PTSD: National Center for PTSD

Psychedelic-Assisted Therapy for PTSD

Leslie Morland, PsyD and Joshua Woolley, MD, PhD

Psychedelics are being increasingly researched as a novel method of augmenting the effectiveness of psychotherapies for the treatment of mental health conditions. The most studied psychedelics to date include psilocybin and 3,4-methylenedioxymethamphetamine (MDMA). This article focuses on the use of psilocybin- and MDMA-assisted therapy (P-AT and MDMA-AT) for the treatment of posttraumatic stress disorder (PTSD) in Veterans.

Overview of Psychedelics for Mental Health

Despite the effectiveness of current evidence-based treatments for PTSD and depression, many people do not benefit enough from these treatments. One exciting area of research is examining psychotherapy augmentation strategies with psychedelic drugs, a subclass of hallucinogenic drugs that trigger non-ordinary states of consciousness. They "alter perception and mood and affect numerous cognitive processes" (1). Two specific psychedelic compounds, MDMA (often referred to as a non-classic psychedelic) and psilocybin, have received most of the research attention to date. While these are both still Schedule I substances—drugs with high abuse potential and no currently accepted medical use—ongoing research efforts have found support for using these compounds in conjunction with therapy to treat various mental health conditions, including PTSD. The Veterans Health Administration's (VHA) Office of Research Development (ORD) is funding research on psychedelic compounds in Veterans.

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MDMA-Assisted Therapy

MDMA-Assisted Therapy (MDMA-AT) involves the use of MDMA as an adjunct to psychotherapy for the treatment of different mental health conditions. MDMA is a monoamine releaser and re-uptake inhibitor with indirect effects on neurohormone release. The effects of MDMA include reduced fear (2), increased social engagement (3), increased openness (4), increased receptiveness to positive affect (5), increased empathy and compassion (6,7), increased feelings of closeness (8), and increased disclosure of emotional content (9). MDMA targets memory reconsolidation and fear extinction processes, allowing for expanded perspectives and positive, affirming experiences. These effects are primarily attributed to MDMA's activation of the 5-HT, or serotonin system (10).

MDMA-AT is currently being investigated for its potential to treat eating disorders (11), anxiety (12), alcohol and substance abuse (13), and PTSD (14). The premise for MDMA-AT is that the therapeutic effects of MDMA are the result of an interaction between the medicine, the psychotherapy component, and the mindset of the participant and the therapists involved. The FDA is reviewing the evidence for MDMA-AT for the treatment of PTSD, which may involve future rescheduling and approval of MDMA for this purpose (15).

Mechanisms of action for MDMA-AT for PTSD

There is interest in examining MDMA to address PTSD due to it being an empathogen-entactogen (i.e., a drug that causes release of serotonin and dopamine) and elevating hormones and neurotransmitters that:

• Lead to greater social engagement, openness, empathy, receptiveness to positive affect, and disclosure of emotional content (4,16);
• Facilitate the release of oxytocin, which increases levels of empathy and closeness while also lowering stress responses (17);
• Increase self-compassion and prosocial feelings, both of which can assist with perspective taking when recalling a traumatic experience (18,19);
• Reopen the social reward learning critical period (20), creating cognitive flexibility that may support unlearning of distorted beliefs developed through traumatic experiences and the relearning of more helpful beliefs (21);
• Allow people to have higher tolerance when remembering unpleasant memories (22)—a finding corroborated in humans following animal studies that showed that MDMA assists with improving fear extinction learning due to reducing amygdala activity (23), thus allowing for easier recall of traumatic memories for PTSD patients who may otherwise become overwhelmed by emotions; and
• Bolster fear extinction through improved hippocampal and ventral/medial prefrontal cortex activity (24), both of which show deficits in people with PTSD (25).

These key areas help individuals with PTSD to overcome avoidance and better address their PTSD symptoms while working through their trauma under the guidance of a therapist.

Evidence for MDMA-AT for PTSD

To date, the greatest evidence base is for the Lykos Therapeutics ("Lykos"; formerly MAPS Public Benefit Corporation) protocol (26), which includes twelve 90-min therapy sessions plus three 6-8-hour medicine sessions. The medication sessions are separated by at least 21 days, and each requires the engagement of 2 therapists. There are three 90-minute preparation sessions prior to the first medicine session and each medicine session is followed by three 90-minute integration sessions during which the patient has an opportunity to process their experience with the therapist(s).

Two recent randomized placebo-controlled phase 3 trials of the Lykos MDMA-AT protocol have demonstrated treatment efficacy with large effect sizes. In both trials, PTSD symptom severity significantly decreased more for participants who were administered MDMA-AT than for participants who received placebo and therapy, supporting the therapeutic value of MDMA itself as an addition to psychotherapy (27-30). Efficacy of MDMA-AT for PTSD has also been demonstrated in one placebo-controlled phase 2 trial (31). Four additional phase 2 studies focused on dose response, with all studies finding that participants in MDMA-AT were more likely to achieve clinically significant PTSD reductions than those in the control group (32-34).

Current research underway

Although MDMA-AT has historically been used with a non-directive therapy approach to help individuals process traumatic memories, as of February 2024, several studies are underway to explore whether MDMA-AT could be further enhanced by augmenting established evidence-based trauma-focused therapies that have been rolled out in VA. These include pairing a single MDMA session with massed Prolonged Exposure (PE; Morland & Schnurr, NCT06117306), combining 2 MDMA sessions with Cognitive-Behavioral Conjoint Therapy (CBCT; Morland, NCT05979844), and group therapy (Stauffer, NCT05961527). There is an additional study focused on military Veterans outside of VA care, which is exploring conducting exposure during a single MDMA session paired with a massed Prolonged Exposure protocol developed at Emory University (Maples-Keller, NCT05746572). These studies will inform next steps for larger clinical trials and implementation. There are also additional pilot studies in VA to examine the Lykos MDMA-AT therapy model (Remick, NCT04264026), as well as a study looking at dose optimization (Yehuda, NCT04784143). There is also a pilot trial of MDMA-AT with Veterans who have co-occurring PTSD and alcohol use disorder, evaluating both changes in alcohol use and PTSD over time (Haass-Koffler, ,NCT05943665 ).

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Psilocybin-Assisted Therapy

Psilocybin is the active ingredient in a variety of hallucinogenic mushrooms. When ingested, psilocybin is converted to psilocin, which then acts as an agonist at several serotonergic and non-serotonergic receptors. Psilocybin has been shown to have low physiological toxicity (i.e., limited negative impacts on physical health) and low abuse potential when orally ingested (35,36).

Individuals who take psilocybin report a wide range of experiences for 4-8 hours depending on the dose, including visual imagery of multicolored geometric shapes, vivid imaginative sequences, synesthesia (i.e., experiencing multiple unrelated senses together, such as tasting color), feelings of bliss and connectedness, dissolution of the self/ego (i.e., loss of a sense of self or the first-person experience), and mystical-type experiences (i.e., experiences that create lasting change in a person's worldview). These psychedelic experiences are often of great personal significance (37). Researchers have begun pairing psilocybin with various forms of psychotherapy, called Psilocybin-Assisted Therapy (P-AT), to support in healing mental health conditions, including PTSD.

Of note, psilocybin remains a Schedule I drug, although as of February 2024, Australia, the states of Oregon and Colorado, and the Canadian state of Alberta have legalized psilocybin for medicinal purposes in supervised settings. Similar bills are currently underway in the states of California, Washington, New Jersey, and Massachusetts. The FDA has been reviewing the evidence for P-AT for mental health treatment, which may lead to legalization of P-AT for this purpose (38).

Mechanisms of action for P-AT

Although psilocybin has shown efficacy for treating depression, anxiety, and substance use (39-41), there has been minimal research on its impact on PTSD symptoms. However, there is great interest in studying the utility of P-AT for treating PTSD given psilocybin:

• Affects neural networks to create positive changes in personality, increased feelings of connectedness, increased openness, improved perspective taking, increased psychological flexibility, and an increased sense of well-being (42-45);
• Facilitates fear extinction and neurogenesis in animals, which may directly counteract the impaired fear extinction and neurogenesis that likely play a key role in the development and maintenance of PTSD (46,47); and
• Induces emotional breakthrough experiences (48) that have been established as a key mediator in long-term psychological change in treatment for other mental health disorders.

Psychedelics can also decrease amygdala reactivity during emotion processing (49,50), which may reverse the heightened amygdala reactivity typically seen in PTSD (51), thereby increasing the ability to process traumatic memories. Psilocybin also increases emotional empathy (51), mindfulness-related capacities (52,53) acceptance, and connectedness while reducing avoidance (54), which may all facilitate PTSD treatment. Alongside sessions of supportive psychotherapy, psilocybin administration may help those with PTSD tolerate challenging emotions and address the traumas that they have experienced, while also finding new perspectives on unhelpful or negative thoughts.

Evidence for P-AT for PTSD

P-AT is showing promise as a powerful treatment for a variety of mental health conditions including treatment-resistant unipolar depression (39), depression and anxiety secondary to serious medical illnesses like cancer (40,55,56), and substance use disorders (41,57). Typical P-AT protocols include a non-directive psychotherapy component focused on preparation and integration of the psychedelic experience, with some including established cognitive behavioral therapeutic modalities, such as Acceptance and Commitment Therapy (58), as part of integration. Protocols typically have about six 60-90-minute therapy sessions and one to two 6- to 8-hour administration sessions (59).

A recent meta-analysis on the effects of P-AT on anxiety and depression showed large and statistically significant reductions of anxiety (60). In the placebo-controlled studies included in the meta-analysis, these results were maintained, indicating the therapeutic potential of psilocybin for treating anxiety and depression. Although there is currently no published data on psilocybin use for treating PTSD, the strong impact of psilocybin on conditions that often co-occur with PTSD, such as depression and anxiety, indicates the potential beneficial impact of the psilocybin augmented PTSD treatment.

While clinical trial data are lacking, anecdotal clinical data from the 1960s-1980s suggests that psychedelic therapy can help individuals deal with severe trauma (61,62). More recently, a survey of U.S. Special Forces Veterans who received ibogaine and 5-MeO-DMT at a psychedelic clinical program in Mexico reported substantial improvement in PTSD symptoms and suicidal ideation after the program (63). Finally, preliminary data suggests that a single administration of psilocybin along with group psychotherapy can decrease symptoms of PTSD in older long-term AIDS survivors (64). For a review of psilocybin use for treating trauma-related disorders, please see Khan et al., 2022 (65).

Current research underway

There are ongoing trials of P-AT for alcohol use disorder, depression, and obsessive-compulsive disorder, among others. Because of the significant theoretical potential for psilocybin to support PTSD treatment, there are also ongoing uncontrolled trials of P-AT for PTSD underway with U.S. Veterans (Davis, NCT05554094 ) and UK Veterans, with the latter study testing P-AT with Cognitive Processing Therapy (CPT; Murphy, NCT05876481 ). Although these studies are oriented toward preliminary evaluation and establishing feasibility and thus have small sample sizes, the results of this research will inform future research studies in P-AT for PTSD, which may include larger-scale trials.

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Gaps in & Challenges with Psychedelic Research

While both P-AT and MDMA-AT findings are promising, there are several challenges with psychedelic research that should be considered when interpreting the evidence. While the double-blind randomized controlled trial (RCT) is considered the gold standard design for identifying treatment-specific effects, the strong physical and psychological effects of psychedelics create difficulties effectively conducting blinded, controlled trials. Participants and investigators can typically tell if the person received the investigational product or a placebo thus breaking the blind. Failing to keep patients (and researchers and staff) uncertain of treatment condition assignment (i.e., maintaining the mask or "masking") introduces expectancy effects (27,66). If participants know they have received the psychedelic treatment they already believe will improve their symptoms, this alone can improve clinical outcomes (i.e., the placebo effect) (67).

Conversely, if participants know they received a treatment they already believe is unlikely to improve their symptoms, e.g., an inert placebo, this alone can worsen outcomes (68,69). Use of "active" placebos that mimic aspects of the psychedelic experience is essential, as is the use of masked assessors. Study staff also should be masked to the extent possible. The adequacy of masking for both patients and providers should be assessed, along with patients' treatment expectations before treatment. Despite the large effects of expectancies on treatment outcomes in psychedelic RCTs, baseline treatment expectancies and masking efficacy typically go unmeasured (70). Indeed, many researchers report their psychedelic studies as "double-masked" without testing such claims (71). There is a critical need for trial designs with psychedelics to better manage expectancy effects (72).

In addition to issues with masking, studies on both MDMA-AT and P-AT for PTSD in Veterans are limited. Indeed, there have been no clinical trials conducted on P-AT for PTSD to date in any population. While phase 3 study findings are promising for the Lykos MDMA-AT model, few Veteran participants were included in these studies (about 19% of each sample), limiting the generalizability of these findings to the Veteran population. Although one phase 2 clinical trial looked at firefighters, police officers, and military Veterans, with Veterans making up 84% of the sample (n=22), additional research with a larger Veteran sample is needed to improve generalizability to the Veteran population.

Many existing studies on MDMA-AT and P-AT also include small sample sizes and maintain some risk of bias, particularly with lack of randomization and unexpectedly high response to low dose control conditions (59,73,74). Therefore, there is an urgent need for additional studies with Veteran participants within the VA medical setting, as well as additional studies on P-AT for PTSD and studies with larger, more diverse samples.

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Clinical Considerations for Implementation of Psychedelics

Set and setting

Both MDMA-AT and P-AT protocols emphasize "set and setting", or the preparation of the patients for medicine administration as well as the creation of a safe and welcoming environment for dosage, as essential to safety and effective treatment (75). There are 2 essential components of set and setting, both of which influence the individual's response to the drug and the overall experience during the medicine session. Set consists of the expectations and intentions that the patient comes in with, whereas setting refers to the physical, social, and cultural context in which the drug is taken (76). Protocols also typically require the presence of 2 therapists for all medicine administration sessions, though only one is required to be present during other pre- and post-administration sessions in some cases (59).

It can be difficult to optimize both set and setting for a patient when attempting to implement psychedelic-assisted psychotherapy. Misinformation regarding the use of MDMA or psilocybin (such as an inaccurate view of the drug as a magic pill/solution) can factor into a patient's set, limiting the effectiveness of the medication experience if not properly addressed and resolved during the preparatory sessions. Medicine sessions are optimal under specific physical settings, aspects of which may be hard to achieve if there is limited space available for private use for extended periods of time or restrictions on physical alterations that can be made to the space being used.

Extensive eligibility and safety criteria

It is important to note that current studies examining P-AT and MDMA-AT include rigorous medical and psychological eligibility criteria, with exclusion criteria preventing many individuals with PTSD from being eligible for the studies. One such criterion is the need to taper SSRIs and other psychoactive medications, with which many patients with PTSD are treated (77). While there will likely be fewer inclusion and exclusion criteria for clinical care, there will still be several medical conditions that would pose safety concerns if the patient were to take MDMA, such as uncontrolled hypertension, underlying cardiovascular or cerebrovascular disease (78), and symptomatic liver disease.

Time demands

Current MDMA-AT and P-AT models involve substantial time requirements. MDMA-AT includes 6-8-hour MDMA sessions, preparatory sessions and integrative sessions in the days before and after the MDMA sessions, and additional weekly therapy sessions, which total to about twelve 90-minute sessions. While P-AT protocols differ in some ways, administration sessions last an average of 7.46 hours and include at least one preparation and typically about 6 integration sessions (59). The time demands of either treatment could serve as a barrier to patients with inflexible schedules due to work, childcare, other medical care, etc.

The time commitment for providers can also serve as a barrier to widespread implementation of both P-AT and MDMA-AT. For example, the Lykos MDMA-AT Training Program consists of 100+ hours of training earned through a combination of in-person retreats and online coursework (12,79). It is also often required that 2 providers attend, at minimum, all medicine sessions with patients, which typically takes up the entire workday for both therapists.

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Takeaways and Resources

The current Lykos psychotherapy model has not been studied as a stand-alone treatment for PTSD and is not mentioned in the current VA/DoD Clinical Practice Guideline for PTSD (80). Information on the Lykos model and research can be found on the Lykos Therapeutics website.

Veterans interested in MDMA-AT can explore opportunities to participate in approved clinical trials underway within the VA setting. Studies examining MDMA-assisted therapy for PTSD can be found on ClinicalTrials.gov.

Additional information on research with psychedelic interventions in VA can be found in the most recent evidence brief regarding psychedelic interventions in VA, Also available is a New Horizons in Health podcast, Exploring Psychedelics for the Treatment of Veterans, co-hosted by VA Undersecretary of Health & Deputy Executive Director of OMHSP (September 2023).

For VA providers, 2 opportunities are available for continued learning:

• Continuing education course with credits via TMS: The State of the Field: Psychedelic Treatments for Mental Health Conditions (VA 131011424)
• VA Teams Channel: Psychedelic Medicine Group (Community of Practice): Request to join. You will be added to the invitation for 2^nd Friday of each month at 12p ET.

The PTSD Consultation Program offered a Lecture by the authors in January 2024. View the free recording: MDMA and Psilocybin Therapies for PTSD Treatment: Updates and Future Direction by Leslie Morland, PhD and Joshua Woolley, MD, PhD.

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