Tripping outside the lines: lessons from observational studies of combination psychedelic use beyond regulated clinical contexts

KEYWORDS:

• ibogaine
• psychedelics
• Veterans
• 5-MeO-DMT

Psychedelics have reemerged as potential novel therapeutics in the mental health space, with preliminary efficacy across a range of psychiatric conditions (1–6). While classic psychedelics include compounds such as psilocybin and LSD, other substances often included under the umbrella term of “psychedelics” include the dissociative anesthetic ketamine and the entactogen 3,4-methylenedioxymethamphetamine (MDMA) (7). There is growing interest in the potential efficacy and safety of psychedelics for alleviating trauma symptoms in Veteran populations. This interest can be traced back to anecdotal evidence of the antidepressant effects of ketamine during its use as an anesthetic in the Vietnam War (8). The first ketamine clinical trial focused on stand-alone ketamine administration for post-traumatic stress symptoms and was supported by the US Department of Defence (9). Since then, the field has experienced a resurgence of research interest (10–14), including trials in which ketamine has been infrequently combined with a psychotherapeutic intervention (15). Subsequent research extended to explorations of MDMA-assisted psychotherapy in Veteran populations (16,17). Recent surveys have also explored Veterans’ experience using psilocybin (18), and ongoing studies are evaluating psilocybin-assisted psychotherapy as a treatment for PTSD in Veterans (clinicaltrials.gov: NCT05554094 and NCT05876481). Together, early findings from research on ketamine, MDMA, and psilocybin suggest promising results for treating conditions such as treatment-resistant depression and post-traumatic stress disorder (PTSD) and related symptoms in Veterans.

Evidence regarding the potential therapeutic effects of psychedelics is growing, but only Spravato, an esketamine nasal spray, has received FDA-approval for treatment-resistant depression (8). Racemic ketamine has made significant strides in the clinical setting, largely due to its availability as an FDA-approved anesthetic, allowing for off-label use. Notably, MDMA-assisted psychotherapy for PTSD was granted Breakthrough Therapy designation by the FDA in 2017 (19), prompting speculation that MDMA could receive approval as soon as 2024 (20). Meanwhile, access to other psychedelics remains restricted. Primary avenues for legally accessing medicinal psychedelics in North America are through participation in clinical trials, tightly regulated federal approval mechanisms (e.g., Special Access Program in Canada), and a patchwork of legislative reforms (21) in the US including Oregon’s Psilocybin Services Program (22), and through the development of Colorado’s Proposition 122 (23). Due to this cautious and steadily evolving regulatory landscape, an increasing number of patient populations, including Veterans, are exploring alternative avenues for accessing psychedelic treatments. These often operate in a legal gray zone, such as retreat centers in countries with less stringent regulations.

Veterans often have complex patient profiles but primarily seek psychiatric treatment related to PTSD symptomatology. Nonpharmacological interventions are the first line of treatment for PTSD, namely cognitive processing therapy and prolonged exposure (24,25). Prolonged exposure therapy is effective in 60% of Veteran PTSD (25,26), although its effectiveness varies, and pharmacological treatments may also be necessary. However, in Veteran populations combining standard psychotherapy with first-line pharmacological interventions is no more effective than either treatment alone (27). New approaches that are safe and effective in alleviating the psychological suffering of Veteran populations are urgently needed.

One group that may particularly benefit from innovative treatments is Special Operations Forces Veterans (SOFV). They are a specially trained elite military unit that undergo rigorous selection and intense training intended to equip them to serve in high-intensity, specialized missions. Despite comprising approximately 3% of the military personnel, they sustain over half of all combat fatalities (28), with double rates of PTSD symptoms compared with conventional units (29), and experience the highest suicide rates in the military (30,31). Reports consistently indicate that traumatic brain injury (TBI) is prevalent among SOFV (32) and is associated with suicide attempts (33). Due to their complex characteristics and existing co-morbidities, including TBI and suicidality, SOFV face difficulties in qualifying for clinical trials, particularly those intended for the broader, non-Veteran population. This is especially true for studies with restrictive exclusion criteria intended to safeguard Veteran populations with physical or psychological vulnerabilities (clinicaltrials.gov identifiers: NCT05554094 and NCT05876481).

When conventional treatments prove ineffective or insufficient for SOFVs, or for those who do not qualify to participate in clinical trials, some seek alternative options abroad. Three studies have surveyed SOFV s who attended a retreat program in Mexico that provides the long-acting dissociative psychedelic ibogaine and short-acting psychedelic 5-MeO-DMT with psychotherapeutic support (34–36). The studies have examined the outcomes of this program across multiple mental health domains (35), assessed reductions in alcohol use and post-traumatic distress symptoms (36), and explored correlations of psychedelic therapy with concurrent risky alcohol use and trauma-related symptoms (34). An emerging trend in these retreat programs is the method known as “stacking” – combining different psychedelic substances in a single session or treatment protocol. The assumed goal is to enhance or modify the therapeutic potential of the overall psychedelic experience beyond what a single substance is thought to achieve alone. Despite its growing attention in retreat settings, sequentially using multiple psychedelic substances as part of an overall treatment has not yet been evaluated in a formal clinical trial setting for safety or effectiveness. Notably, this approach contrasts with that of most clinical trials, which assess a single substance at a time.

In this issue of the American Journal on Drug and Alcohol Abuse, Davis et al (37) report on combined psychedelic use in a trauma-exposed Veteran population in the article “Open-label study of consecutive ibogaine and 5-MeO-DMT assisted-therapy for trauma-exposed male Special Operations Forces Veterans: Prospective data from a clinical program in Mexico.” SOFVs (N = 86) reporting PTSD symptoms self-selected into a retreat program in Mexico. During this 3-day retreat, participants were administered ibogaine in a group setting, and on the third day they received up to five doses of 5-MeO-DMT. Outcomes included satisfaction with life, PTSD, suicidal ideation, anxiety, depression, insomnia, disability, neurobehavioural symptoms, and cognitive functioning. Results from the study suggest profound improvements across multiple domains of stress and trauma-related symptoms, general improvements in quality of life, and even increases in spirituality. The breadth of outcomes reported on in this study indicates the possibility of Ibogaine and 5-MeO-DMT-assisted therapy to holistically affect the life of a SOFV.

While encouraging, these preliminary conclusions must be accompanied by notable caveats, largely centered around patient safety. The open-label survey study does not provide clearly defined inclusion and exclusion criteria or specify whether the SOFV were being treated for psychiatric conditions as recognized by DSM diagnostic categories. This makes it difficult to determine the applicability of findings to other populations who might benefit from this treatment. The retreat program is operated outside of a standard healthcare setting, limiting generalizability to North American healthcare practice, and provided by practitioners whose professional backgrounds were not detailed. The therapeutic modality (e.g., type of psychotherapy) used as part of the assistive nature of the program was not described, nor are any safety or adverse events data reported. Importantly, ibogaine and 5-MeO-DMT (38) are among the lesser-studied psychedelics, with limited research in clinical trials or healthy populations. As a result, our understanding of their individual safety and effectiveness is sparse. Ibogaine is known to be potentially fatal (39), have adverse effects on the cardiovascular system (40) and may not outweigh the potential benefits, hampering our ability to evaluate the rationale and appropriate methodology for sequential administration as part of a treatment model. Beyond the aforementioned observational studies, only a single case study has been published using the ibogaine and 5-MeO-DMT combination, specifically within the context of addiction (41). Furthermore, the regulatory environment for such psychedelic treatments differs from those in the United States, and the structure of the retreat center may differ from conventional medical programs. Just as the factors of set and setting are considered influential in psychedelic studies, so too do they need to be considered within the context of this type of intervention (42). The international retreat style element can present a unique set of challenges, particularly when it comes to the post-retreat process of integration and assimilating experiences, including ongoing professional support.

Davis and colleagues (37) have enabled the opportunity for an important discussion around the safety and efficacy of international retreat-based treatment programs for trauma-exposed SOFVs. Programs using ibogaine and 5-MeO-DMT are operating irrespective of existing scientific evidence, so we commend the authors for their initiative in incorporating data collection methods into these settings. Such integration between clinical practice and scientific investigation creates a way to better understand these interventions, their effects, and safety profiles, thereby informing future research and policy decisions. It also provides a foundation for structured clinical trials exploring efficacy in controlled contexts. Trauma among SOFV is a particularly high-priority area to address, and preliminary results suggest ibogaine and 5-MeO-DMT assisted therapy has potential to improve symptoms of PTSD and general positive changes in quality of life. These initial findings must come with a careful analysis of the therapy in controlled settings, a recognition of crucial gaps in knowledge, and a consideration of equity in access to these treatments. Given that trauma-exposed SOFV are traveling outside their home country for psychopharmacological treatment, there is a pressing need for rigorous research on the safety and effectiveness of Ibogaine and 5-MeO-DMT assisted-therapy in Veteran populations, with special attention to long-term (i.e., off-site) support that may be needed. While the results are promising for the possibilities of ibogaine and 5-MeO-DMT assisted therapy, we have underscored the need for a measured approach placing priority on conducting further research into the safety of this drug combination.

Disclosure statement

Dr. Mayo is a Clinical Advisor for Heroic Hearts Project Canada.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.