Ethical Considerations for Clinical Trials of Psychedelics

Puzzle piece with rainbow coloring

Clinical Researcher—August 2023 (Volume 37, Issue 4)


Currien MacDonald, MD, CIP




Psychedelics, often associated with “magic” mushrooms, are gathering attention, and for good reason. Psychedelics’ potential treatment areas include major depressive disorder,{1} alcohol abuse,{2} tobacco and other addictions,{3} cancer-related anxiety disorder,{4} obsessive-compulsive disorder, post-traumatic stress disorder,{5} eating disorders,{6} Alzheimer’s disease,{7} and fibromyalgia.{8}

That is a long list of illnesses that currently have high disease burdens, and some without any good current treatment options when first-line treatments fail. It is not an exaggeration to describe their potential benefits in terms of being breakthroughs in treatment. It is tempting to join those who are all-in on the drug class, such as those projecting its economic growth to more than $10 billion by 2027.{9} Unsurprisingly, some are calling this enthusiasm an unfounded hype bubble that is sure to pop.{10}

So, which is it? A revolution in treatment, or unsupported hype over the chance to legalize getting high?

Babies and Bathwater

First, it is important to understand that psychedelics are not a monolithic topic. Psychedelics are an unofficial name for a set of compounds that differ in mechanism of action and, therefore, in effects.{11} “Classic” psychedelics include psilocybin, the active ingredient in “magic” mushrooms, and often include MDMA, also known as “Ecstasy.” However, there are other compounds lumped into that term, including those not typically thought of as psychedelics; for example, esketamine, which has been approved by the U.S. Food and Drug Administration (FDA) for treatment-resistant depression with an oral antidepressant. (Another is ketamine, a much less expensive drug currently approved for anesthesia and used off-label for depression treatment.{12}) The risks of esketamine, including dissociation and the potential for abuse and misuse of the drug, make it only available through a restricted distribution system and a specific risk evaluation and mitigation strategy (REMS). For drugs found to have a high abuse potential, that strict level of control makes sense.

At the same time, the well-known risks of classic psychedelics are reported in the context of the use of illicit substances of unknown potency in unsupervised, non-medical situations.{13} The risks of a pharmaceutical grade psychedelic in the context of a full-psychiatric treatment regimen may be much different. The consideration of the potential risks of psychedelics in these situations needs to include appreciation of the patient’s expectations, the setting of the therapy, and the clinician-therapeutic relationship.{13} That is not to say the risks are lower, but they are more complex, and would need an individual assessment instead of a blanket or over-attentive focus on reducing the risks of abuse.

Pharmaceutical companies are well-versed in taking a raw source and producing a purified medical product to maximize benefits while reducing risks. Treating medicinal psychedelics as if they all had the same risk profile as illegal, uncontrolled drugs would be short-sighted. Similarly, dumping controlled therapeutic use in the same bathtub as self-medication attempts by those with mental illness or situations of recreational use will exaggerate risks and rob society of potentially great benefits.

Careful evaluation of the abuse potential of these drugs puts many of them lower than would be expected. For example, when evaluated according to the eight factors of the Controlled Substances Act (CSA), psilocybin had an abuse potential appropriate for CSA scheduling if approved with one review, suggesting that placement in Schedule IV may be appropriate,{14} which is similar to many other approved drugs.

Paving the Road or Setting Up Roadblocks

With the potential for a classic psychedelic drug to be approved, FDA has issued timely guidance.{15} The agency identified this class of drugs, including related drugs like MDMA, as having “unusual characteristics” that should be considered, and noted “there is limited experience as to the configuration of programs that may support approval of a psychedelic drug.” The guidance is described not as “specific recommendations on study design,” but instead as “foundational constructs” to consider. In a press release,{15} the FDA specifically notes the potential for abuse of these drugs as a necessary consideration. The guidance points out several large considerations for study approach that are the same as for other drugs, but which, when applied to this drug class, may represent substantial issues for drug approval. These include:

  • manufacturing steps for what may be considered a “botanical” product,
  • a study intervention with effects so obvious that a control arm is difficult, and
  • the fact that these drugs are often used in a psychotherapy program instead of just as daily pills.

There are also ethical issues with these trials. For example, psychotherapy’s main tenet is that all healing occurs in relationship with the therapist. A limitation of therapy, then, is the patient’s lack of allowance for the therapeutic relationship. Building trust, especially when you have a psychiatric illness, is difficult and arduous work. One of psychedelics’ main mechanisms is (easily but not completely accurately) described as inducing a psychologic flexibility. Long-held mental constructs are relaxed, potentially allowing for overcoming what was otherwise insurmountable mental disease.

At the same time, this psychologic flexibility can also be translated as increased suggestibility, potentially exposing patients to risks from others. FDA’s guidance states, “Subjects receiving active treatment with psychedelic drugs remain in a vulnerable state for as long as 12 hours.” The guidance follows with recommendations for monitoring by two monitors during the treatment session and consent disclosure of this risk during the treatment session.

With the potential for greater participant suggestibility comes a particular need for training regarding how and what specifically a participant is consenting to, what is being monitored by each monitor, and the likelihood of stronger and more complex emotional effects. The potential for either the patient or the therapist to form more than professional attachments is always a risk, and is especially heightened with psychedelic treatment. Use of touch, which can be powerfully therapeutic, can also be very damaging in psychedelic treatment. These issues, including touch, should be specifically addressed, as outlined in the Multidisciplinary Association for Psychedelic Studies Code of Ethics,{16} which was created to address issues arising in MDMA clinical trials.

However, let us not lose sight of the fact that it is this very risk which has the potential for effectiveness that has not been previously achieved.{17} It is not unusual in medicine to have a drug’s powerful effect be inextricable from its potential for serious side effects.

The concept of vulnerability is not a new one for institutional review boards (IRBs); however, the temporary nature of the vulnerability makes the standard IRB methods such as exclusion of vulnerable participants or inclusion of a legally authorized representative problematic. In review of these trials, IRBs need to carefully consider what additional safeguards have been included in the study to protect the rights and welfare of these participants. These safeguards will be different in a “take home pill” study of anxiety compared to a study involving intensive psychotherapy sessions.

Other Roads Than the Highway

Additionally, FDA is considering the path to approval of a standardized medicinal product. With the compounds being illegal but readily available, FDA approval may not be the route all are considering, and studies “about” the drugs without requiring their use deserve attention.

For example, therapists working in these disease areas may well encounter people who are wanting to try or are already using psychedelics to self-treat. Caring and ethical therapists, committed to helping their patients, may struggle to navigate supporting a patient without increasing their patient’s or their own risk.{18} Carefully navigating the use of illegal substances in therapy other than working toward cessation is problematic. Supporting the use of an illegal substance puts a strain on therapists they may not know how to handle. The strain increases especially if the self-treatment appears promising, but really would do better with a trained clinician. A trial looking at data collection of illegal use vs. illegal use with a trained clinician may be very beneficial.

Illegal access is also an issue during review of clinical trials administering these drugs. We must carefully consider the ethics of psychedelics in research after the clinical trial ends. Starting a person on a treatment during the trial and then stopping when the trial is over is not unfamiliar, but it is unique in this case. A participant who was benefitting from a psychedelic trial faces a difficult choice when leaving the study, and the clinician treating them faces a different but similarly difficult one. The illegal versions of psychedelics are not difficult to obtain, and are often much cheaper than those versions available even through expanded access of experimental drug products.{19} The ethical obligations of the sponsor, clinician, and reviewing IRB will need careful attention.

True Measure of Any Society

Another societal issue is that certain mental health disorders have very limited options once initial treatment has failed. Moreover, some populations currently with challenges accessing healthcare are the ones with these illnesses and treatment-resistant diseases. Sadly, they are under-represented in clinical trials, but are the very populations for which psychedelic treatment may be especially effective. Paying attention to diversity in clinical trials will be especially important for these studies. When designing clinical trials with psychedelics, additional effort and emphasis on recruitment strategies, appropriate communication, multicultural competence, and flexible study designs are required.{20} When considering the REMS for approving psychedelics, similar considerations must also be made for these populations. A risk mitigation strategy that sets such a high barrier for use may functionally put a prescription version of these drugs out of reach of these populations. That could lead again to difficult decisions and rationalization for use of illegal and more risky versions.


We in the research field especially need to ensure that we do not lose sight of the potential benefits of these compounds while not under- or over-valuing the very complex risks from several perspectives. When conducting psychedelics research, including retrospective data collections, surveys, real-world evidence, post-approval studies, and comparative effectiveness research, we must be additionally attentive. We must not forget that the initial research temptingly hints that this class of drug may greatly help those we have so far failed, including populations who have significant additional burden. Extra attention is deserved to ensure neither unsupported enthusiasm nor unfounded fear rules the day.


  1. Agin-Liebes G, Davis AK. 2021. Psilocybin for treatment of depression: a promising new pharmacotherapy approach. Current Topics in Behavioral Neurosciences.
  2. Armstrong SB, Xin Y, Sepeda ND, Polanco M, Averill LA, Davis AK. 2023. Prospective associations of psychedelic treatment for co-occurring alcohol misuse and posttraumatic stress symptoms among United States Special Operations Forces Veterans. Military Psychology.
  3. Bogenschutz MP, Johnson MW. 2016. Classic hallucinogens in the treatment of addictions. Progress in Neuro-Psychopharmacology & Biological Psychiatry 64:250–8.
  4. Yaden DB, Nayak SM, Gukasyan N, Anderson BT, Griffiths RR. 2022. The potential of psychedelics for end of life and palliative care. Current Topics in Behavioral Neurosciences 56: 169–84.
  6. Salib V. 2022. FDA Approved Psilocybin Investigational New Drug Application.
  7. Garcia-Romeu A, Darcy S, Jackson H, White T, Rosenberg P. 2021. Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms. Current Topics in Behavioral Neurosciences.
  8. Glynos NG, Pierce J, Davis AK, McAfee J, Boehnke KF. 2022. Knowledge, perceptions, and use of psychedelics among individuals with fibromyalgia. Journal of Psychoactive Drugs.
  9. Phelps J. 2022. The Rapid Rise in Investment in Psychedelics—Cart Before the Horse. JAMA Psychiatry 79(3):189–90. doi: 10.1001/jamapsychiatry.2021.3972.
  10. Yaden DB, Potash JB, Griffiths RR. 2022. Preparing for the bursting of the psychedelic hype bubble. JAMA Psychiatry 79(10):943–4.
  11. Yaden DB, Earp BD, Griffiths RR. 2022. Ethical issues regarding nonsubjective psychedelics as standard of care. Cambridge Quarterly of Healthcare Ethics 31(4):464–71.
  12. Pharmacoeconomic Report: Esketamine Hydrochloride (Spravato): (Janssen Inc.): Indication: Major Depressive Disorder in Adults. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2021 Apr. Appendix 1, Cost Comparison Table. Available from:
  13. Tupper KW, Wood E, Yensen R, Johnson MW. 2015. Psychedelic medicine: a re-emerging therapeutic paradigm. CMAJ 187(14):1054–9. doi: 10.1503/cmaj.141124. Epub 2015 Sep 8. PMID: 26350908; PMCID: PMC4592297.
  14. Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE. 2018. The abuse potential of medical psilocybin according to the 8 factors of the Controlled Substances Act. Neuropharmacology 1–24.
  17. Yaden DB, Griffiths RR. 2021. The subjective effects of psychedelics are necessary for their enduring therapeutic effects. ACS Pharmacology & Translational Science 4(2):568–72.
  18. Jacobs E, Yaden D, Earp BD. 2023. Towards a Broader Psychedelic Bioethics. AJOB Neuroscience.
  19. Code of Federal Regulations. 21 CFR 312.305.
  20. Ortiz CE, Dourron HM, Sweat NW, Garcia-Romeu A, MacCarthy S, Anderson BT, Hendricks PS. 2022. Special considerations for evaluating psilocybin-facilitated psychotherapy in vulnerable populations. Neuropharmacology 214:109127.

Currien MacDonald

Currien MacDonald, MD, CIP, is Medical Chair Director at WCG.