International Regulatory Developments For Key Psychedelics

The role of psychedelic therapy in neuropsychiatry is a subject of major current interest. Companies developing psychedelic drugs are making expansive and immodest claims. Compass Pathways “want to transform the patient experience in mental health care”. GH Research is “dedicated to transforming the treatment of psychiatric and neurological disorders.” And Cybin is “on a mission to revolutionize mental healthcare.”

There is little modesty to be seen in the ambitions of the pharmaceutical companies riding this wave. Investors have seen psychedelics as potential money-spinners and the market for psychedelic medicines is projected to grow to more than $10 billion by 2027¹.  

But what exactly is a psychedelic medicine?

Defining a psychedelic

In correspondence between Aldous Huxley and Humphry Osmond, Huxley proposed the term “phanerothyme” (literally, to reveal the soul). The psychiatrist Osmond countered with the term psychedelic (literally, mind-manifesting) and the latter term stuck. There is no precise definition except that a psychedelic drug is one that produces an altered state of consciousness characterized by hallucinations. Its effects on consciousness were described by Osmond as follows:

“To fathom hell or soar angelic, just take a pinch of psychedelic.”

The naming of the psychedelics presents an interesting regulatory conundrum. While the drugs all have a similar but not identical pharmacodynamic response, they do not necessarily share the same pharmacology. The classic psychedelics are partial agonists at the brain’s 5-HT2a receptor. These include mescaline, psilocybin, LSD, and di-methyl tryptamine. But other drugs produce alterations of consciousness and hallucinations, and opinions differ as to whether drugs such as phencyclidine, ketamine, esketamine, and others should be called psychedelics. 

Equally, MDMA, a serotonin releaser, is also regarded as a psychedelic drug. There are authorities who describe cannabis as a psychedelic. For a useful review of the pharmacology of psychedelic drugs, see Nichols DE, 2016². Essentially, this discussion is a matter of semantics, whereas the regulatory approach to all these compounds is one of evidence and data.

Getting approved

The requirements for gaining marketing authorization for a new medicine are essentially the same for all new molecular entities, regardless of their pharmacology (with variations in the case of biologics and botanical medicines). These requirements are embodied in guidelines issued and updated by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) publish helpful guidelines that incorporate the ICH requirements. Regardless of the artisanal use of psychedelics and the torrent of social media advocacy for the therapeutic effects, the road to market authorization is long and winding.

Many of these psychedelic compounds are available as plants or plant extracts. Psilocybin is a component of certain mushrooms, while mescaline is found in various cacti, and N, N-Dimethyltryptamine (DMT) is found in several plants. Similarly, Ibogaine has been used traditionally as a plant extract, as has 5-methoxy-DMT. LSD, however, was discovered by the Sandoz corporation in an effort to identify new ergot compounds; ketamine, by the Parke-Davis company in an effort to find an improved version of phencyclidine. MDMA was synthesised by Merck in 1912.

The point here is that sponsors of psychedelic drug development programs have a choice of whether to follow the botanical drug guidelines and aim to develop a botanical product. Or they may choose to isolate the active compound and develop a synthetic version. The latter route has been chosen by the companies currently developing psychedelics, even though there are several recent examples of botanical extracts getting approved, such as GW Pharmaceuticals’ Epidiolex, which was approved by the FDA in 2018.

Table 1 lists the companies, compounds and indications currently being pursued in the psychedelics space (the author apologizes to those he may have missed!). Almost all the candidates are synthetic and will therefore have to follow the route to NDA in the same way that any synthetic New Molecular Entity would have to do.

Analytical Cannabis asked Shaun Stapleton, until recently vice president of regulatory and pharmacovigilance at Reneuron, about the pros and cons of each approach.

“The differences would be most significant in the quality control and characterization of the product. A synthetic compound would need to address the usual aspects of proof of structure, quality control (including impurities) and stability of the synthetic drug substance. For a plant extract, characterization would be more complex,” he said.

“There would need to be consideration of which components of the extract are responsible for the relevant pharmacological effect (mechanism of action). An assay for one or more of those components would need to be in place to control the potency of the extract. Consideration as to whether other components may have a deleterious effect and therefore need to be controlled as impurities would also need to be considered.”

Table 1 is a probably incomplete list of those companies currently developing psychedelic drugs and raises some interesting points. Firstly, it must be unusual that a class of drugs (the psychedelics) is being developed simultaneously across so many different indications by so many companies.

Table 1: a list of several companies currently developing psychedelic drugs. 

There has been some speculation that the FDA is inclined to the development of psychedelics. Senators Brian Schatz (Democrat - Hawaii) and Cory Booker (Democrat - New Jersey) recently wrote to the National Institutes of Health (NIH) and FDA urging them to support a comprehensive and science-led approach to the development of psychedelics for mental disorders. While the FDA encourage the development of any new drugs that may bring benefits to patients in need, or where existing treatments are either absent of inadequate, there is no evidence that it is providing any particular incentives to psychedelics research. At the time of approval of Epidiolex, FDA Commissioner Scott Gottlieb stated, “Research to demonstrate that marijuana or its components could be safe and effective in the treatment of medical disorders should be held to the same standard as other drug compounds. And certainly it should not be held to a lower standard, as some proponents would suggest.” He went on to suggest that the availability of unproven cannabis-based preparations might compromise the availability of FDA approved medicines.

Although these comments applied to the development of medicines based on marijuana, the same sentiments could apply to psychedelic medicines, too. But how will the unique aspects of psychedelics, such as associations with traditional rituals, affect their appraisals? Analytical Cannabis asked Shaun Stapleton whether the history of social or ceremonial use of psychedelics might create a favorable regulatory environment. He said, “Absolutely not. Psychedelic drugs will need to meet the evidential requirements for quality, safety and efficacy described in ICH [International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use], FDA and European guidelines. Meeting these requirements will be a pre-requisite for making medical claims for these substances.”

“The uncontrolled use of these substances in a ceremonial or recreational setting will not provide the robust level of data to meet the current requirements of global regulators for demonstration of safety. Case reports or even small, uncontrolled clinical trials in specific clinical indications will similarly not provide the requisite data to demonstrate either safety or efficacy.”

Hence, the regulatory pathway for all psychedelics is one where the three fundamental pillars of drug approval must be respected: quality, safety, and efficacy. The ICH outlines comprehensive guidelines as to how the evidence that accompanies a new drug application (NDA) must be generated in each of these three areas.

There is one more factor to consider, too. At present, all psychedelics are categorised as Schedule 1 substances under the US’s Controlled Substances Act. This means that the drugs are deemed to have a high potential for abuse and to have no recognized medical use. If one of the drugs under development is deemed by the FDA to have a recognized medical use, and NDA approval guarantees this, then the drug can no longer remain in Schedule 1 and must be re-scheduled.

The demonstration of the abuse liability of any substance depends on its chemistry, manufacturing, and controls (CMC), as well as pre-clinical, clinical, and social factors. These factors are put together by the sponsor and guided by the FDA guidance document, Assessment of Abuse Liability of Drugs³. This used to be known as an eight-factor analysis, since there are eight factors to be considered. However, it is now an integral part of the NDA submission document, and the FDA guidance identifies where in the submission document the relevant discussions should be placed. The sponsor is also requested to make a proposal for re-scheduling the drug (in Module 1).

From a regulatory perspective, this is an important part of the approval process, since the requirements of being in Schedule 2, for example, are considerably more onerous than a lower Schedule. Historically, when Schedule 1 drugs have been re-scheduled, they have, by default, been placed in Schedule 2 (Marinol, for instance). However, Epidiolex (plant-derived, purified cannabidiol) was re-scheduled from Schedule 1 to Schedule 5 in 2018, showing that, subject to the available data included in the abuse liability analysis, the sponsor can be optimistic about the re-scheduling process.

Finally, almost all of the companies developing psychedelic medicines emphasize the importance of set and setting. In almost all cases, patients are supported by trained therapists. And in this digital world, much of this psychological support framework is likely to be embodied in an app of some sort. There is a danger that the combination of drugs and an app may be viewed as a combination product, and thus face additional hurdles to development.

“In the case of a software app/device being developed in conjunction with a psychedelic drug, this could be considered as a combination product and require more complex studies to demonstrate that both components of the product are providing a contribution to the effectiveness of the combination,” Shaun Stapleton told Analytical Cannabis.

In summary, the regulatory pathway for psychedelic medicines is not different from that for non-psychedelic new molecular entities with abuse liability. The hurdles of quality, efficacy, safety (including abuse liability) are hurdles that can only be jumped with a well-designed development strategy and good data.

Dr Stephen Wright was the head of R&D and chief medical officer of GW Pharmaceuticals throughout the development and approval process for Sativex (nabiximols) and Epidiolex. He is a visiting professor in the School of Pharmacy at Reading University. He now consults in the drug development process.

References

1. https://www.prnewswire.com/news-releases/psychedelic-drugs-market-size-is-projected-to-reach-10-75-billion-by-2027--301273405.html
2. Nichols DE.  Psychedelics. Pharmacol Rev. 2016; 68: 264-355.
3. https://www.fda.gov/media/116739/download. Assessment of abuse liability of Drugs: Guidance for Industry.