Why and How to Infuse Methodological Rigor into Psychedelic Clinical Trials

Christine Moore, PhD

The recent revitalization of neuroscience drug development is welcomed by those seeking innovative mental health solutions. Most existing treatments for neuropsychiatric diseases such as anxiety, depression, substance use disorders (SUDs), and post-traumatic stress disorder (PTSD) are only modestly effective, and many have significant side effects.

Thus, sponsors, investors, and the public are enthusiastic about once again researching psychedelic compounds. More than 80 organizations are now publicly engaged in psychedelic drug development.¹ By 2027, the market for psychedelic substances is predicted to grow to $10.75 billion from $2 billion in 2020.² However, while longstanding stigmas around mental health and psychedelic drugs may be dissipating, misunderstandings remain about why it is imperative to design methodologically rigorous clinical trials designed to fully characterize safety and efficacy.

The reason for rigor is simple: If approved, psychedelics could be widely used in a vulnerable patient population. Rigorous trials provide data to develop a roadmap for how to best use these compounds in different types of patients. So, this article will:

• examine two misconceptions about psychedelic pharmacotherapies that undermine rigor,
• discuss the current research landscape, and
• delve into ways sponsors can infuse rigor into psychedelic studies.

Misconceptions

Some argue that formal, rigorous trials of psychedelics are unnecessary, given that Indigenous cultures have used them for millennia. This view perhaps comes with the misconceptions that: 1) psychedelic compounds are natural and therefore safe, and 2) the population that may ultimately use these compounds is homogeneous.

Misconception 1: Psychedelics are safe and natural.

Classic psychedelic drugs are defined by their mechanism of action. They act as agonists at serotonin 2A receptors (5-HT2A), which can alter consciousness and perception. Among the drugs considered classic psychedelics are psilocybin (found in “magic mushrooms”), lysergic acid diethylamide (LSD), mescaline (found in peyote), and dimethyltryptamine (found in various plants).

It is true that some psychedelic compounds are derived from nature and have been safely used for millennia by Indigenous cultures, and we should not discount the experience gained from generations of traditional use. However, scientifically sound clinical trials are critical for several reasons:

• The pharmacology of psychedelic compounds is complex and variable. Their precise mechanisms of action remain poorly understood.
• Some of these substances are not natural; many modern psychedelics have been newly developed, chemically manipulated, or manufactured synthetically.
• Adverse effects are not uncommon. While some may be relatively mild (e.g., nausea, vomiting), others may be severe (e.g., cardiac events, seizures, hyperthermia, suicidal ideation, and death).^3,4,5

Misconception 2: The population with mental health issues is largely homogeneous; if psychedelics safely work for some patients, they will safely work for all patients.

Patients’ clinical presentations and medical histories are highly variable—both within and across mental health conditions. Careful attention to obtaining a proper diagnosis and detailed medical history is critical, but additional considerations should include the following:

• condition severity and stability. It is unclear if psychedelics should be reserved for severely ill patients or if they should also be considered for a mildly ill population. This is a testable hypothesis in a carefully designed study; patients should meet predefined severity requirements using cutoffs on standard assessments (e.g., the Hamilton Depression Rating Scale [HAM-D] or Montgomery-Asberg Depression Rating Scale [MADRS] for depression, or the Clinician-Administered PTSD Scale for DSM-5 [CAPS-5] for PTSD). Further, highly variable symptoms make it difficult to identify if treatment effects are due to the drug or other nonspecific factors, so symptoms should also be relatively stable.
• family history or personal history of psychosis. Patients with a personal or family history of psychosis, such as schizophrenia or bipolar disorder, may be at higher risk of a psychotic episode after taking a psychedelic substance. These patients should be excluded from early psychedelic trials until safety is further characterized.
• previous use of psychedelics. It is also unclear if frequent use of psychedelics is safe at varying dose levels, or if efficacy response changes with frequent use. Formal clinical trials can assess whether previous use (for clinical treatment or recreation) is associated with poorer safety outcomes or different response rates. Early clinical trials often exclude patients with a history of psychedelic use, particularly if they experienced a negative or no response in a medical treatment setting.
• SSRI use. Concomitant use of selective serotonin reuptake inhibitors (SSRIs) may blunt the effectiveness of psychedelics. Further, patients taking both SSRIs and psychedelics may be at increased risk for developing serotonin syndrome. These are also testable hypotheses, but the safety and efficacy of concomitant use have not yet been well established.

Psychiatry studies are uniquely intricate, even when they don’t involve psychedelics. Psychedelics add extra layers of regulatory and operational difficulty, partly because the drug class differs significantly from other pharmacotherapies for mental health conditions. Ethical considerations are magnified, too, as vulnerable patient populations become even more vulnerable when administered consciousness-altering compounds.

Why rigorous studies? Why now?

Despite the inherent complexity of psychedelic trials, psychedelics could change the treatment landscape for challenging neuropsychiatric diseases. Rigorous trials offer tremendous opportunities to shed light on:

• the short- and long-term safety profiles of psychedelics.
• the durability of psychedelic treatment effects and how often redosing should occur.
• which patients might be helped vs. harmed by psychedelic treatments.
• whether treatment effects are due solely to psychedelic compounds or the combined effect of the drug plus psychotherapy.

Better understanding these current unknowns requires conclusive results from large, well-controlled studies. The good news: Regulators seem willing to ease the path to such studies.

For example, FDA and the UK Medicines & Healthcare products Regulatory Agency (MHRA) have granted breakthrough designation and fast-track status for several psychedelic-assisted mental health therapies. The US Drug Enforcement Agency (DEA) has also accelerated its Schedule I research licensing process.⁶

What sponsors should consider

Designing and running a methodologically rigorous psychedelic clinical trial is difficult, but it can be accomplished when sponsors, contract research organizations (CROs), and sites work together. Sponsors, for example, may not be prepared for the extended timelines required to successfully conduct a psychedelic trial because of the need to:

• obtain a Schedule I license. Psychedelic compounds almost always fall into the Schedule I category, so a license is needed to transport and use them in a research setting.⁷ Researchers that have never had a Schedule I license must be inspected, and the process can take many months.
• submit a new license application for each protocol. In the United States, licenses are granted on a protocol-specific basis for research only.
• build in extra time for site selection. While more and more sites are capable of conducting psychedelic trials and have the appropriate licenses, staff, training, facilities, equipment, and processes in place, thorough feasibility studies are crucial to assess each site’s capacity to manage a study within the study's projected time frame due to demand.

Sponsors should also be aware that many psychedelic trials entail three preparatory sessions, one to two dosing sessions, and two to three integration sessions to help patients assimilate the experience and to ensure psychological stability. Although patient retention is usually not a significant issue, one vital aspect of psychedelic trials is seeing how long the drug dose is effective. That makes it critical to keep patients in the trial through the follow-up visit(s), which may be after six months or longer. Sponsors are encouraged to offer an open-label extension to help with patient recruitment and to assess the durability of effect.

Along with these and the patient enrollment considerations discussed above, here are a few additional considerations for strengthening site selection, staffing, safety monitoring, and post-study care continuity for patients:

Site selection

Studies generally benefit from leveraging a good mix of academic institutions and non-academic psychiatric sites. Some academic institutions have years of research knowledge about psychedelic substances, as well as appropriate research facilities and infrastructure. However, they may need support for working in a regulatory-controlled environment.

Conversely, sites that conduct industry-sponsored psychiatric trials may be experienced with regulatory-controlled research. They also may have established referral networks for patient recruitment, but may not commonly employ psychotherapists or have experience specifically with psychedelic compounds.

Ideally, sponsors should look for sites with the proper Schedule I licensing and staff training, standardized facilities, session recording technology, trained raters, and specialized therapists who are distinct from the safety monitors. The good news is that an increasing number of sites now have these capabilities.

Staffing

For psychedelic-assisted psychotherapy models, the therapist’s role is to prepare patients for the trial experience, support them during dosing sessions (as the psychedelic experience can often be difficult), and then help patients integrate their experience after dosing. In a research setting, therapists also walk a fine line in setting treatment expectations for patients and their families. Therapists must develop trust and rapport with patients, yet also convey that patients may not get better after participation in the trial. Therefore, assessing therapist qualifications and providing quality study-specific training are critical.

It’s also tough to blind these trials given the pronounced and well-known effects of psychedelic compounds. To minimize non-specific therapeutic treatment effects on efficacy outcomes, therapists and clinical efficacy raters should never be the same individuals. Raters have a different responsibility from therapists; they must collect unbiased outcome data and thus should remain independent from and blinded to dosing sessions, safety monitoring, and other study processes. To improve the collection of unbiased data and minimize potential rater inflation, sponsors can:

• Train raters on their role and the proper administration of the outcome measurement instrument (e.g., the HAM-D, MADRS, or CAPS-5).
• Employ centralized, third-party raters blinded to patients’ study visits and experiences.
• Use one scale to qualify patients for study enrollment (e.g., the Hospital Anxiety and Depression Scale for Depression [HADS-D]) but another scale (e.g., the HAM-D) for baseline and subsequent measurements.
• Blind the study’s entry criteria in the protocol. We sometimes suggest that sponsors avoid including entry criteria in public disclosures (e.g., their clinicaltrials.gov postings). Only the Institutional Review Board (IRB) sees the unblinded protocol. Sites, staff, and patients would then not know required threshold scores in entry criteria, reducing the possibility of rater inflation, patient or staff manipulation, etc.

Safety monitoring

Safety monitoring carries its own unique challenges. Altered states of consciousness caused by psychedelics can last anywhere from a few minutes to many hours, depending on the compound, with lingering effects after the initial response has worn off. Proper safety monitoring is needed during dosing sessions and afterward to protect not only vulnerable patients—whose vulnerability may be heightened by the psychedelic—but also site staff and therapists.

To strengthen safety monitoring, ideally:

• The informed consent process should be detailed and include active facilitation by site staff.
• “What if” boundaries should be established with therapists. For example, the patient could stipulate whether physical touch should be used if the session becomes challenging or difficult.
• Two trained staff members should be in the room during dosing sessions. Ideally, one male and one female; at least one should be a licensed therapist.
• Sessions should be videotaped and monitored—either observed in real-time or reviewed as needed by a third party (with proper patient consent).
• Sites should have safeguards for psychological or physical adverse effects—including real-time availability of medical personnel.
• Patients should have regular post-dose check-ins and be closely monitored between clinic visits for adverse effects, including worsening symptoms and suicidality. The protocol should establish suicidality measures that are actively monitored, and each site should have a written action plan to follow if patients develop suicidal ideation.

We recommend incorporating a discharge readiness evaluation before patients leave the dosing session. It should work in tandem with preparatory sessions given to family members and caregivers that explain what they should expect once the patient gets home and what to do should concerns arise.

Ensuring post-study continuity of care

Sponsors, CROs, and sites should work together proactively to define how care will persist once a psychedelic study is over, whether the patient continues with the study therapist or is referred to another therapist to ensure continuity of care. We recommend that sites have a documented plan for individual patient care when the patient completes or discontinues from the study—and sponsors should confirm that plan is in place. Best practices encourage coordination between the site, study therapists, and referral providers to ensure that much-needed psychotherapy doesn’t simply cease once the trial concludes.

In summary

The renewed interest in psychedelic research and promising data have opened encouraging new paths for treating neuropsychiatric diseases. Yet less experienced sponsors must be alert to common misconceptions undermining the urgent need for methodological rigor in psychedelic study designs.

These trials often involve fragile patients in desperate need of relief. Sponsors, CROs, and sites that create scientifically rigorous clinical trials stand the best chance of developing psychedelic pharmacotherapies that can materially enhance these patients’ lives.

Christine Moore, PhD, VP, neuroscience, scientific solutions at Worldwide Clinical Trials

References

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2. Phelps J., Shah RN, Lieberman JA. The Rapid Rise in Investment in Psychedelics—Cart Before the Horse. JAMA Psychiatry. 2022; 79(3):189-190. DOI:10.1001/jamapsychiatry.2021.3972
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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6. U.S. Drug Enforcement Administration. DEA speeds up application process for research on Schedule I drugs. January 18, 2018. https://www.dea.gov/press-releases/2018/01/18/dea-speeds-application-process-research-schedule-i-drugs
7. U.S. Drug Enforcement Administration. Drug Scheduling. https://www.dea.gov/drug-information/drug-scheduling#:~:text=Schedule%20I%20drugs%2C%20substances%2C%20or,)%2C%20methaqualone%2C%20and%20peyote