Psychotherapy as a Treatment Element

Psychotherapy is integral to maximizing the treatment effect and ensuring safety, said Muñiz, but it has not been rigorously defined and standardized for use during psychedelic treatment. It is typically involved at three stages of psychedelic trials—at the preparatory stage to help build rapport and establish goals and intentions; during the in-drug treatment sessions to facilitate the sessions and reduce adverse psychological reactions; and in the weeks and months following the administration of psychedelics to process and integrate the experience and ensure psychological stability. “However, we don’t know which features of the psychotherapy intervention are critical for efficacy or what minimum components of the psychotherapeutic intervention are necessary to ensure safety,” said Muñiz, adding that this information is critical for labeling. For example, Sanacora mentioned that if psychedelics are inducing long-term plasticity in humans similar to what the preclinical studies show, it might be better to implement psychotherapeutic augmentation strategies after giving participants a chance to recover from the treatment.

To fully tease out the safety and efficacy contributions of psychotherapy would require well-done factorial studies, said Muñiz. He noted, however, that while FDA regulates labeling, it does not regulate the practice of medicine, which includes off-label prescribing and psychotherapy. They have, however, written labels specifying that a drug should be used only in conjunction with another mode of therapy, said Muñiz. For example, the label for naltrexone as a treatment for alcohol and opioid dependence states that the drug should be part of a “comprehensive management program that includes psychological support.” Another approach FDA uses to ensure safe use of a drug is by requiring a risk evaluation and mitigation strategy¹ that could include elements such as provider training or certification, said Muñiz, noting that this requirement must not be unduly burdensome to patients or the health care system. He added that while risk evaluation and mitigation strategy (REMS) is usually proposed by a sponsor, FDA is considering developing a REMS program for psychedelics given the complexity of the risks associated with these agents.

Steven Levine, senior vice president of patient access and medical affairs at COMPASS Pathways, noted that the model of psychological support used in psychedelic therapy was designed not to provide psychotherapy per se, but to accompany, facilitate, and ensure safety within trials. Video recordings are also used to ensure patient safety, including with regard to the patient–therapist relationship, added Levine. Corine de Boer, chief medical officer of Multidisciplinary Association for Psychedelic Studies (MAPS) Public Benefit Corporation (PBC), agreed that therapists are important for both safety and efficacy, and with the long duration of treatment sessions, two therapists are essential for practicality and safety. “During psychotherapy outside of the psychedelic world, there is always a power relationship between the therapist and the patient, and psychedelics are no different,” she said. Psychedelics may introduce additional risk by creating more openness and more trust, de Boer said.

In addition, the potential for sexual misconduct during treatment sessions has long been a concern to FDA, said Muñiz, in part because of media exposure from specific cases. However, he said this aspect of safety might be beyond the scope of FDA’s authority. The agency is working closely with sponsors to discuss specifics about monitoring, video recording, who is in the room, and what degrees and experience the therapists must possess, he said. How this will translate in the real world in terms of cost-effectiveness and delivery burden if these drugs are approved is unknown, said Muñiz.

Set and Setting

Set and setting are considered integral to a positive psychedelic treatment effect, said Muñiz. The regulatory challenges, he said, are (1) identifying the minimum parameters required to ensure safety, and (2) communicating these requirements on the label. He added that the agency is also working with sponsors to protect patients in clinical trials from the “unique risks that may be associated with the nature of these treatments, including sexual misconduct.”

Guides or “sitters” are key to ensuring a therapeutic set and setting, yet there are few data to characterize different approaches that sitters may take, said Srinivas Rao, chief scientific officer and co-founder of atai Life Sciences. For example, while many practitioners emphasize the need for a music playlist and eyeshades, he questioned whether there are data to support those elements. He added that the role of sitters is complex and extends beyond the psychedelic experience, reiterating the need for prep work, expectation setting, and support.

Concerns about scaling and standardizing the training and actions of sitters motivated Rao and colleagues to explore digital approaches to standardize therapy. Virtual reality systems could be especially helpful, he said, for example, by enabling the detection of incipient anxiety and modulating it. He suggested that visual stimulation or changing the music might help modulate safety and/or efficacy.

Rao’s company is also exploring much shorter acting compounds that could substantially alter the role, or even the need, for a sitter. “Digital may be particularly well suited for some of these compounds,” he said.

Minimizing Bias

Sponsors and regulators have also considered various approaches to enable making valid comparisons, minimizing bias, and accounting for the “dramatic functional unblinding,” said Muñiz. For psychedelic drug development, the use of traditional placebo controls has significant problems, he said.

Placebo effects, or changes in the neurobiological underpinnings of a clinical outcome, result from positive expectations, prior experience, and other aspects of the therapeutic encounter, such as the patient’s mindset, and the psychosocial setting, said Luana Colloca, professor of pain and translational symptom science at the University of Maryland, Baltimore, and an expert in placebo mechanisms. Conditioning can also contribute to the placebo phenomenon, and some people are stronger placebo responders than others (Colloca and Barsky, 2020; Colloca and Miller, 2011). Sanacora added that non-specific effects, or placebo effects, are not unique to psychedelic treatments, but they contribute to a large portion of the effects of most central nervous system treatments.

Some of the strategies researchers have employed include using active controls, subperceptual doses of psychedelics as controls, blinding questionnaires, and raters blinded to the treatment allocation, said Muñiz, noting that each of these approaches has limitations. For example, it may be difficult to identify an active control that has similar subjective effects but is not therapeutic, he said. Low doses of psychedelics may still have psychoactive properties, potentially reducing statistical power and increasing the likelihood of false-negative results. Colloca added that expectations should be measured in both patients and health care providers, and that conditioning can be used to manage placebo effects.

Acknowledging how difficult it is to minimize functional unblinding, Muñiz proposed conducting pivotal dose-response trials without a placebo control, which is explicitly allowed by the Code of Federal Regulations, Title 21, Section 314 and has been addressed in a guidance document from FDA (2003). He said that an NDA could conceivably include just two of these trials but recommended that at least one include a placebo arm for safety characterization.

Additional challenges mentioned by Muñiz include the poorly understood dose-response relationship of psychedelics (Sellers et al., 2018), the generalizability of the treatment given the highly selective patient population enrolled in current studies, the need to understand parameters for retreatment, the need for a non-clinical safety database, and the need for formal studies of abuse potential (Calderon et al., 2018; Sellers et al., 2018). Colloca noted the need for much larger trials than have been conducted thus far, as well as replication studies and data-sharing consortia.

The Role of the Conscious Experience

One remaining unanswered question regarding the critical elements in psychedelic trials is how much the conscious experience has to do with the enduring effects of these drugs, said Sanacora. Charles Raison, the Mary Sue and Mike Shannon Distinguished Chair for Healthy Minds, Children, and Families at the University of Wisconsin–Madison, took the question one step further, asking whether it might be possible to modulate the therapeutic benefit by tweaking the state of consciousness of patients during their psychedelic treatment session.

In Chapter 3, David Olson discussed the development of non-psychedelic psychoplastogens—drugs that have been engineered to remove hallucinogenic-causing properties. If these agents prove to retain therapeutic effects, the implication would be that the conscious psychedelic experience is not necessary, said Raison. Similarly, if people were sedated before taking psychedelics and still experienced relief from their psychiatric symptoms, or even if 1 week or so later they said, “I can’t tell you why, but I feel like a different person. I want to live my life differently. I look at the world differently,” this too would suggest that the conscious experience is not necessary, said Raison. Blinding trial participants would likely be relatively simple, and such a drug would have enormous commercial appeal, he said. He cautioned, however, that anesthetics might disrupt whatever brain effects were linked to psychedelics and also have antidepressant effects.

Raison suggested that doing those kinds of studies is, from a scientific perspective, one of the most important steps the field needs to take. Moreover, he said that if indeed the conscious experience is not importantly causal, “I think the field has a mandate to figure out what is the least amount of psychosocial support [in which] these agents can be safely administered.” Needing less support would improve the cost effectiveness of these treatments and make them easier to scale and standardize, he said.

However, if consciousness is a key player and the narratives that come out of it are driving benefits in some real way, it immediately raises questions about how to optimize the treatment in terms of the depth and longevity of the response, and fully blinding a study would be “more or less logically impossible,” said Raison. “We know that unexpected, untoward conscious experiences can produce long-term changes in mental functioning—posttraumatic stress being a classic example of that,” he said. “So we would expect to see differential lengths of benefit and hence, differential needs for re-dosing depending on whether or not the conscious experience has causal power or whether it’s really more of these basic synaptogenic-type mechanisms.”

Raison added that even if the conscious experience is not essential for therapeutic benefits, there might be other potential benefits. He cited a recent 12-month follow-up study of 27 patients treated with psilocybin for moderate to severe depression, in which mystical experiences correlated with increased well-being but did not correlate with persistent antidepressant effects (Gukasyan et al., 2022). “This is an interesting complexity,” he said. “Maybe the conscious narrative elements are more impactful on certain relevant metrics than on others.” He added that if the conscious experience is not driving efficacy, more frequent re-dosing may be necessary, and relatively similar benefits might be seen both in people who have treatment resistance and in those who are earlier in their disease course. However, if narrative consciousness elements do play a key role, these agents would likely be more impactful early in the disease course or on a recurrent basis in people with treatment-resistant depression, he said.

Sanacora suggested that it is unrealistic to think that the conscious effects are unrelated. “The much harder question is how they are related,” he said, and whether other elements that influence the conscious experience, such as set and setting, would need to be optimized individually for each person.

MDMA-Assisted Therapy Trials for PTSD

Between 2014 and 2017, MAPS conducted six randomized, double-blind Phase 2 clinical trials of MDMA for the treatment of PTSD, which were reported in a pooled analysis by Mithoefer and colleagues (2019). Collin Reiff, assistant professor of psychiatry at the New York University Grossman School of Medicine, summarized the data from the 105 participants in those trials, who had a mean duration of PTSD of 215.3 months. Most participants (86.8 percent) had a lifetime history of suicidal ideation and 30.9 percent had a history of suicidal behavior, said Reiff. Prior to starting treatment, there were three non-drug, 90-minute therapy sessions, he said. Approximately two-thirds of the participants received MDMA at doses between 75 and 125 milligrams, while about one-third received a placebo/control dose of 0 to 40 milligrams of MDMA, coupled with manualized psychotherapy in 2- to 3-hour sessions about 1 month apart, said Reiff. Study participants also had three 90-minute, non-drug therapy sessions prior to the first MDMA session, and three to four additional non-drug therapy sessions following each treatment session.

The primary outcome measure was change in total score on the Clinician-Administered PTSD Scale for DSM-IV² (CAPS-IV), which was administered at baseline and at follow-up visits. After two blinded experimental sessions, the active group had significantly greater reductions in the CAPS-IV total scores from baseline than the control group, with a Cohen’s D effect size of 0.8, which indicates a large treatment effect, said Reiff. Also after two sessions, 54.2 percent of participants in the active group no longer met the DSM-IV PTSD diagnostic criteria compared with 22.6 percent in the control group. Dropout rates were much lower than the average dropout rate for clinical trials, said Reiff.

These Phase 2 trials led to a Phase 3 trial that included 90 adults with chronic PTSD across 15 clinical sites (Mitchell et al., 2021). A CAPS updated with the DSM-5 criteria was used in this trial (CAPS-V), said Reiff. Participants were tapered off their existing medication prior to the study and participated in three preparatory sessions with a male/female therapeutic dyad, followed by an experimental session with MDMA or placebo, and three integration sessions. Each participant received MDMA three times, followed by a set of three integration sessions. In this study, overall scores in CAPS-V dropped nearly 25 points in the MDMA plus psychotherapy group compared with 14 points in the placebo plus psychotherapy group, said Reiff. He added that the MDMA plus psychotherapy group had double the reduction in severity of their PTSD symptoms compared with the placebo group and an effect size of 0.9, “suggesting a large and meaningful difference for MDMA-assisted psychotherapy,” said Reiff. As a comparison, he said selective serotonin reuptake inhibitors (SSRIs) approved for the treatment of PTSD have effect sizes between 0.3 and 0.5 in clinical studies.

Figure 4-2 graphically illustrates the results of this trial. “The difference for remission is staggering,” said Reiff. About 30 percent of participants taking MDMA achieved remission compared with only about 5 percent in the placebo group. He added that MDMA did not induce adverse events of abuse potential, suicidality, or QT c prolongation, a heart condition that can be induced by some drugs.

FIGURE 4-2

Treatment response in a Phase 3 trial of MDMA-assisted therapy for PTSD. Response and remission rates as a percentage of total participants randomized to MDMA (red) versus placebo (blue) after each of three treatment sessions. Responders defined as ≥ (more...)

In 2018, Jerome and colleagues at the MAPS PBC published the results of a pooled analysis of six Phase 2 trials of MDMA-assisted psychotherapy for the treatment of PTSD. The results showed that after two to three active doses of MDMA, there was a reduction in PTSD symptoms within 1 to 2 months of treatment completion and increasing symptom improvement for 12 months (Jerome et al., 2020). The percentage of patients who no longer met PTSD criteria increased by 56 percent at treatment exit to 67 percent at the 12-month follow-up session, according to de Boer. Yet, she noted that MDMA did not work for all participants. Despite having data from 375 patients who were exposed to MDMA in these trials, de Boer said they have not been able to identify prognostic indicators of who will respond to this treatment. “I think this is critical both for the field and for patients and participants,” she said. de Boer added that while MDMA is given three times over the course of 4 months, other antidepressants are often given for weeks, months, or years, only to have symptoms return when the medication is stopped.

On the basis of these results, a Phase 3 study was conducted comparing 46 participants who received MDMA to 44 who received the placebo. At the end of the study period, placebo participants were invited to cross over. Long-term data are still being collected, said de Boer. Colloca noted that outcomes observed in crossover designs can be altered by conditioning responses due to prior therapeutic experiences. Response to both placebos and active drugs can be affected by conditioning and learning effects, she said.

In addition to not working for all participants, de Boer said this treatment has clear risks. The Phase 2 study showed that low-dose MDMA does not provide symptom relief and can cause anxiety, she said. Therefore, they used an inactive placebo in the Phase 3 trial. Participants on SSRIs also needed to be tapered off those medications before they could receive MDMA.

de Boer added that increasing diversity among participants and therapists in clinical trials is important. “As we all know, in clinical trials, marginalized communities are underrepresented.” Part of the MAPS PBC mission is to make sure these modalities will become available for these communities, she said.

Psilocybin Trials for Depression

Several studies have been reported of the successful use of psilocybin for the treatment of depression and treatment-resistant depression, according to Reiff. In an open-label feasibility trial, 12 participants received two oral doses (10 mg and 25 mg) of psilocybin 7 days apart in a supportive setting, with psychological support provided before, during, and after each session (Carhart-Harris et al., 2016). Depressive symptoms were substantially reduced at week one and at follow-up 3 months later, he said.

This study led to a Phase 2 double-blind, randomized controlled trial comparing psilocybin to the SSRI escitalopram, said Reiff. Patients in the psilocybin group received two doses of 25 milligrams 3 weeks apart, plus 6 weeks of daily placebo (akin to taking escitalopram), while those in the escitalopram group received a 1 milligram dose of psilocybin (control) 3 weeks apart plus 6 weeks of daily oral escitalopram (Carhart-Harris et al., 2021). While this study did not show a significant difference in antidepressant effects between psilocybin and escitalopram, Reiff said secondary outcomes “generally favored psilocybin over escitalopram.”

In 2019, COMPASS Pathways launched the Phase 2b COMP360 trial to assess the safety, efficacy, and appropriate dosing of psilocybin in participants with treatment-resistant depression. Levine recapped the design and key elements of the trial, in which 233 participants at more than 20 sites in 10 countries received a single dose of an oral synthetic GMP (Good Manufacturing Practice)-grade formulation of psilocybin. Following preparatory sessions, the treatment was given at one of three doses (1, 10, 25 milligrams) with psychological support from a trained therapist in a standardized, controlled therapeutic setting; integration sessions followed, said Levine. The primary outcome was changed in the Montgomery-Åsperg Depression Rating Scale (MADRS) from baseline to 3 weeks, he said.

Nearly all participants (94 percent) had no prior experience with psychedelics before the trial, said Levine. Two-thirds had a history of suicidal thinking or behavior, although candidates with active suicidality were excluded from the trial, he said. He added that participants were withdrawn from other antidepressants before the trial.

Although the results of this study have not been peer reviewed and published, Reiff reported top-line findings that were disseminated by the company through press releases. These reports indicate that the study achieved its primary endpoint with a 25-milligram dose, demonstrating a significant reduction in MADRS score compared with the 1-milligram dose at 1, 3, and 6 weeks after drug administration.

Although the trial used a psychological support model that provided the minimum components of therapy necessary, robust responses were seen with a dose-response relationship, said Levine. A durable effect was seen in a subset of participants, and investigations are under way to understand who responded and who did not, he said.

“This trial is the largest to date and provides a response rate at about one-half of those observed in prior open-label and randomized clinical trials,” said Reiff. “This is probably the most explicit evidence we have right now on what treating TRD [treatment-resistant depression] might look like with psilocybin.”

Levine also described a separate, small (19-participant), open-label study in which psilocybin was given as an adjunct to an existing SSRI. Although not powered for significance, the study signaled a robust response and remission, said Levine. He called these findings “unexpected” given that there had been preclinical evidence suggesting that chronic administration of serotonergic antidepressants downregulated the availability of the 5-HT_2A receptor as well as anecdotal reports that SSRI antidepressants interfered with the efficacy of psilocybin. Reiff commented that this study suggests that SSRI medication can be taken safely with psilocybin with minimal interference and that COMP360 psilocybin therapy can be taken as a monitored therapy or an adjunctive treatment to SSRI antidepressants.

Levine added that participants in both the 10- and 25-milligram dose groups reported psychedelic experiences. “Also, to some degree that happened with the 1-milligram group,” he said. More information on this aspect of the study will be published and presented at upcoming conferences, he said. Reiff suggested that the 1-milligram dose may be similar to what is referred to as a microdose,³ and could reflect a placebo effect.

Psilocybin Trials for Anxiety and Depression in Patients with Life-Threatening Illness

Patients with life-threatening illnesses, such as cancer, often develop depression and anxiety, which contributes to treatment non-adherence, prolonged hospitalization, increased suicidality, and an overall decreased quality of life (Griffiths et al., 2016). In a double-blind, randomized crossover study of patients with life-threatening cancer and a diagnosis of anxiety or mood disorder, Griffiths and colleagues showed that a high dose (22 or 30 mg) of psilocybin, but not a low dose (1 or 3 mg) (which served as an active control), produced significant decreases in depression and anxiety symptoms after 5 weeks, which persisted through the 6-month follow-up period. A similar double-blind, placebo-controlled randomized crossover study evaluated the efficacy of a single dose of psilocybin combined with psychotherapy in cancer patients with anxiety and depressive symptoms (Ross et al., 2016). This study also demonstrated significant and persistent reductions in all primary measures of depression and anxiety in the psilocybin group compared with the control group.

Psilocybin Trials for Substance Use Disorder

Clinical trials have also demonstrated the effectiveness of psilocybin for treating alcohol use disorder and promoting smoking abstinence, said Reiff. One study enrolled 10 participants who met the DSM-IV criteria for alcohol dependence and had at least 2 heavy drinking days in the previous 30 days. They received 14 sessions of psychotherapy that included motivation enhancement therapy and preparatory sessions, followed by two psilocybin-assisted psychotherapy sessions and two debriefing sessions, said Reiff (Bogenschutz et al., 2015). The study demonstrated a significant and sustained increase in abstinence through 36 weeks and has prompted a much larger study by Michael Bogenschutz and his team at New York University that is currently ongoing, he said.

Another study of 15 participants who wanted to quit smoking combined a 15-week course that combined cognitive behavioral therapy with two or three psilocybin treatments, said Reiff (Johnson et al., 2017). At the 6-month follow-up, 80 percent of participants were laboratory verified as abstinent, he said.