Inside a Psychedelics Clinical Trial

Posted on September 13, 2026October 7, 2026

a man colors a flower in a coloring book next to a green pillow

Before a BCSP study participant takes a capsule of psilocybin, researchers must prepare in ways unlike almost anything else in basic science research: navigating state and federal approvals, inspections by DEA (Drug Enforcement Administration) agents, and guiding the volunteer study participants through their expectations of the experience and what kind of support they could need. Clinical trials are central to the BCSP’s mission—but unlike in therapeutic trials, the goal isn’t to test novel treatments or new psychiatric drugs. “We’re doing basic investigations into the neuroscience of psychedelics, rather than doing drug development for treatment of mental health disorders,” says faculty director Michael Silver. “We hope that our research will lead to a broader understanding of how psychedelics work in the brain and on the mind and that this foundational knowledge will eventually lead to better treatments.”

Even for experienced researchers, working with psychedelics can pose new challenges, from procuring Schedule I substances to guiding participants through potential psychoactive effects to appropriately documenting adverse events.

How to get FDA and DEA approval

Depending on which federal Schedule a substance falls under, it may require additional steps for approval. Schedule II substances, like opioids, cocaine, and Adderall, are designated as having a high abuse potential but some medical use; they require strict storage security and registration with the DEA. Schedule I substances, including psychedelics, have been designated by the DEA as having no medical use and a high potential for abuse, so they require even higher levels of regulatory oversight.

Many psychedelic substances are Schedule I, which means that the BCSP’s psilocybin studies require additional steps: at UC Berkeley, human subjects research with psilocybin must be approved by the University’s institutional review board, the Regulatory Advisory Panel of California, the Food and Drug Administration, or FDA, and the DEA.

On September 14, the FDA held a public hearing to talk about the potential future therapeutic use of psychedelic drugs in supervised and supportive settings, which would require the rescheduling of psychedelics from Schedule I. Those opposed to rescheduling often argue that psychedelics have not yet been proven to have an acceptably low potential for abuse or addiction; other experts disagree. “Some of these substances are natural products that have been used as medicines for centuries,” says Silver. “The potential for abuse of some psychedelics is far less than some drugs that are typically considered to be medications in Western societies.”

Where do you store a Schedule I substance?

Once the trial has been approved by the FDA, researchers need to obtain the substance itself. “Because it’s an FDA-regulated clinical trial, it needs to be pharmaceutical grade,” explains Silver. “There are only a handful of viable suppliers that have clearance from the DEA.”

Once researchers have the substance, there are strict protocols to keep it secure. “We have very intense safes where the drug is stored, extensive logging and record-keeping, and 24/7 temperature monitoring. The DEA has sent agents to inspect our facility so the drug doesn’t get into the wrong hands,” says Silver, who is the official Schedule I DEA license holder for the BCSP’s human subjects research.

Preparing and dosing participants

It might be labor-intensive to obtain the federal agencies approvals for this research, but the current excitement about psychedelics research makes it easy to recruit participants. “We literally have hundreds of people on a wait list,” says Silver. “Some people are interested for pro-social reasons, and some just because they think it would be cool to have a psychedelic experience in a Berkeley lab, but recruitment has been a piece of cake.”

Preparing the participants for their research experience is largely the work of the BCSP’s clinical research coordinators, Michael Zadeh and Erin Vinson, and session monitors, physicians and licensed nurse practitioners who also stay with a participant during the dosing to provide support. The study’s protocol includes conversations between team members and participants about their preconceptions about psychedelics: if they’ve had negative or positive experiences in the past and what their expectations may be about the dosing.

The preparatory conversations include setting intentions, understanding a patient’s current stressors in case they come up, and talking about techniques for grounding and self-awareness. These conversations are different from those in more typical clinical trials, because a psychedelic experience will likely be different than that of other drugs. “In a lot of drug trials, the goal is to quell some symptoms, to reduce problems that the participant has,” says Zadeh. “Psychedelic dosings aren’t usually as straightforward.”

In the pre-dosing conversations, BCSP staff also talk with participants about how they would like to be supported while experiencing the effects of psychedelics. Zadeh explains, “We ask them questions like, would you welcome session monitors to talk you through things that are coming up, or would you rather be left alone?” Session monitors are trained to provide psychological support and to attend to any adverse events during the study, including any need for psychological support should difficult thoughts or feelings arise.

a man and a woman sit down and have a conversation in a clinical room — Before dosing, BCSP staff talk with participants about how they would like to be supported while experiencing the effects of psychedelics. These photos are are-enactments and not of actual BCSP research participants.

Clinicians also examine a participant’s physical health.

Recording adverse events

During the session itself and in conversations in follow-up study visits, BCSP staff track the experiences of participants to learn how psychedelics affect the mind. That includes recording adverse events, which are defined as any untoward or unintended medical occurrence, including symptoms, experienced while a participant is undergoing a clinical trial.

“Fundamentally, the purpose of adverse events is to better understand how drugs affect people, and to do it in a systematic way that can really be analyzed and doesn’t have bias to it,” says Alia Lilienstein, a research physician at the BCSP.

It’s a common misconception that “adverse events” are necessarily negative. In fact, drugs can also have unintended positive side effects. For example, Viagra was initially developed as a medication for angina (cardiac chest pain). “It turned out it wasn’t helpful in their early clinical trials for chest pain for angina, but they noticed an interesting adverse event: men in the drug group were reporting spontaneous erections and men in the placebo group were not,” says Lilienstein. “It was enough of a difference that they decided to study it for erectile dysfunction.”

Positive adverse events can be cause for concern, which is part of why the FDA has issued guidance to report positive adverse events as well. As the FDA published in July 2026, “Some expected psychoactive effects such as euphoria, hallucinations and other perceptual distortions, and alterations in cognition should also be recorded as AEs for psychedelic drugs given their association with abuse potential, even if subjects do not describe these effects as adverse.”

To track adverse events, Lilienstein and other BCSP staff include participants’ spontaneous reports, in which they notify researchers within 48 hours of any change from their baseline health. “We counsel them about specific things that we’re trying to measure, but also that they should notify us about all events, even tripping off a curb or the common cold, because there’s always the chance that a drug will make some people more susceptible to the common cold,” says Lilienstein.

But with psychedelic substances, adverse events are often far more subjective than the common cold. “When people experience love for family members, or self-compassion, should those be recorded as adverse events? What about awe or expansiveness or oneness?” asks Lilienstein. “Establishing a baseline can be really hard, but if anything happens that seems different than someone’s baseline, it’s worth reporting as an adverse event.”

A meaningful process

Although working with psychedelics can be more complicated for researchers compared to other substances, it can also be highly rewarding. “We learn a lot about our participants’ lives that isn’t necessarily standard for this kind of study,” says Zadeh. “For other trials, you don’t need to know about the challenging things they may or may not want to process, but it’s really important that these things are understood by our staff so that we can all remain sensitive and be supportive.”

While that creates additional responsibilities, it’s also a privilege. “Even if it’s not the goal of the study to treat anyone for their problems, a lot of people come in really excited and curious about what insight the psychedelic might give them into themselves or the world, and I’ve seen a lot of people come out of the study feeling really positive,” says Zadeh. “It’s a joyful thing to be a part of.”

Expectancy Effects in Psychedelic Trials

Abstract

Clinical trials of psychedelic compounds like psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltrptamine (DMT) have forced a reconsideration of how nondrug factors, such as participant expectations, are measured and controlled in mental health research. As doses of these profoundly psychoactive substances increase, so does the difficulty in concealing the treatment condition in the classic double-blind, placebo-controlled trial design. As widespread public enthusiasm for the promise of psychedelic therapy grows, so do questions regarding whether and how much trial results are biased by positive expectancy. First, we review the key concepts related to expectancy and its measurement. Then, we review expectancy effects that have been reported in both micro- and macrodose psychedelic trials from the modern era. Finally, we consider expectancy as a discrete physiological process that can be independent of, or even interact with, the drug effect. Expectancy effects can be harnessed to improve treatment outcomes and can also be actively managed in controlled studies to enhance the rigor and generalizability of future psychedelic trials.

Section snippets

Placebo Response, Placebo Effect, and Expectancy

Expert consensus distinguishes the placebo response from the placebo effect (6,7). The placebo response includes all health changes that result after administration of an inactive treatment, which includes behavior related to being observed, i.e., the Hawthorne effect (8), regression to the mean (9), and other nonspecific effects of clinical care (10).

The placebo/nocebo effect refers to the changes that are specifically attributable to placebo mechanisms and can be defined as the difference

Unblinding and Its Relationship to Expectancy

Unblinding occurs when patients recognize their treatment allocation in a randomized controlled trial (RCT). Usually, unblinding is captured by asking patients at the end of the trial to guess their treatment. If this treatment guess/perceived treatment matches the actual treatment at a higher than chance rate, then the trial has weak blinding integrity.

Most psychiatric trials have not assessed blinding integrity; it has been estimated that in this domain, only 2% to 7% of trials report

Changing Expectancy

Expectancy is not a static trait; rather, it changes dynamically according to new information and experiences (27). The ViolEx model has been proposed to account for both how expectancies change and why they are sometimes maintained even when contradictory information is obtained (27). For example, consider the fact that many psychedelic treatments include more than 1 psychedelic drug session. It is reasonable to assume that patients change their expectations in-between drug sessions as a

Measuring Expectancy and Blinding Integrity

Studies that assess expectancy often use a self-constructed questionnaire rather than a standardized and validated measure, which hinders generalization. To help overcome this issue, here we list validated expectancy measures. The most popular one is the Credibility and Expectancy Scale, which has been shown to have good psychometric properties (34). Alternative measures are the Stanford Expectations of Treatment Scale (35), which focuses on perceived benefits and risks of treatments; the

Macrodose Trials

Blinding integrity has been found to be poor in psychedelic macrodose RCTs that measured it (42, 43, 44). For example, Holze et al. noted that only 1 patient of 20 mistook lysergic acid diethylamide (LSD) for a placebo (95% correct guess rate) (45). Similarly, Bogenschutz et al. reported that 90 of 95 treated patients correctly guessed their treatment allocation (94% correct guess rate), showing that blinding integrity was almost nonexistent in these trials (4).

Expectancy has only been measured

Separating Expectancy and Drug Effects

Attempts to conceal treatment allocation in psychedelic studies often involve incomplete disclosure of the study design. In some nontherapeutic studies, investigators inform participants that they may receive one among many psychoactive substances, although the actual study design may only involve a limited number of drugs and doses (61,62). For example, in an LSD microdose trial, de Wit et al. told patients that they might receive a hallucinogen/cannabinoid/opioid/stimulant/sedative or placebo

Drug-Placebo Interactions

Most trials consider the observed treatment effect to be the sum of the placebo and the drug effect. However, this simple arithmetic may not apply to all circumstances, for example where interactions exist between drug and placebo effects, i.e., the total treatment effect may be less or more than the sum of the drug and placebo effects (79). Such drug × placebo interactions can be demonstrated in balanced placebo designs; for example, Hammami et al. (80) used a crossover variant of the balanced

Lessons From the Pain Literature

Outsized placebo responses have been problematic for clinical trials of novel pain management drugs and interventions for decades and have contributed to the difficulty in developing novel analgesics despite an impressive array of novel molecular targets validated in animal models (82). Pain, as a sensory experience, can be quantified using various psychophysical measures, which allows for clear delineation of drug-induced relief. In contrast, depression, which is the subject of most

The Neurophysiological Basis of Expectancy

When placebo first appeared in medical dictionaries and texts from the 18th and 19th century, the term was generally defined as an inert substance whose primary value is to soothe, rather than benefit, the patient (61). Since the mid-20th century, most usages of the term preserved the distinction between true benefit and psychological benefit (62), perhaps reflecting the increasing emphasis across medicine and psychiatry that drug therapy could be explained primarily in terms of the drug’s

Conclusions

Expectancy effects are widely expected in psychedelic trials, but to date, only a few studies have assessed them. We distinguish between expectancy and unblinding and recommend treating these as separate but related concepts. A deeper understanding of these effects in psychedelic trials will require, first and foremost, a consistent effort across research groups to incorporate standardized measures of both expectancy and blinding integrity throughout the life cycle of these complex trials, as

I Got a Tour of the First Psychedelic Therapy Clinic in Britain

The CIPPres Clinic in London is all Scandi chic, leafy houseplants and psilocybin trials.

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.

United States National Institutes of Health grant funding for psychedelic-assisted therapy clinical trials from 2006-2020

Background: Medicine is currently experiencing a “psychedelic renaissance”, said by many to have commenced in 2006. Since then, clinical trials have consistently demonstrated promising findings for psychedelic-assisted therapies in the treatment of various mental health conditions and addictions. While most of this work has been privately funded, governmental biomedical research funding bodies in countries such as Australia, Canada, Israel, New Zealand, and the United Kingdom have begun supporting it. Given that the United States National Institutes of Health (NIH) is the largest public funder of biomedical research in the world, it is important to understand the degree to which the organization is supporting clinical trials of psychedelic-assisted therapies. We are unaware of existing literature quantifying direct NIH grant support for psychedelic-assisted therapy clinical trials, so we sought to answer this important question by searching all NIH grants awarded since the beginning of the psychedelic renaissance.

Methods: We queried NIH RePORTER, NIH’s grant database, for grants awarded from 2006-2020 mentioning the psychedelics 3,4-Methylenedioxymethamphetamine (MDMA), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ayahuasca, dimethyltryptamine (DMT), ibogaine, lysergic acid (LSD), mescaline, peyote, and psilocybin. We manually reviewed resulting grants to determine whether they directly funded psychedelic-assisted therapy clinical trials.

Results: We identified zero NIH grants directly funding psychedelic-assisted therapy clinical trials during the study period.

Conclusion: While governmental biomedical research funding bodies in other countries have begun funding clinical trials of psychedelic-assisted therapies during the psychedelic renaissance, NIH has yet to directly fund a single psychedelic-assisted therapy clinical trial. Concerns about risks related to psychedelics, a federal law preventing promotion of legalization of Schedule 1 drugs, and prioritization of grants for other types of studies on psychedelics may explain the dearth of NIH funding for psychedelic-assisted therapy clinical trials.

Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects

Background: After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans.

Methods: In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects.

Results: Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed.

Conclusions: In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.

Psychiatry & the psychedelic drugs: Past, present & future

The classical psychedelic drugs, including psilocybin, lysergic acid diethylamide and mescaline, were used extensively in psychiatry before they were placed in Schedule I of the UN Convention on Drugs in 1967. Experimentation and clinical trials undertaken prior to legal sanction suggest that they are not helpful for those with established psychotic disorders and should be avoided in those liable to develop them. However, those with so-called ‘psychoneurotic’ disorders sometimes benefited considerably from their tendency to ‘loosen’ otherwise fixed, maladaptive patterns of cognition and behaviour, particularly when given in a supportive, therapeutic setting. Pre-prohibition studies in this area were sub-optimal, although a recent systematic review in unipolar mood disorder and a meta-analysis in alcoholism have both suggested efficacy. The incidence of serious adverse events appears to be low. Since 2006, there have been several pilot trials and randomised controlled trials using psychedelics (mostly psilocybin) in various non-psychotic psychiatric disorders. These have provided encouraging results that provide initial evidence of safety and efficacy, however the regulatory and legal hurdles to licensing psychedelics as medicines are formidable. This paper summarises clinical trials using psychedelics pre and post prohibition, discusses the methodological challenges of performing good quality trials in this area and considers a strategic approach to the legal and regulatory barriers to licensing psychedelics as a treatment in mainstream psychiatry.

Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression

Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments’ therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.

Breakthrough for trauma treatment: Safety and efficacy of MDMA-assisted psychotherapy compared to paroxetine and sertraline

Unsuccessfully treated posttraumatic stress disorder (PTSD) is a serious and life-threatening disorder. Two medications, paroxetine hydrochloride and sertraline hydrochloride, are approved treatments for PTSD by the Food and Drug Administration (FDA). Analyses of pharmacotherapies for PTSD found only small to moderate effects when compared with placebo. The Multidisciplinary Association for Psychedelic Studies (MAPS) obtained Breakthrough Therapy Designation (BTD) from the FDA for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD on the basis of pooled analyses showing a large effect size for this treatment. This review covers data supporting BTD. In this treatment, MDMA is administered with psychotherapy in up to three monthly 8-h sessions. Participants are prepared for these sessions beforehand, and process material arising from the sessions in follow-up integrative psychotherapy sessions. Comparing data used for the approval of paroxetine and sertraline and pooled data from Phase 2 studies, MAPS demonstrated that MDMA-assisted psychotherapy constitutes a substantial improvement over available pharmacotherapies in terms of safety and efficacy. Studies of MDMA-assisted psychotherapy had lower dropout rates compared to sertraline and paroxetine trials. As MDMA is only administered under direct observation during a limited number of sessions, there is little chance of diversion, accidental or intentional overdose, or withdrawal symptoms upon discontinuation. BTD status has expedited the development of MAPS phase 3 trials occurring worldwide, leading up to a planned submission seeking FDA approval in 2021.