Where are we with Psychedelic Research?
If you’ve been following our podcast and blog, you will have learned (if you were not previously aware) that psychoactive compounds such as MDMA and psilocybin are well on their way to becoming approved to be used medically under US Law. This is thanks to a plethora of high quality research results demonstrating that not only are these psychedelic compounds quite harmless when used professionally, but crucially, that they appear to be effective in significantly relieving a great deal of individuals’ suffering associated with mental health disorders like major depression, anxiety, and PTSD.
As such, we thought it might be helpful to write up a little (well, that was the idea) overview of the status quo of psychedelic policy for each of the psychedelics being studied at length currently.
We thought it would be helpful to additionally explain how currently illicit drugs become legally approved for medical use by federal governments, including the role regulatory agencies, such as the MHRA (UK) or FDA (US) play in this process.
The Classification of Drugs
Generally, when federal governments decide on how to classify a drug, there are two main questions asked: 1. Can it be abused? And, 2. Does it have any medical value? If the answer to Question 1 is yes, it is put on a Schedule.
The Scheduling system came about as a consequence of the Vienna Convention of 1971, when the UN (heavily influenced by the US) suggested that drugs should be classified into different categories of harm, and all agreeing countries could abide by this system and schedule all synthetic psychoactive substances. So far, 183 out of 195 countries have signed up. Classification systems may vary slightly by country, but to give an example, in the US and UK, there are 5 different Schedules, with Schedule 1 having the most restrictions, and Schedule 5 having the least.
The answer to Question 2 helps to determine which schedule it is classified under. If a drug is deemed to have abuse potential and no medical value, for example, it would be classified under Schedule 1. Schedule 1 drugs are the only ones that are deemed to have no medical value whatsoever, and include cannabis, LSD, and other psychedelics, such as psilocin and mescaline (seems a little backwards, given the swathes of research to the contrary, right?).
From there, the abuse potential would dictate how far down the scheduling list it goes. For instance, under Schedule 5 are substances deemed to have little to no abuse potential, such as cough mixtures with low levels of codeine, and antidiarrheal medications.
If, for example, you wanted to get a drug moved from Schedule 1 to another schedule, it would have to be shown to have some medical value. In order for any drug to be shown to have medical value, it must go through a rigorous testing process to ensure that it is safe and effective at treating what it is meant to treat.
Psychedelic compounds are no exception to these rules. And these are the rules that are being navigated by researchers, policy reformers, and therapists worldwide in order to help millions of people overcome mental health problems, as I write.
Before we go any further, it may be helpful to get our heads around some useful terms, which seem to commonly get misused or mixed up in this context:
Decriminalisation: In a drug context, this means the action or process to stop treating a substance as illegal or a criminal offence. For instance, Psilocybin has just been decriminalised in Denver, Colorado. They have taken away funding from criminalising the substance, so personal use can no longer be treated as an offence. Decriminalisation is not the same as legalisation.
Legalisation: The act of makes something that was previously illegal permissible by law. Sometimes the terms, ‘medically legalised’ and ‘recreationally legalised’ are used to distinguish between whether or not it is legal to use the substance in solely a medical context, or more broadly, a recreational context. For instance, cannabis was recently recreationally legalised in Canada, although it has been medically legal since 2001. Recreational legalisation essentially means that the substance can be legally consumed, produced and sold.
Descheduling: The act of taking removing a substance from the scheduling system. If a federal government decided to legalise a currently illegal drug, it could technically be removed from the scheduling system. This would be highly complex, however, and might more likely involve the drug being rescheduled to another schedule.
Rescheduling: The act of changing the classification of a substance, such that it is scheduled differently, based on the evidence about its medical value and/or abuse potential. For instance, cannabis may be rescheduled in the US from a Schedule 1 drug (deemed to have no medical value) to any of the other Schedules, based on the current literature evidencing its medical benefits.
The Current and Projected Legal Status of Psychedelic Drugs
To give you an idea of where some of these compounds are in this process, We have dissected the current status of a number of compounds that have shown promise in the scientific literature, starting with MDMA, below.
MDMA
3,4-Methylenedioxymethamphetamine is not technically a psychedelic compound, however its psychoactive effects have meant that it is commonly grouped together with the more classic psychedelics such as psilocybin and LSD.
In the US and UK, MDMA is currently a controlled substance (Schedule 1, and Class A, respectively) meaning that it is deemed to have no medical value and a high potential for abuse, and is illegal to manufacture, possess or distribute. Not even medical professionals or scientists can do so without a license, which is, under current legislation, generally painstakingly difficult to acquire.
This controlled classification is much the same all over the world, with a few exceptions: In Australia, it is classified slightly differently under Schedule 9, meaning that it can be used for research purposes, as long as the research is approved by a recognised human ethics committee. Otherwise, it is illegal to manufacture, possess or distribute.
In some European countries, like Portugal, personalised use is de-criminalised, meaning that it is still technically illegal, however being caught with less than a 10-day supply (in the case of MDMA, less than 1g) would mean an administrative punishment, such as therapy or community services, rather than a criminal one, such as a fine. However, the drug is still liable to be confiscated and the perpetrator may be issued a summons to court.
Right, so that’s the legal state of affairs for MDMA right now – seems simple enough.
But this is very likely to change in the very near future.
You may have heard about the promising research being done using MDMA to assist psychotherapy for individuals with Post Traumatic Stress Disorder (PTSD)[1]. If not, you can find out more about it here [https://maps.org/research/mdma/]. To cut a long story short, after years of meticulous research, scientists and therapists have demonstrated that, when used in a controlled, therapeutic environment, MDMA in conjunction with psychotherapy can help people to completely overcome longstanding, treatment-resistant PTSD. The brilliant thing about this treatment is that stable results are being found after just a few sessions with MDMA (nested within a series of talk therapy sessions), whilst current pharmacological therapies for this psychologically crippling condition stipulate a lifetime on medication. Evidence-based talk therapy, such as trauma-focussed CBT is definitely helpful, however the results that have been found for MDMA have eclipsed this ‘gold standard’ treatment quite significantly in efficacy rates, thus far.
What effect have these findings had on policy?
Before becoming approved for medical use by regulatory administrations like the FDA (US), the MHRA (UK), or the TGA (Aus), drugs must be subjected to a rigorous evaluation, known as a multiphase clinical trial, comprising a number of phases (typically 4) to test whether they will actually work to treat the particular malady in question in humans safely. So far, research on MDMA-assisted psychotherapy for PTSD has progressed through Phase I and II trials, and Phase III clinical trials have now commenced.
If the concept of clinical trials sounds familiar but a little hazy to you, here might be a good intersection to digress a little to read about exactly what the phases of clinical research are, and how they work. If you are clever enough to already know how clinical trials work, then you can skip ahead (smarty pants).
Phases of Clinical Research
Preclinical studies
Generally, before clinical trials are tested, pre-clinical studies are conducted in test tubes or with animals to garner preliminary information about the efficacy, toxicity and pharmacokinetics of the substance. If you’re wondering what on Earth pharmacokinetics is, you can learn all about it here [https://www.sciencedirect.com/topics/neuroscience/pharmacokinetics] (essentially, it’s the study of what happens to a drug once it’s introduced to the body). From here, it can be decided whether the treatment should be further investigated.
Phase 0
This is an optional phase, commonly included as a phase to potentially fast-track the development of promising drugs. Phase 0 studies might involve microdosing in humans to determine whether a substance acts in humans as expected based on preclinical studies. However, these trials don’t give us any information on the safety or efficacy of the substance. If the substance acts as expected, the research can move on to Phase I. However if there are any anomalies, the investigators might return to preclinical research before deciding whether or not to continue.
Phase I
If Phase 0 has not been completed, Phase I is the first proper testing of the treatment on humans. This phase tests the safety, side effects, best dose, and formulation method of the substance, by seeing what the highest dose of the substance that humans can take without serious side effects is, and what the best method of administering the drug is (e.g., orally, intravenously, etc.). Typically, a relatively small number of healthy[2] participants are recruited (approx. 20-80 people), given the drug in ever-so-slightly increasing quantities, and observed carefully for any side effects over the course of the drug’s life in the body. This phase might take a couple of months to complete.
Phase II
Phase II continues the research on safety from Phase I, by studying the effects of the drug on a larger number of participants (approx. 100-300), but this time, the participants are not ‘healthy’, i.e. they are living with the condition that the drug is designed to treat. This phase commonly involves randomised trials, whereby half of the participants are given the drug, whilst a ‘control’ group receive standard treatment, or a placebo, and the two groups are compared in terms of the outcomes. Very good scientific trials will also be ‘double blind’ – both the participant and the investigator are ‘blind’ to whether they are receiving/administering the real treatment, or the placebo. In psychedelic research, you can imagine that this is quite tricky, as it’s pretty difficult not to know when you’ve taken a psychedelic substance! The reason that blinding is so important, however, is that it controls for expectancy effects [https://en.m.wikipedia.org/wiki/Subject-expectancy_effect]; if a participant knows they’ve received the real treatment, they might be unconsciously biased to feel better or simply to report feeling better, even if they don’t really. But anyway, that’s a discussion for another day… Anyway, the researchers working on these trials have managed to come up with a good enough placebo that still gives the user some psychoactive effects. Essentially, Phase II allows the investigators to compare safety and efficacy between people who took the drug, and people who didn’t, in quite a sizeable sample, over a longer period – Phase II can take from a couple of months to a couple of years to complete. It’s also much trickier to get past this phase; according to FDA data, only about 33% [https://www.fda.gov/patients/drug-development-process/step-3-clinical-research] of medications being tested move past this phase.
Phase III
Time to bring out the big guns. Phase III trials are conducted on much larger samples (approx. 300-3000 participants) and can last for several years. Again, randomised, controlled studies are used to attempt to demonstrate that the treatment in question is at least as safe and effective as the current ‘gold standard’ treatment. Phase III trials are conducted at more than one medical centre or clinic, so that a wider range of population groups with varying demographics can be included. If the findings are similarly positive across the board, the results can be more easily ‘generalised’ to the population at large. Given the large number of participants and the multiplicity of testing sites, it’s easy to understand why Phase III trials are by far the most time-consuming and expensive trials to run. Before approval by the appropriate regulatory agency is granted, there must be at least one successful Phase III trial (but it seems that it’s usually two) that shows that the drug is up to par in terms of efficacy and safety. If this is the case, then the findings are packaged into a huge document called a ‘regulatory submission’ describing all the methodological details and results of the trials in human and animal studies, as well as details on how the drug is made, and what kind of shelf life it has. Then, it’s up to the regulatory agency to review this document, and to permit the drug to be marketed. Interestingly, in the US, many drugs can still be marketed while they are going through Phase III trials, on the proviso that they are immediately recalled if any adverse effects are reported.
So! Now you know the process by which these substances have to pass through to be shown to have some medical value, perhaps you might have a better understanding of the weight of the phrase “MDMA-assisted psychotherapy has passed Phase I and Phase II testing, and is currently undergoing Phase III trials”.
In fact, MDMA showed such promise in Phase I and Phase II trials, that the FDA granted “Breakthrough Therapy Designation” to MDMA for the treatment of PTSD, meaning that this therapy will be ‘fast-tracked’ through the process of clinical development and review. This designation is only specified for treatments that are designed to treat life-threatening or serious diseases or conditions, and that have a good basis of clinical evidence to indicate that the treatment may be more effective than existing therapies.
The trials for Phase III include the initial
“MAPP1: A Randomised, Double-Blind, Placebo-Controlled, Multi-Site Phase 3 Study of the Efficacy and Safety of Manualised MDMA-Assisted Psychotherapy for the Treatment of Severe Posttraumatic Stress Disorder”.
It’s a mouthful, but it means that:
Participants will be randomly allocated to either a treatment group or a control group
Neither the investigators nor the participants themselves will know which group they are in (i.e., whether they will receive MDMA or a placebo)
It will be tested whether or not MDMA actually results in any benefits over a placebo pill
The trial will take place across 14 research sites in the US, Canada, and Israel
Therapists providing the therapy will be working from a manual, to control for any differences in therapeutic approach (each therapist should be delivering a pretty standardised therapy)
The PTSD that the participants of the study have is long-standing, and has not subsided even with previous treatment
If this trial and the follow-up “MAPP2” trial go as planned and result in positive effects, we could be seeing MDMA-assisted psychotherapy as a mainstream treatment for PTSD in the US as early as 2021. The implications of this are amazing to think about.
Please bear in mind, however, that these trials have been completed in relation to medicalising MDMA in the US only at this stage. With the exception of Israel and Canada which are part of the Phase III US multisite studies, there is currently only one other MDMA trial in play internationally – and that is going on in the UK. In order for MDMA to be medicalised in other countries and nations, it will need to go through a similar process.
What will happen once Phase III trials have been completed?
Well, it’s tricky to say for sure at this point in time, however it’s looking extremely likely that MDMA will be approved in the US as legal medicine that can be prescribed by anyone with a license to prescribe by 2021. In terms of scheduling, it could be that the DEA moves this drug from Schedule 1 to either Schedule 2 or Schedule 3.
Just briefly, the DEA still describe Schedule 2 drugs as substances with high potential for abuse that may lead to psychological or physiological dependence, while Schedule 3 drugs are described as substances with moderate to low potential for physical or physiological dependence.
What will that mean for other countries?
Having a drug approved for medical use in the USA is always quite handy for other countries, as they can lean on the evidence-base already established to help potentially fast-track the treatment through the process of clinical testing in their own country.