Can groundbreaking treatments for depression and other psychiatric conditions come from substances once considered purely recreational or even taboo? A recent study by researchers at Johns Hopkins Medicine suggests the answer may be yes. They found that high doses of DXM (dextromethorphan) and psilocybin, substances known for their hallucinogenic effects, can lead to significant psychological benefits when administered in a controlled, supportive setting.
Their findings were published in the journal Psychedelic Medicine.
Dextromethorphan (DXM) and psilocybin are two psychoactive substances with distinct mechanisms of action, yet both have captured the interest of researchers for their potential therapeutic benefits. DXM is a common ingredient found in over-the-counter cough suppressants, acting primarily on the N-methyl-D-aspartate (NMDA) receptors, which play a role in pain sensation, mood regulation, and memory.
Psilocybin, on the other hand, is a naturally occurring psychedelic compound found in certain species of mushrooms. It primarily affects the serotonin receptors in the brain, leading to profound alterations in perception, mood, and thought.
The motivation behind this research stems from a growing interest in alternative treatments for depression and other mental health disorders. Traditional pharmacotherapies often take weeks or months to show benefits, and not all patients respond to these treatments. In contrast, psychedelic substances like psilocybin, found in so-called “magic” mushrooms, and dissociatives such as ketamine, which like DXM is an NMDA receptor antagonist, have shown promise for their rapid and profound effects on mental health.
“There has been keen interest in dissociative and psychedelic medicines as a broader category of rapidly-acting mental health treatments. We had a unique opportunity to compare the psychological effects of dextromethorphan (an NMDA-receptor mediated dissociative drug, like ketamine) to psilocybin (a ‘classic’ serotonergic psychedelic) in a sample of healthy volunteers,” said study author David Mathai, a board-certified psychiatrist, owner at Sattva Medicine, and assistant professor at The Johns Hopkins University School of Medicine.
The researchers conducted a double-blind, within-subjects crossover study involving 20 participants. These individuals were not only medically and psychiatrically healthy but also had prior experience with hallucinogens. Over several sessions, participants received doses of either DXM, psilocybin at various levels, or a placebo, with sessions spaced about ten days apart. The study environment was designed to be comfortable and supportive, encouraging participants to focus inwardly while listening to music, with trained monitors available for assistance.
The effects of these substances were assessed through a variety of measures, including questionnaires that evaluated the personal meaning, spiritual significance, psychological insight, and challenge of the experiences. Additionally, the study looked at physical discomfort and disembodiment sensations and tracked the persisting effects on participants’ attitudes toward life, self, mood, relationships, behavior, and spirituality one week after dosing.
Both DXM and psilocybin, across all tested doses, were consistently associated with experiences rated as more personally meaningful, spiritually significant, psychologically insightful, and challenging compared to placebo conditions. These effects were noted immediately after the drug sessions and remained significant one week later. Notably, psilocybin, especially at higher doses, led to more extensive domains of positive change than DXM, indicating dose-dependent effects on psychological well-being.
“Psychedelic research has been criticized for inadequate blinding/masking of treatment condition, so we took various steps to make it difficult for participants to guess which drug they had received, and we measured how effective we were in this process,” Mathai told PsyPost. “We found that individuals struggled to guess which drug or dosage range they had received, but there was still a ‘dose-dependent’ effect for psilocybin, wherein higher doses of drug had more significant effects.”
“It isn’t surprising to see that higher doses of psilocybin would do this, but it was unexpected to see this even when participants were confused about what they had received. This supports the idea that the benefits of psychedelic use exist beyond specific expectations of benefit.”
Further analysis of the study’s findings showed qualitative themes that emerged from the participants’ experiences, including profound personal and transpersonal insights. One week after dosing, both DXM and psilocybin were linked to positive persisting effects across various aspects of psychological health compared to placebo.
These findings underscore the potential of these substances to induce meaningful experiences that contribute to lasting positive changes in attitudes toward life, self-perception, mood, relationships, behavior, and spirituality.
“These drugs are associated with experiences of personal meaning, spiritual significance, and psychological insight that contribute to wellbeing when administered under carefully supervised conditions,” Mathai said. “In this study, both dextromethorphan and psilocybin produced increases over placebo in ratings of drug experience that were predictive of psychological benefit at one week. These effects tended to favor psilocybin, especially as psilocybin dose increased. As clinical and research applications of these drugs emerge, it seems important to prioritize the psychologically valuable drug experiences involved.”
However, the study also noted some challenges, particularly with DXM, related to physical discomfort and tolerability. Interestingly, physical discomfort during DXM sessions, but not experiences of disembodiment, was found to predict negative mood changes one week later, highlighting the importance of minimizing physical side effects in therapeutic applications.
“It would be easy to look at the data here and say that classic psychedelics outperform dissociatives across the psychological measures examined,” Mathai told PsyPost. “However, there are other variables to consider. First, these findings are unique to the highly specific conditions of drug administration for dextromethorphan and psilocybin used in this study, which may not generalize to other conditions of use.
“Second, dextromethorphan was poorly tolerated by participants, and physical distress was also related to negative changes in mood. It’s therefore possible that outcomes for dextromethorphan would improve with enhanced tolerability. Finally, the experimental conditions at our Center have been optimized over several decades for classic psychedelics, and not dissociatives. The ideal parameters and context for dissociative administration may vary, in ways we are still learning about.”
However, the study is not without its limitations. The crossover design, while useful for comparing effects within the same participants, may be influenced by the lingering effects of the substances, potentially confounding the results. Additionally, the applicability of these findings to clinical populations remains to be seen, as the study involved healthy volunteers. Future research will need to explore how these substances affect individuals with specific psychiatric conditions and whether the profound experiences they induce can be effectively integrated into therapeutic settings.
“My hope is that this study will highlight the importance of building on meaningful drug experiences with supportive preparation and aftercare, as is common for psychedelic-assisted therapy trials but not routine for clinical applications of dissociatives (the latter of which are already underway),” Mathai said. “This approach may allow for greater and more durable forms of therapeutic benefit, while also minimizing the psychological risks associated with these drugs.”
The study, “Double-Blind Comparison of the Two Hallucinogens Dextromethorphan and Psilocybin: Experience-Dependent and Enduring Psychological Effects in Healthy Volunteers,” was authored by David S. Mathai, Samantha Hilbert, Nathan D. Sepeda, Justin C. Strickland, Roland R. Griffiths, and Albert Garcia-Romeu.
