Not scheduled	2	2	Not scheduled (if THC does not exceed 0.2%)	1	1
Post-amendment Schedule (UK)	2	2	4	Not scheduled	2	2	Not scheduled (if THC does not exceed 0.2%)	1	1
Can be prescribed in the UK?	Doctors on General Medical Council specialist register; named patient basis	Doctors on General Medical Council specialist register; named patient basis	Specialist doctors with expertise in treating multiple sclerosis	No restrictions on prescribing; named patient basis. Likely to be a specialist prescribing due to the proposed indications	No restrictions on prescribing; named patient basis	No restrictions on prescribing. Preferably administered in a hospital setting. GPs may prescribe once treatment initiated	No	No	No

At the time of writing, in the US cannabis is available for medicinal use in 33 US states and for non-medicinal use in 10 US states, although both remain illegal under federal law. Other recent developments include the legalisation of cannabis for non-medicinal use in Canada on 17 October 2018. The World Health Organization has proposed that cannabis should be rescheduled within international law because of growing evidence of its medicinal applications.6

What types of product are available and where?

The cannabis plant can produce at least 144 naturally occurring compounds known as cannabinoids.7 The most widely researched cannabinoids are ∆9-tetrahydrocannabinol (THC) and CBD. THC is the primary constituent of cannabis that causes the “high” whereas CBD is not intoxicating at typical doses. Several different products exist for medicinal use and these differ in THC/CBD profile, formulation, licensed indications, and conditions for prescribing (table 1). See the glossary of terms (box 1) for accepted definitions.

Cannabinoid—a drug that acts on the endocannabinoid system. The cannabis plant synthesises many cannabinoids such as THC and CBD

THC—∆9-tetrahydrocannabinol, a cannabinoid used for medicinal purposes and non-medicinally for its intoxicating effects

CBD—cannabidiol, a cannabinoid with contrasting mechanisms of action and therapeutic indications to THC. Not intoxicating at typical doses

Cannabis based products for medicinal use—medicinal products containing cannabis or cannabinoids derived from the cannabis plant (eg, THC and/or CBD)

Synthetic cannabinoids for medicinal use—medicinal products containing synthetically produced cannabinoids which typically mimic the effects of THC

Non-medicinal CBD products—products containing CBD that are widely sold as herbal remedies but are not regulated as medicinal products

Non-medicinal cannabis—material from the cannabis plant that is not regulated as a medicinal product, widely used for its intoxicating effects

Non-medicinal synthetic cannabinoids—synthetic cannabinoids that are not structurally related to naturally occurring cannabinoids and are not currently recognised for medicinal use (eg, synthetic cannabinoid receptor agonists, which are found in products such as “Spice”)

Cannabis based products for medicinal use

Cannabis based products that were previously listed in Schedule 1 can now be prescribed by doctors on the General Medical Council Specialist Register in the UK, on a named patient basis. Currently, general practitioners in the UK cannot prescribe them.

These products are not licensed for specific medical indications but are used off licence for medicinal purposes in many countries, and are certified for quality according to good manufacturing practice. Examples include herbal cannabis (floral material from the cannabis plant). The recommended route of administration is through a medical vapouriser device9 and smoking is currently prohibited under NHS guidance.10 Extracts from the cannabis plant (such as cannabis oils containing THC) are also available for oral administration.

Some cannabis based products were already available for medicinal use before rescheduling in 2018. Sativex, an oral spray derived from the cannabis plant containing THC and CBD in a 1:1 ratio, is licensed for the treatment of spasticity in multiple sclerosis in 29 countries, including the UK, Israel, Canada, Brazil, and Australia. However, meta-analysis suggests its effectiveness may be limited11 and it is not recommended by the UK’s National Institute for Health and Care Excellence (NICE) because of poor cost effectiveness.12 Epidiolex, an oral CBD solution derived from the cannabis plant, was licensed by the US Food and Drug Administration in June 2018 for the treatment of seizures in two rare and severe forms of childhood epilepsy—Lennox-Gastaut syndrome and Dravet syndrome. At the time of writing, an application for the same indication is under review by the European Medicines Agency, and it can currently be prescribed on a named patient basis in the UK.

Synthetic cannabinoids for medicinal use

Dronabinol and nabilone are synthetically produced medicinal products that mimic the effects of THC. Dronabinol has an identical structure to THC, while nabilone has a related structure and is more potent than dronabinol, requiring lower doses to achieve clinical efficacy. Countries including the US, the Netherlands, Germany, Austria, and Croatia have licensed the use of both products. They are licensed for the treatment of weight loss in patients with AIDS and of nausea and vomiting in people receiving chemotherapy who have failed to respond adequately to conventional anti-emetics. Nabilone is licensed in the UK while dronabinol is not licensed but can be prescribed on a named patient basis.

Non-medicinal products

CBD products are also widely available in health food shops and on the internet in the UK and elsewhere (fig 1) and are not scheduled or regulated as medicines. Their THC or psychoactive content is legally controlled not to exceed 0.2% in the EU.8 As with other herbal remedies, the declared contents of non-medicinal CBD preparations is variable, and often inaccurate,2 13 and these products sometimes exceed the legal limit of THC.13 Moreover, the amount of CBD in these products is typically far lower14 15 than in clinical trials16 (eg, 25 mg in a non-medicinal product versus 150-1500 mg/day in clinical trials). Advise patients that these widely available CBD products lack quality assurance and should not be treated as medicines.

Fig 1

Non medicinal CBD products are widely available

Other products include non-medicinal cannabis and non-medicinal synthetic cannabinoids, which are both currently illegal in the UK.

Why and how are cannabis based products and cannabinoids therapeutic (or harmful)?

THC and CBD have contrasting mechanisms of action on the endocannabinoid system,17 18 which is widely expressed in the mammalian central and peripheral nervous systems. These actions may account for their therapeutic effects. For example, CBD increased plasma endocannabinoid levels in a clinical trial in schizophrenia, which correlated with the degree of symptom improvement.19 When taken together with THC, CBD may offset some of the adverse effects of THC, such as memory impairment and paranoia.20 21 Therefore, the balance of THC and CBD may contribute to safety as well as therapeutic effects. CBD has an excellent safety profile and is well tolerated, even at high doses.22 THC carries an increased risk of adverse events (including serious adverse events). In a systematic review and meta-analysis, cannabinoids (primarily THC) were associated with a fivefold increase in rates of disorientation and dizziness, compared with placebo or active comparators.11

What is the evidence underpinning medicinal use of cannabis based products and cannabinoids?

Table 2 summarises evidence from systematic reviews of cannabis based products and cannabinoids for the treatment of chronic pain, multiple sclerosis, treatment resistant epilepsy, and nausea and vomiting associated with chemotherapy.11 23 24 There is less available evidence to estimate the effectiveness of these products for other indications, such as appetite and weight loss associated with HIV/AIDS, Tourette syndrome, anxiety, post-traumatic stress disorder, and schizophrenia.11 26 27

The limited number of randomised trials for unlicensed cannabis based products is partly attributable to the regulatory challenges of conducting research on drugs in Schedule 1.28 Removing these barriers is an important benefit of rescheduling, which should lead to a stronger evidence base to guide clinical decision making. At the time of writing, the UK National Institute for Health Research (NIHR) has pledged dedicated funding and has called for grant proposals to investigate cannabis based products for medicinal use.

Limitations of current evidence include the inappropriate handling of withdrawals from treatment, selective reporting of outcomes, and inadequate descriptions of randomisation, allocation concealment, and blinding.11 Heterogeneity in the types of product tested, including differences in pharmacokinetics and the balance of THC and CBD content, makes it difficult to establish optimal therapeutic formulations and dosing regimens. More larger and rigorous clinical trials are needed, including further exploration of dose-response and interactions with other medicines.27 For example, both nabilone (THC) and epidiolex (CBD) may increase the effects of central nervous system depressants such as alcohol.29 30 Epidiolex is metabolised by cytochrome P450 enzymes and may increase the risk of adverse effects from other medicines metabolised by this pathway, such as clobazam and valproate.29

Consider

Is this indication supported by evidence from randomised clinical trials? (table 2)

What is the cannabinoid profile of the medicinal product being requested (THC, CBD, THC+CBD?)

Is this medicinal product available, and who can prescribe it? (table 1)

Might this medicinal product interact with other prescribed drugs?

Are specific considerations necessary for young people, children and babies, older people, people with mental health problems, people with a learning disability, pregnant women, and women who are breastfeeding?

If a prescription is not offered, might this patient seek or use a non-medicinal product lacking safety and quality assurance?

How should doctors manage requests for cannabis based products and cannabinoids? (box 2)

Guidelines are currently being prepared by NICE, which will initially focus on the indications listed in table 2. Interim guidance from England’s Chief Medical Officer states that unlicensed cannabis based products can only be prescribed by doctors on the General Medical Council Specialist Register.10 The same guidance also stipulates that doctors should prescribe products only for disorders within their specialty; when there is clear published evidence or UK guidelines to support treatment; when clinical need cannot be met by a licensed medicine; and when established treatment options have been exhausted. Additional guidance has been provided by the Royal College of General Practitioners31 and NHS England.32

Within this framework, specialists in the UK will need authorisation from their medical director and agreement from the multidisciplinary team, using existing protocols on controlled drugs. Therefore, use of unlicensed cannabis based products in the UK may be limited initially, even in specialist settings. Active, compassionate, and fully informed engagement with patients requesting treatment remains important, and questions to consider are given in box 2. As this is a rapidly evolving field, seek confirmation from the relevant statutory authorities before changing practice.

To what extent might it be stigmatising for a patient to request and use a cannabis based product, and how can this be managed?

Are patients fully aware of the difference between medicinal and non-medicinal products, their legal status, and the risk of harm or prosecution associated with them?

How can I record and share information from my practice on requests for, uses of, and responses to cannabis based products to ensure that future regulations and guidance better meet the needs of patients?

We used the most up to date and relevant information available to us from systematic reviews, meta-analyses, and key clinical trials. Summary statistics and grading of evidence were obtained from systematic reviews for indications included in forthcoming NICE guidelines. We referred to NICE, the Department for Health & Social Care, NHS England, the UK Home Office, and the Advisory Council for the Misuse of Drugs (ACMD). We discussed our article with clinicians, researchers, and patients.

We discussed our article with patients who had health conditions for which there is evidence that cannabis based products or cannabinoids may be effective. We conducted interviews with them asking what they thought would be helpful for patients and clinicians to learn from this article. We showed them drafts of this article and invited them to provide feedback which was incorporated into subsequent versions of the article. On the basis of this feedback, we adapted the structure of the article such that recent policy developments were presented first. We expanded our discussion of the differences between medicinal products and health food supplements, and added a new table to provide an accessible overview of these different products. We highlighted that some patients may seek unlicensed or illegal products if they are unavailable on prescription, and that requesting cannabis based products from a doctor and using them could be stigmatising.