Mental illnesses, such as depression and post-traumatic stress disorder (PTSD), are a leading cause of disability worldwide. Conventional anti-depressants have a high rate of partial or no response, often fail to improve symptoms, and can cause unpleasant side effects, thus identifying a great need to expand the range of available treatments. Could psychedelics provide a solution?
In the 1950s and 1960s, psychedelics were intensively studied and seen as a breakthrough in psychiatry, but their ban in 1970 under the United States’ Controlled Substances Act put a stop to most research. Over the past few decades, there has been a gradual change in perspective, owing to a lack of innovation in conventional psychiatric medications and expanding knowledge of how psychedelics work.
In the last 10 years, there has been a surge of interest in psychedelics within the pharmaceutical industry, and there is growing evidence from scientific studies that psychedelics could be effective treatments for a variety of mental illnesses. Examples of psychedelic drugs that have been studied include: psilocybin, N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA).
At Quotient Sciences, our scientists are experienced at handling controlled substances and actively working on drug development projects with psychedelic compounds in both the laboratory and the clinic, including psilocybin, psilocin, DMT, and analogues.
In this article, we explore what psychedelics are, how they are thought to work, and what scientific research is currently being done on them. We also discuss the challenges of conducting clinical research on psychedelics and handling them in the laboratory and in the clinic, and what the future holds for this somewhat controversial research area.
What are psychedelics?
Psychedelics are a class of psychoactive substances that produce changes in perception, mood, and cognitive processes. They have been known to cause different types of both visual and auditory hallucinations, including seeing or hearing things that do not exist or that are distorted. Psychedelics also have a high potential for misuse as recreational drugs and are classed as controlled substances, making them illegal to possess, produce, and supply without a license in most parts of the world.
How are psychedelics thought to work?
There is a strong belief arising that psychedelics could help to treat depression, possibly more effectively than the current marketed treatments, because they may target different areas of the brain that current methods do not access.
Currently, the most common category of anti-depressants is selective serotonin reuptake inhibitors (SSRIs). Serotonin is a neurotransmitter that is thought to help regulate your mood, and SSRIs work by increasing the amount of serotonin available to bind to serotonin receptors in the brain. SSRIs are typically taken as tablets 1–3 times a day. It can take up to 6 weeks to tell if an SSRI is working, and if it does not work, the patient must taper off the drug and try a different treatment.
In contrast, it is thought that psychedelics may be able to impart neuroplasticity, which is the ability to reorganize connections in the brain’s synapses. This may provide longer-lasting effects than conventional treatments and require less frequent doses, but more research and data is needed to obtain a deeper understanding of how psychedelics work.
LSD and MDMA are synthetic psychedelics, whereas psilocybin and DMT are naturally occurring psychedelics. DMT is one of the key active ingredients in the hallucinogenic drink ayahuasca. Psilocybin is the active ingredient in “magic mushrooms”, and it is a prodrug that is converted by the body to psilocin. Psilocin, DMT, and LSD have similar chemical structures to serotonin, so they are able to cross the blood-brain barrier and activate serotonin 2A receptors. This is thought to be what produces the psychedelic effects. MDMA has a different type of chemical structure, and it is thought to act by increasing the reuptake and release of serotonin, dopamine, and norepinephrine.
What scientific research is currently being done on psychedelics?
The US Food and Drug Administration (FDA) has designated psilocybin and MDMA as “breakthrough therapies”, which is a priority status given to promising drugs targeting an unmet need. This means that companies receive ongoing support from the FDA throughout the clinical trial process and priority review when data is available. There are currently hundreds of clinical trials registered on clinicaltrials.gov to test the effects of psychedelics on a variety of mental illnesses.
While some pharmaceutical companies are focusing on first-generation psychedelic compounds, others are tweaking the chemical structures to see if they can improve safety and effectiveness. Some companies are even hoping to create new chemical entities (NCEs) that remove all hallucinogenic effects while retaining the features responsible for therapeutic benefits. However, it is not yet known whether this is possible, and many scientists argue that the psychedelic “trip” brings about a change in perspective that is critical for treating mental illnesses. There is also the potential to look at fundamentally different molecules that can act on the same targets as psychedelics.
Recent notable breakthroughs in this field include the 2019 FDA approval of Spravato, developed by Janssen Pharmaceuticals, for treatment-resistant depression [1]. Spravato is a nasal spray with the S enantiomer of ketamine. While ketamine is not technically a psychedelic compound, this approval lent credibility to the idea of using a controlled substance to treat mental illness. In May 2021, the Multidisciplinary Association for Psychedelic Studies (MAPS) published results of a Phase 3 clinical trial on PTSD, where MDMA combined with psychotherapy showed sustained improvement in symptoms 2 months after treatment compared to placebo [2]. In November 2022, Compass Pathways published encouraging results from the Phase 2b clinical trial of Comp360, a patented polymorph of psilocybin, for treatment-resistant depression, which is the largest trial of psilocybin reported to date [3].
What are the challenges with conducting clinical research on psychedelics?
Conducting clinical research on psychedelics presents many challenges. In clinical trials, a synthetic form of the drug is tested on healthy volunteers or patients with specific mental illnesses under strict medical conditions, and expert psychological support must be provided before, during, and after the drug is taken.
It is difficult to conduct a truly double-blind trial with a psychedelic drug, as it is likely that participants will know whether they have received the active drug or a placebo. This raises the question of whether people are truly seeing therapeutic benefits, or if they just think they are because they know they received the active drug.
Currently, clinical trials of psychedelics typically exclude vulnerable populations, such as people with bipolar disorder, who might be vulnerable to psychotic episodes when taking psychedelics. However, these people would be exposed to the drug when it reaches the market, so it is important to include vulnerable populations in clinical trials to assess safety.
In addition, depression and anxiety can sometimes last for many months and can also recur in susceptible individuals. For this reason, long-term studies in different patient populations will ultimately be required to assess if the potential benefits in early trials can be sustained over time.
Quotient Sciences has recently started performing clinical trials with psychedelic investigational medicinal products (IMPs) on healthy volunteers for customers. As a precaution, a trained psychologist is present during the clinical trial to manage any adverse events and to help the volunteer manage the experience in a calm and relaxed environment.
How do you legally and safely handle psychedelics in the laboratory?
There are stringent regulations in place for handling controlled substances like psychedelics, which presents many challenges for drug developers. Pharmaceutical companies need to be licensed to handle controlled substances, and strict security is required for production and storage. Safety is a critical consideration in order to protect employees and the facility from cross-contamination. While acute toxicity is typically low with psychedelics, they can exhibit observable effects at very low doses. The main risks are altered perception, poor decision-making, and subsequent accident or injury in the laboratory. Therefore, ensuring containment and minimizing exposure of staff is important. Capabilities and facilities for handling controlled substances can be prohibitively expensive for small pharmaceutical companies, so this creates opportunities for contract development and manufacturing organizations (CDMOs) that are licensed to handle controlled substances.
Quotient Sciences is licensed by the UK Home Office to possess, produce, and supply Schedule 1–4 controlled substances under the Misuse of Drugs Regulations 2001. Psilocybin, DMT, LSD, and MDMA are all classed as Schedule 1 drugs, which means they have no currently accepted medical use and a high potential for abuse. To ensure security, controlled substances are stored in a defined locked cabinet, and key access is restricted. All usage and production are recorded on controlled substance usage forms, and all activities are signed and witnessed. To ensure safety, a specific risk assessment is conducted for all laboratory activities involving psychedelics. All dispensing, packaging, and weighing of materials is done in a Class 3 isolator, and personnel must wear appropriate personal protective equipment (PPE). To avoid cross-contamination, there is a dedicated project-specific high-performance liquid chromatography (HPLC) and rotary evaporator for each psychedelic project, and use of the house vacuum is forbidden. Additionally, transfer of material between laboratories requires double containment in high-density polyethylene (HDPE).
What does the future hold for psychedelics?
Psychedelics are a rich and fertile research area. While results from scientific studies appear promising, most research is still in the early stages, and there are many challenges to overcome before medications could become widely available.
Even if pharmaceutical companies can succeed in formulating psychedelics into effective drugs, commercial success will heavily depend on overcoming pre-conceived opinions of regulatory authorities, doctors, and patients on the use of recreational drugs as safe and effective medications.
There is also the question of how scalable psychedelics could be to meet the high occurrence of mental illnesses. How do you make treatment convenient, controllable, accessible, and affordable? With the current generation of potential medicines necessitating close medical supervision, it would only be possible to administer psychedelics at a doctor’s office. Treatments would be time-consuming, taking patients away from work and other responsibilities. Access to treatments may also be difficult for patients living in rural locations. While the potentially long-lasting effects of psychedelics might make them more cost-effective than conventional treatments in the long term, there could be large, up-front costs, which insurance companies may be reluctant to cover.
As an organization with a culture focused on science and innovation, the team at Quotient
Sciences is excited to see how developments will progress in this space.
References
2. Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine 2021;27:1025–1033.
3. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med 2022;387:1637–1648.
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