Understanding Unlicensed Cannabis-Based Products for Medicinal Use (U-CBPMs)
Unlicensed Cannabis-Based Products for Medicinal Use (U-CBPMs) are a legal category of medicine that was brought into existence in the UK on 1st November 2018. They are distinct from licensed cannabis pharmaceuticals. They are legal (but restricted and regulated).
Disclaimer
This article should not be considered medical advice or legal advice. It is intended for interest only. This article is also not intended to promote any unlicensed product for treatment, as only a doctor can legally do that. Every effort was made to ensure its accuracy as at July 2020 but things move fast in the cannabis industry, and I’m only human, so please forgive any errors and report them to me!
In this article…
In this article, we shall explore:
- What is a licensed medicine and whether a medicine needs to be licensed
- The benefits and limitations of randomized placebo-controlled double blind clinical trials
- The reasons an unlicensed medicine might be prescribed or taken
- The safety and efficacy of unlicensed drugs
- The availability of evidence for cannabis-based medicines as a medical treatment
What is a licensed medicine?
A licensed medicine is one that has successfully completed the marketing authorization process, during which the European Medicines Agency (EMA) (or its equivalent in countries outside Europe) weighs up the scientific evidence that the medicine:
- assists in the treatment of a particular condition (e.g. sore throat)
- when given to a particular demographic of patients (e.g. women aged 18–55 who are not pregnant)
- in a particular dose (e.g. 1 mg daily)
- in a particular preparation (e.g. tongue drops)
The marketing authorization is typically valid for five years but relatively easy to renew afterwards. A manufacturer may not advertise the drug for use in any purpose except exactly what is covered by its Marketing Authorization(s).
There are a small number of licensed cannabis-based pharmaceuticals on the UK market, including:
- Sativex, a mixture of cannabidiol (CBD) and tetrahydrocannabinol(THC) produced by GW Pharma, licensed in the treatment of Multiple Sclerosis (MS)-related spasticity when a person has shown inadequate response to other symptomatic treatments or found their side effects intolerable.
- Epidiolex, isolated CBD, also by GW Pharma, licensed to treat seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome in patients 2 years of age and older
Does a medicine have to be licensed to be prescribed?
No. A medicine does not need to be licensed for doctors to prescribe it. They can prescribe whatever they judge is in the best interest of the patient on the basis of available evidence, and they can consider many kinds of evidence when making such a decision.
If a doctor prescribes a licensed medicine for its licensed purpose, then the license holder (i.e. the drug manufacturer) can be held responsible for adverse reactions resulting from the use of the medicine. However, when prescribing and dispensing unlicensed medicines, there is no licence holder to take responsibility for adverse reactions associated with the medicine’s use and this means any liability rests with the prescriber. The same is true when a licensed medicine is prescribed for a type of patient, or purpose, or in a preparation or dosage outside the scope of its licence. For this reason, drug manufacturers may invest time and money in getting a licence for their drug in order to make it more likely that doctors will prescribe it.
Whether prescribing a licensed or an unlicensed medicine, it is the responsibility of the prescribing doctor to exercise professional judgement based on his/her theoretical knowledge, research, experience and evidence to choose a course of treatment for the patient, but they have a greater professional liability when prescribing an unlicensed medicine.
There is a synthetic cannabinoid called Dronabinol (marketed as Marinol, Syndros) that is not currently licensed for any purpose in the UK, but it can be used unlicensed to treat loss of appetite in people with AIDS and severe nausea and vomiting caused by cancer chemotherapy. It is not derived from cannabis plants, but its chemical makeup is designed to be similar to the naturally occurring cannabinoid THC.
A medicine can be licensed in the UK and still not recommended for use by the NHS. Epidiolex, for example, had enough evidence for its safety and efficacy in the treatment of epilepsy for the MHRA to award it a Marketing Authorization, but not enough evidence to convince the National Institute for Clinical Excellence (NICE) to recommend its use on the NHS until many months later.
So, if a doctor can prescribe whatever is in the best interests of the patient, and NICE can ignore the existence of the licence in its recommendations, why is a licence important at all?
A license/marketing authorization tells you that a drug has been thoroughly tested for a particular condition and is generally safe and effective at treating it in a particular demographic of patient.
A marketing authorization does not guarantee that:
- the drug works for every patient. It may not have been tested on patients outside of the demographic for which it was licensed and even within that demographic, every patient is different.
- there won’t be side-effects. Every drug has side-effects, although the known side-effects of a licensed drug should have been identified during the research phase and be well-documented for doctors and patients.
- it is safe for every patient. There may be individual patients who experience something known as an adverse reaction to the drug, which is a negative side effect (side effects can be positive or negative)
- it works better than anything else on the market. There may be plenty of licensed and unlicensed drugs competing with it that work just as well, or better. The marketing authorization is a strong indicator that the drug will work, on average, significantly better than the placebo when used for its licensed purpose, but it doesn’t require the drug to work better than alternatives.
The pharmaceuticals industry and its regulators require a very high standard of evidence (in terms of reliability) to grant a marketing authorization. They emphasize the importance of double-blind, randomized, placebo-controlled clinical trials containing large sample sizes of patients to the exclusion of almost all other types of evidence, as this is considered to be the gold standard of evidence.
Just as a licensed medicine cannot legally be advertised for any purpose except exactly what is covered by its Marketing Authorization, an unlicensed medicine cannot legally be advertised for any purpose at all. This applies to U-CBPMs including medicinal cannabis buds (flos), and medicinal preparations derived from them such as extracts, oils, tinctures, nasal sprays and soft gel capsules.
Nonetheless, price lists and factual information about an unlicensed drug’s contents can be given out to healthcare professionals for them to prescribe when they judge it to be in their patients’ best interests.
What’s the importance of double-blind, randomized, placebo-controlled clinical trials?
There is a well-documented effect known as the placebo effect in which patients who believe they are receiving an effective treatment report feeling better even if they are only receiving an inactive compound called the placebo. Their mind is tricked into feeling better by a simple sugar pill or plain water that they believe is medicine.
Having two groups in a clinical trial, where one group (the experimental group) is given the real drug and the other (the control group) is given a placebo, allows a comparison of the two groups to check that the experimental group benefits more than the control group, so we know that there is more than just a placebo effect going on.
The randomization and large sample sizes help reduce accidental or deliberate sample skewing. The double-blind nature of the study ensures that neither the patient nor the person administering the medicine can inadvertently affect the expectations of the other (and hence the result).
That is why the double-blind, randomized, placebo controlled clinical trial is perceived as the gold standard of clinical evidence, and most modern marketing authorizations are given only off the back of this type of evidence.
After centuries of widespread cannabis and hemp use in Britain and British territories, cannabis was made illegal in the UK in 1928, casually tagged on to the International Opium Convention. The decades of prohibition that ensued made it particularly difficult for medical trials to be carried out with respect to medicinal cannabis, and a lot of healthcare officials and individual doctors now justifiably complain about the lack of evidence. One thing that proponents and opponents of cannabis-based medicine both seem to agree on is that more research would be a good thing.
That’s not to say that there are no double-blind, randomized, placebo controlled clinical trials showing the benefits of unlicensed cannabis-based medicines, though. Here is a non-exhaustive list of such studies. I have not included the many studies in support of cannabis-based medicines that are already licensed in the UK (e.g. Sativex for MS-related spasticity) but I have included studies in support of cannabis-based medicines being used for a purpose for which they are unlicensed (e.g. Sativex for arthritic pain).
- Abrams, D. I., Hilton, J. F., Leiser, R. J., Shade, S. B., Elbeik, T. A., Aweeka, F. T., et al. (2003). Short-term effects of cannabinoids in patients with HIV-1 infection. A randomized, placebo-controlled clinical trial. Ann Intern Med, 139, 258–266.
- Abrams, D. I., Jay, C. A., Shade, S. B., Vizoso, H., Reda, H., Press, S., et al. (2007). Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology, 68(7), 515–521.
- Ellis, R. J., Toperoff, W., Vaida, F., van den Brande, G., Gonzales, J., Gouaux, B., et al. (2008). Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology, 34(3), 672–680.
- Abrams, D. I., Vizoso, H. P., Shade, S. B., Jay, C., Kelly, M. E., & Benowitz, N. L. (2007). Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther.
- Blake, D. R., Robson, P., Ho, M., Jubb, R. W., & McCabe, C. S. (2006). Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford), 45(1), 50–52.
- Brady, C. M., DasGupta, R., Dalton, C., Wiseman, O. J., Berkley, K. J., & Fowler, C. J. (2004). An open-label pilot study of cannabis based extracts for bladder dysfunction in advanced multiple sclerosis. Multiple Sclerosis, 10, 425–433.
- Haney, M., Gunderson, E. W., Rabkin, J., Hart, C. L., Vosburg, S. K., Comer, S. D., et al. (2007). Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep. J Acquir Immune Defic Syndr, 45(5), 545–554.
- Lynch, M. E., Young, J., & Clark, A. J. (2006). A case series of patients using medicinal marijuana for management of chronic pain under the Canadian Marijuana Medical Access Regulations. J Pain Symptom Manage, 32(5), 497–501.
- Musty, R. E., & Rossi, R. (2001). Effects of smoked cannabis and oral delta-9-tetrahydrocannabinol on nausea and emesis after cancer chemotherapy: A review of state clinical trials. Journal of Cannabis Therapeutics, 1(1), 29–42.
- Notcutt, W., Price, M., Miller, R., Newport, S., Phillips, C., Simmonds, S., et al. (2004). Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “N of 1” studies. Anaesthesia, 59, 440–452.
- Nurmikko, T. J., Serpell, M. G., Hoggart, B., Toomey, P. J., & Morlion, B. J. (2005). A multi-center, double-blind, randomized, placebo-controlled trial of oro-mucosal cannabis-based medicine in the treatment of neuropathic pain characterized by allodynia. Neurology, 64(6, Suppl. 1), A374.
- Russo, E. B. (2008). Cannabinoids in the management of difficult to treat pain. Therapeutics and Clinical Risk Management, 4(1), 245–259.
- Schley, M., Legler, A., Skopp, G., Schmelz, M., Konrad, C., & Rukwied, R. (2006). Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Curr Med Res Opin, 22(7), 1269–1276.
- Wade, D. T., Robson, P., House, H., Makela, P., & Aram, J. (2003). A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehabilitation, 17, 18–26.
- Wallace, M., Schulteis, G., Atkinson, J. H., Wolfson, T., Lazzaretto, D., Bentley, H., et al. (2007). Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology, 107(5), 785–796.
- Walther, S., Mahlberg, R., Eichmann, U., & Kunz, D. (2006). Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. Psychopharmacology (Berl), 185(4), 524–528.
- Ware, M. A., Ducruet, T., & Robinson, A. R. (2006). Evaluation of herbal cannabis characteristics by medical users: a randomized trial. Harm Reduct J, 3, 32.
- Wilsey, B., Marcotte, T., Tsodikov, A., Millman, J., Bentley, H., Gouaux, B., et al. (2008). A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain. J Pain.
This shows that there are indeed clinical trials on U-CBPMs out there.
So why would you ever want to take, or prescribe, an unlicensed medicine?
There are lots of reasons why a doctor might prescribe an unlicensed medicine or a patient might benefit from taking one.
- Maybe a drug that has been licensed in other countries is still waiting for a license to be granted by the EMA. If a doctor is convinced by the evidence, and believes a patient should benefit from that drug now without having to wait for the domestic license to be granted, he/she may wish to prescribe it straight away.
- Maybe a drug is still undergoing testing in a clinical trial but results of pilot trials were promising, or other types of evidence exist, and the doctor judges it is in the patient’s best interests to prescribe the drug before the end of the study.
- The potential market for the medicine may be so small that it is not economical for the manufacturers to apply for a license (which is an expensive process) so a doctor who wishes to prescribe the medicine may have no choice.
- Some licensed drugs are highly addictive. In the USA, it is estimated that 21 to 29 percent of patients prescribed licensed opioid painkillers misuse them, and that 80 percent of people who use heroin first misused their prescription opioids. There may be unlicensed pain killers that are far less addictive.
- All drugs have side-effects, including licensed ones. If the documented side-effects of the available licensed drugs are particularly bad, or are especially strong in a certain patient, a doctor might consider unlicensed alternatives with fewer or milder side-effects.
- Doctors may have already prescribed several licensed medicines to treat a patients’ illness or symptoms and not had satisfactory results. This might make them more inclined to try an unlicensed medicine to see if it helps. A good doctor would base this professional judgement on evidence rather than just guesswork, but will be able to weigh up many kinds of evidence, not just the placebo-controlled, randomized, double-blind, clinical trials that the EMA would consider.
- Patients ultimately choose whether or not to take a doctor’s advice. Since the internet has made medical information (and misinformation) widely available, patients and carers of patients are increasingly opinionated about their treatments. If a patient or carer is reluctant to try the doctor’s first recommendation, the doctor is likely to suggest another, which might be an unlicensed alternative.
- One extremely common scenario for using an unlicensed medicine is when a licensed drug is used in a different dosage or for a different patient demographic than its licence permits. For example, if a drug is not licensed for people under 18, but a doctor believes that a child of 14 would benefit from it, he/she might prescribe a smaller dose for that patient, which would be an unlicensed (or “off label”) use for the medicine. Around 1 in 10 children seen in general practice is prescribed at least one unlicensed medicine.
- Similarly, an unlicensed preparation of a licensed medicine might be specially prepared for a patient based on need. For example, if a patient’s hands are too shaky to administer a carefully measured amount of licensed liquid medication, a compounding pharmacy could turn it into an unlicensed gel capsule preparation, nasal spray, tongue drops or something else designed to be easier for them to take.
- Finally, it is common for a drug licensed for one purpose to be used “off licence” for another purpose. Sometimes this becomes so well known and widely practiced that the manufacturer loses any incentive to license the drug for the new purpose, as doctors are prescribing it anyway. For example, it is common to prescribe a drug called Galantamine, licensed to treat Alzheimer's disease, along with Methadone, to increase the patients chances of beating an addiction to opiods. Galantamine is not licensed for this purpose but there is evidence that it works nonetheless. It is also common to prescribe a licensed oral contraceptive pill to treat acne, a purpose for which it is not licensed. Another drug Metformin (also known as Glucophage) is an insulin-sensitizing biguanide licensed to treat elevated blood glucose levels in people with Type 2 Diabetes. However, it is often used to treat polycystic ovarian syndrome (PCOS) even though it is not licensed for this purpose.
All the explanations above for prescribing or using an unlicensed medicine are much more compelling in cases where the patient is very seriously ill, or has exhausted the conventional options for treatments, or has experienced serious side effects or addiction from licensed medicines. In these cases, the benefits to trying off licensed or unlicensed drugs are potentially much greater in relation to the risks. Indeed, in a worst case scenario, a prescriber might be choosing between an unlicensed medicine and likely death of the patient.
To take an example now famous in the UK; the use of U-CBPMs to treat drug-resistant forms of epilepsy in children (like Alfie Dingley) has had remarkably positive results where licensed anti-epileptics failed and even performed much better than cannabis-based medicines (like Sativex and Epidiolex) used off-licence.
Why do U-CBPMs need their own category? Can’t they just be “unlicensed medicines” like any other?
U-CBPMs are not a special category of medicine that defies the scientific conventions and evidential requirements expected of other medicines (as is sometimes claimed); rather, they are a category of unlicensed medicine like any other that happens to be legal when intended for a medical prescription, but remain illegal (a Class B drug) otherwise. That’s the only reason they have their own category.
The category of U-CBPMs that came into existence in 2018 is more of a legal one than a scientific one. It created a distinction between medicinal cannabis (which moved into Schedule 2 of the Misuse of Drugs Regulations 2001 as amended) and other cannabis products (which remain under Schedule 1).
It doesn’t really change how the NHS or NICE or doctors should approach cannabis as a medicine. It doesn’t relax the need for scientific rigour. From a medical perspective, they are treated the same as all unlicensed medicines (medical “Specials”) in that they must:
- only be supplied in response to an unsolicited order
- be manufactured and assembled in accordance with the specification of a suitably qualified medical professional (in the case of CBPMs, a doctor on the Specialists Register)
- be for a patient for whom that doctor is directly responsible
The new category brings about opportunities for research and makes it possible to write prescriptions that really help people, which wasn’t possible prior to November 2018.
Do U-CBPMs lack evidence of their safety?
All medicine manufacturers must legally be approved by the UK Government’s Medicines and Healthcare products Regulatory Authority (MHRA) or equivalent in other countries. To get this approval, they must demonstrate that their manufacturing procedures are consistent with Good Manufacturing Practice (GMP), a very high quality standard suitable for producing medicines, including total traceability back to the raw ingredients. They must also demonstrate Good Pharmacovigilance Practice (GPvP), a means of reporting adverse reactions to products to the MHRA and (if required) a method to recall a batch from sale. This “licence” to produce drugs is separate from the “licence” (i.e. Marketing Authorization) for the drug.
So we can be reasonably confident that the ingredients, process of manufacture and management systems in place at any MHRA-approved company are sufficient not to pose a particular threat to a patient, and we can be sure that the chemical compounds in the products are known and accurately labelled. After that, it’s up to the doctor to decide if a cannabis-based medicine is safe for a particular patient to try.
There are some known side-effects — most are not especially serious — and patients should always discuss these with their doctors and switch to a different U-CBPM or stop taking U-CBPMs altogether if a side-effect is not tolerable to them. The most common side effects of cannabis-based medicines are:
- Drowsiness — Some people take cannabis-based medicines to treat anxiety or help with sleeplessness, but if that’s not the effect you want, drowsiness can be a problem. It’s especially important if you are driving or operating machinery or doing anything that requires you to be alert.
- Dry mouth and dry or bloodshot eyes — Not painful but may be perceived as undesirable by some patients.
- Diarrhoea (and less commonly nausea and vomiting) —if the patient is using cannabis oil, this might be due to the carrier oil rather than the cannabis itself. If the patient is ingesting a lot of oil in order to get the cannabinoids into their system their gut might react badly. Discontinuing or trying another cannabis preparation, such as vaping, might be considered.
- Lower blood pressure — In most cases, this isn’t dangerous but, if you experience serious symptoms of low blood pressure such as feinting, racing heart rate or dizziness, you need to seek medical attention.
- Change in appetite — Typically cannabis is associated with an increase in hunger (due to THC) but there are some cannabinoids (CBD, but others too) that actually reduce appetite. This is not typically a problem unless it results in rapid weight loss or weight gain.
As with any drug, the higher the dosage of active substances, the more likely and more pronounced the side effects may be. Nonetheless, compared to very many widely used licensed drugs, cannabis-based products have relatively few and relatively minor side-effects.
Some researchers have associated episodes of psychosis with very heavy use of very strong cannabis. These claims were based on black-market cannabis, not legal medical cannabis. Other researchers attribute the episodes to the patients’ existing predisposition to psychosis. Rates of psychosis and mental illness have remained largely static over the decades, even though cannabis use (and the strength of available cannabis) has waxed and waned greatly. This undermines the claim of a causal relationship between the two, but there is not evidence to say for sure.
According to the Centres for Disease Control and Prevention (CDC), you can’t overdose on cannabis in the way that you can overdose on opioids, paracetamol and many other common drugs. To date, there have not been any reported deaths resulting directly from the use of cannabis. However, there have been deaths that can be indirectly associated with the effects of using cannabis, such as accidents caused by poor decision making and poor physical coordination under the influence of too much THC.
In conclusion, U-CBPMs have risks that should be understood by prescribing doctors and patients, but these risks can be mitigated and are not especially grave compared to other widely used licensed medicines on the market.
Do unlicensed medicines lack evidence of their efficacy?
That depends. It varies a great deal from case to case, and doctors should be qualified to weigh up the evidence of risks and benefits to help patients make an informed decision. Most doctors were not given formal medical training in the endocannabinoid system or the use of cannabis-based medicines at medical school, but there are free courses available to doctors interested in learning more about it so that they can be better at assessing the risks and choosing a suitable treatment.
What about U-CBPMs particularly? Do they lack evidence of their efficacy?
Professor Michael P Barnes MD FRCP, Honorary Professor of Neurological Rehabilitation at Newcastle University and Dr Jennifer C Barnes, DPsychol Clinical Psychologist at Northumberland, Tyne & Wear NHS Foundation Trust produced a thorough review of the medical literature on the efficacy of cannabis-based medicines.
They recognized that the evidence was more compelling for the treatment of some medical conditions than in others. They graded the evidence for the efficacy of one or more cannabis products or “natural” cannabis flos in a range of medical indications as either good, moderate, limited or none. I paraphrase them below:
Good evidence for: chronic pain, including neuropathic pain; spasticity; nausea and vomiting, particularly in the context of chemotherapy; and in the management of anxiety.
Moderate evidence in; sleep disorders; appetite stimulation in the context of chemotherapy; fibromyalgia; post-traumatic stress disorder; and for some symptoms of Parkinson’s disease.
Limited evidence (but further studies are required) in; the management of agitation in dementia; epilepsy, particularly drug resistant childhood epilepsies; bladder dysfunction; glaucoma; and Tourette’s syndrome.
There is a theoretical basis (but so far no convincing evidence of efficacy) for: the management of dystonia; Huntington’s disease; headache; brain protection in the context of traumatic brain injury; depression; obsessive compulsive disorder; gastrointestinal disorders; anti-psychotic agent (CBD); and a role in cancer/tumour control.
So it depends what is being treated. There is a sound theoretical basis for treating a very wide variety of conditions with cannabis-based medicines, but the evidence is very strong in some cases and quite weak in others. It is up to the prescriber to make a professional judgement on whether a U-CBPM is suitable for their individual patient and which U-CBPM is likely to be most effective.
How are U-CBPMs different to Complimentary Alternative Medicine (CAM) such as homeopathy?
Homeopathy (which is treatment with substances so diluted that they are chemically indistinguishable from water) is one of a range of “treatments” that are known as Complimentary Alternative Medicines or “CAM”.
There are very many clinical trials that prove convincingly that homeopathy has no effect beyond the placebo effect. No matter what you read, nobody is saying that cannabis does nothing — in fact the opposite is true — people are worried about what it does do. As we have read above, there is plenty of evidence that demonstrates the benefits of U-CBPMs in the treatment of some conditions. For other conditions, there is a sound theoretical basis and some interesting reports of success that warrant further research into U-CBPMs, whereas there is no sound theoretical basis for homeopathy.
A 2010 House of Commons Science and Technology Committee report on homeopathy said that homeopathic remedies perform no better than placebos and that the principles on which homeopathy is based are “scientifically implausible”.
By contrast, a 2016 Inquiry Report by the All Party Parliamentary Group for Drug Policy Reform said that:
There is now a sound evidence base for…the legalization of cannabis for medical use [to] promote the health and welfare of very sick people and the policy respects human rights and public health values…
A 2018 recommendation from the Government’s Advisory Council on the Misuse of Drugs (ACMD) said that it:
…agrees with the Chief Medical Officer for England (CMO) that there is now evidence of medicinal benefit for some Cannabis-derived products in certain medical conditions for some patients…[and] advises that clinicians in the UK should have the option to prescribe cannabis-derived medicinal products that meet the requirements for medicinal standards to patients with certain medical conditions.
There is a world of difference between Complimentary Alternative Medicine and the use of unlicensed cannabis medicines.
