Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences

Abstract

Psilocybin and lysergic acid diethylamide (LSD) experiences can range from very positive to highly challenging (e.g., fear, grief, and paranoia). These challenging experiences contribute to hesitancy toward psychedelic-assisted psychotherapy among health care providers and patients. Co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences and enhances positive experiences associated with psilocybin/LSD. However, limited research has investigated the acute effects of co-use of MDMA and psilocybin/LSD. In a prospective convenience sample (N = 698) of individuals with plans to use psilocybin/LSD, we examined whether co-use of MDMA with psilocybin/LSD (n = 27) is associated with differences in challenging or positive experiences. Challenging experiences were measured using the Challenging Experiences Questionnaire and positive experiences were measured using the Mystical Experience Questionnaire and single-item measures of self-compassion, compassion, love, and gratitude. Potentially confounding variables were identified and included as covariates. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium–high) dose of MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love and gratitude. Co-use of psilocybin/LSD and MDMA was not associated with differences in mystical-type experiences or compassion. Findings suggest co-use of MDMA with psilocybin/LSD may buffer against some aspects of challenging experiences and enhance certain positive experiences. Limitations include use of a convenience sample, small sample size, and non-experimental design. Additional studies (including controlled dose–response studies) that examine the effects and safety of co-administering MDMA with psilocybin/LSD (in healthy controls and clinical samples) are warranted and may assist the development of personalized treatments.

A dual-receptor model of serotonergic psychedelics

“…Looking ahead, increasing clinical interest is being placed on the biased 5-HT1a agonist psychedelic 5-MeO-DMT (Dourron et al, 2023), a substance which is capable of inducing powerful and long-lasting antidepressant effects in minutes (Uthaug et al, 2019). Clinical attention is also beginning to be paid to the positive effects of co-administration of MDMA along with LSD or psilocybin (Straumann et al, 2023; Zeifman, Kettner, et al, 2023), a combination which may also result in a net 5-HT1a agonism bias and greater tolerability (Schechter, 1998). Rather than focusing on the development of non-hallucinogenic psychedelics, which may prove to have limited efficacy outside of animal models (Yaden & Griffiths, 2020), significant evidence exists in support of exploring the pharmacological design space of psychedelic substances with a biased 5-HT1a binding profile similar to that of 5-MeO-DMT or LSD co-administered with MDMA.…”

“…There is also a research literature on the anxiolytic effects of biased 5-HT1a agonists, such as 8-OH-DPAT, in rodent models of psychopathology (Luscombe, Martin, Hutchins, Gosden, & Heal, 1993; Schreiber & De Vry, 1993), and these effects are consistent with those of MDMA and other 5-HT releasing drugs. Reductions in anxiety and avoidance are key mediators in a variety of common psychopathologies and their treatment by psychedelic therapy (Zeifman, Wagner, Monson, & Carhart-Harris, 2023), suggesting a potential link between these effects and 5-HT1a agonism. Notably, outcomes from MDMA assisted therapy are characterized by a significant acute decrease in experiential avoidance (Mitchell et al, 2023).…”

Open MDMA: An Open Source Framework and Practical Guide for the Therapeutic use of MDMA

“…I think LSD and psilocybin are potent tools for reducing resistance. Mixing LSD or psilocybin with MDMA is widely practiced, though poorly studied [171]. We suggest starting with very low doses because LSD or psilocybin-assisted psychotherapy are known for deeply challenging experiences.…”

“…This combination is common practice in MDMA-therapy, but no studies have been done [28]. Acutely safe co-use is known from recreational contexts [171].…”

Palliative care patients’ attitudes and openness towards psilocybin-assisted psychotherapy for existential distress

“…In a pilot study, 20 patients with life-threatening illnesses received MDMA with two psychotherapy sessions resulted in a significant reduction in trait anxiety compared to placebo in patients with anxiety secondary to a life-threatening illness, with results remaining stable after 6 months and 1 year ( 14 ). Moreover, a recent survey study with 27 respondents has shown that co-use of 3,4-Methylenedioxy methamphetamine (MDMA) with psilocybin/LSD anecdotally reduces challenging experiences such as anxiety and fear, while enhancing positive experiences such as self-compassion and gratitude associated with psilocybin/LSD use ( 15 ). These survey results were limited by use of convenience sample and small sample size.…”