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

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.

Classic psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), are non-selective 5-HT2A receptor agonists with therapeutic potential for treating psychiatric disorders and mental health concerns (for a review, see 1 ).Classic psychedelics show a fairly strong safety profile, including minimal adverse effects, toxicity, and potential for abuse [2][3][4][5] .A primary concern associated with classic psychedelics relates to their alteration of consciousness 3 , which can range from highly positive 'peak' experiences 6,7 to psychologically challenging experiences (often referred to as "bad trips" 8,9 ), such as grief, paranoia, and fear 10 .
Challenging experiences following use/administration of classic psychedelics have been reported in both controlled (e.g., clinical trials) and uncontrolled (e.g., ritual or recreational use) studies (e.g., [11][12][13][14][15][16][17][18][19] ).For instance, in a clinical trial in which individuals with major depressive disorder received two doses of psilocybin alongside psychotherapy, 65% of individuals described one of their psilocybin experiences as one of the five most psychologically challenging experiences of their life and 25% of individuals described it as the single most psychologically challenging experience of their life 13 .Furthermore, across their two psilocybin experiences in this clinical trial 13 , 92% of individuals reported that they felt like crying (although note that catharsis-related responses such

Results
Demographics and identification of covariates.The final sample included 698 individuals.For participant demographics, see Table 1.342 individuals reported using LSD and 356 individuals reported using psilocybin during their experience.27 individuals co-used psilocybin/LSD and MDMA (psilocybin + MDMA = 14; LSD + MDMA = 13).For further details regarding LSD/psilocybin dosage, see Fig. 2. For means and standard deviations for dependent variable and Kruskal Wallis tests (and post hoc Dunn's tests), see Table 2.
MDMA use (none, low dose, and medium-high dose) was significantly associated with: (a) conscientiousness (F = 3.20, p = 0.041; individuals who co-used low dose MDMA were significantly lower than those who did not co-use MDMA); (b) openness (F = 3.23, p = 0.040; individuals who co-used medium-high dose MDMA were significantly lower than those who did not co-use MDMA); and psilocybin/LSD use in the following contexts (c) recreational/social (χ 2 = 18.80, p < 0.001; more common among co-users of low and medium-high dose MDMA); (d) live singing (χ 2 = 9.81, p = 0.007), (e) emotional support (χ 2 = 9.38, p = 0.009), and (f) strangers (χ 2 = 15.88,p < 0.001; higher among co-users of low dose MDMA relative to those who did not co-use MDMA).Correlation coefficients and VIFs were all below cutoffs (i.e., all r < 0.4 and all VIF < 5), indicating that multicollinearity was not of significant concern.These variables were therefore included in the primary analyses (see below) examining the relationship between co-MDMA use with psilocybin/LSD and acute challenging and positive experiences.See Supplementary Material (Supplementary Table 1) for a full list of analyses examining potential confounds.

Discussion
Psilocybin/LSD experiences can range from being profoundly positive to overwhelmingly challenging.Anecdotal reports indicate that individuals sometimes co-use MDMA to buffer against challenging experiences and enhance positive experiences associated with psilocybin/LSD 55 .To date, only a single study had examined the association between co-use of MDMA and psilocybin/LSD and acute subjective drug effects.Therefore, in a convenience sample, this study examined whether co-use of MDMA with psilocybin/LSD is associated with lower challenging experiences and higher positive experiences.Controlling for potential confounds, co-use of MDMA (specifically low dose) with psilocybin/LSD was associated with lower levels of total challenging experiences, as well as grief and fear (measured by CEQ Total and CEQ subscales, respectively).These reductions in total challenging experience, fear, and grief are in line with research indicating that MDMA reduces experiences of sadness and fear 44,45 and anecdotal reports regarding the effects of "hippy flipping" and "candy flipping" 41,55 .Although death-related challenging experiences were also significantly lower among individuals that co-used low dose MDMA and psilocybin/LSD, when controlling for potential confounds, co-use of MDMA was not associated with significant differences in death-related or other aspects of challenging experiences (i.e., physical distress, insanity, isolation, and paranoia).These non-significant results may be explained by: (1) co-MDMA use targeting affective/emotional systems over cognitive systems, explaining why emotions like fear and grief were altered, while having limited influence on more cognitivelydependent states like death and paranoia; (2) floor effects and high variability (i.e., 'fear of death' was low across groups, and the mean score for the low dose MDMA group was 0; 'isolation' and 'insanity' have large standard deviations); and/or (3) underpowered sample size for small-to-moderate effects in non-parametric analyses.
Regarding positive experiences, co-use of low dose MDMA (but not medium-high dose MDMA) with psilocybin/LSD was associated with enhanced feelings of self-compassion, love, and gratitude relative to psilocybin/ LSD alone.These findings are in line with previously reported motivations for co-using MDMA with psilocybin/ LSD 41 , as well as research indicating that MDMA (alone) may increase acute positive experiences (e.g., 46,47 ).We did not find significant differences between groups for mystical-type experiences (MEQ-30 total score or subscale scores) and compassion (single-item measure) suggesting that these experiences may be unaffected.However, it is noteworthy that (compared with LSD/psilocybin alone) co-use of low dose MDMA was associated with relatively higher mean scores for compassion and relatively lower mean scores for total mystical-type experience.Interestingly, while several MEQ-30 subscales (i.e., positive mood and ineffability) were descriptively higher in the group that co-used low dose MDMA, other subscales (i.e., mystical and transcendence) were descriptively lower in this group, suggesting a potentially complex relationship between co-use of MDMA and mystical-type experiences.Further research in larger samples is needed to causally elucidate these relationships.
We did not observe any significant differences between co-use of medium-high dose MDMA and the psilocybin/LSD alone groups for acute challenging or positive experiences.This dose-dependent relationship is similar to that previously observed for co-use of cannabis with classic psychedelics 40 , which found that while co-use of low dose cannabis was associated with lower challenging experiences, co-use of high dose cannabis was associated with greater total challenging experiences, fear, and grief.These null findings are also in line with a recently conducted placebo-controlled study in which (relative to LSD [100 µg] and placebo) co-administration of LSD www.nature.com/scientificreports/with a medium-high dose of MDMA (100 mg) was not associated with significant differences in challenging or positive experiences 56 .While neither found statistically significant effects for co-use of medium-high dose MDMA, we caution against inferring that co-use of medium-high dose MDMA does not impact the acute psilocybin/LSD experience (i.e., the analyses fail to reject the null but do not provide evidence for the null hypothesis; for discussions, see [57][58][59] ), especially given the relatively small sample sizes.Further studies with larger samples will remain necessary.Nonetheless, these findings suggest that the relationship between co-use of MDMA and LSD/ psilocybin may be dose dependent and that further research with exact doses of psilocybin/LSD and MDMA are necessary to understand the potentially complex relationship between these substances.Findings from this study suggest that co-use of low dose MDMA with psilocybin/LSD may buffer against negative or challenging experiences and enhance certain positive experiences.These findings may inform future clinical trial designs and provide early insights into recreational co-use of MDMA with psilocybin/LSD.Given the nontrivial presence of challenging experiences within clinical research (e.g., 13 ) and non-clinical (e.g., 11,12,17,19,21 ) administration/use of psilocybin/LSD, these findings suggest that co-administration of MDMA may help to mitigate such experiences, as well as post-acute distress, functional impairment, and medical attention seeking that is sometimes reported following challenging psychedelic experiences 11,18,[23][24][25][26][27] ).
Provided that pharmacokinetic and larger controlled studies confirm the present preliminary findings and establish the safety and feasibility of co-administering MDMA with psilocybin/LSD, individuals with elevated anxiety about challenging experiences and clinical presentations/profiles (e.g., individuals with elevated neuroticism 34 , avoidant attachment style 60 , borderline personality disorder 61,62 , poor therapeutic alliance 63 ) at a greater risk of challenging experiences may benefit from MDMA co-administration.However, further research will be necessary to examine such speculative hypotheses.MDMA-attributed increases in positive experiences may also be particularly beneficial in specific therapeutic contexts, including couples-based treatment (e.g., see 64 ), positive psychology interventions (which are often gratitude focused; e.g., see 65 ), and group-based treatment/ sessions 66,67 .
Importantly, addressing concerns about challenging experiences through potential co-administration of MDMA, may help to reduce anxiety and increase openness to psychedelic-assisted psychotherapy among health care providers [28][29][30] and users [31][32][33] .Considering the unique mechanisms of action of MDMA and psilocybin/LSD and the growing preliminary support for their efficacy for specific psychiatric diagnoses (posttraumatic stress disorder 68 and depression, anxiety, and alcohol use 1 , respectively), it is also possible co-administration might potentiate the potential efficacy of either compound alone.Contrarily, it remains unclear if challenging experiences are integral to the therapeutic process and mental health improvements-as has been reported by some 9,22 , leaving open the possibility that co-administration of MDMA may interfere with the therapeutic process.
Limitations and future directions.The present study has considerable limitations including a small sample size, convenience sampling method, and uncontrolled design.The small sample size and potential floor effects may have contributed to null findings and a risk of Type 2 errors (i.e., false negatives).Additionally, given the exploratory nature of the present study and the limited power (due to the sample size and number of covariates included in the models), the present analyses were not corrected for multiple comparisons.Followup confirmatory studies are therefore needed to establish confidence in the replicability of the present findings.While the study did not use a controlled design (i.e., precise dosages are unknown, lack of random assignment, self-selected sample etc.), the use of a convenience sample bears some benefit to generalizability, as it is likely more reflective of "hippy-flipping" and "candy-flipping" in Western recreational users.The prospective recruitment and consistency in post-co-use data collection (day after use) are superior to other retrospective studies, which may be more confounded by time and memory-related effects.Additionally, the study examined and controlled for a wide range of potential confounds, including personality factors and the context in which LSD/ psilocybin (with or without MDMA) were used.Use of psilocybin vs. LSD was also examined as a potential confound, providing preliminary support for the present effects generalizing across both psilocybin and LSD.Considering the sample largely consisted of psychedelic-experienced users of a particular demographic, further research is needed to determine whether these findings generalize to those who are psychedelic-naive and of other demographic status (e.g., minoritized individuals 69,70 ).Additionally, the majority of the positive experiences (i.e., self-compassion, compassion, gratitude, and love) were measured using single non-validated items, limiting interpretation.Finally, information was not available regarding the exact timing of psilocybin/LSD and MDMA co-use or the MDMA dosage that was considered low, medium, or high (while some research identifies low dose MDMA as 50-75 mg 71 , other research identifies low dose MDMA as 30-49 mg 68 ), which will be important for designing future controlled studies on co-administration of psilocybin/LSD and MDMA.Future studies are needed to confirm these findings utilizing larger sample sizes, healthy and clinical samples, validated psychometric instruments, and randomized controlled designs.Dose-response designs in which interactions between precise doses of MDMA and psilocybin/LSD (ranging from low to very high dosages) are administered, as well as interactions with individual traits and psychiatric diagnoses, may benefit clinical application and precision-based medicine.

Methods
Design and procedure.The present study examined the impact of co-use of MDMA and psilocybin/LSD (relative to psilocybin/LSD alone) on acute challenging and positive experiences.Data was collected as part of two online prospective surveys of individuals with upcoming plans to use a psychedelic substance in a naturalistic setting.Data unrelated to co-use of MDMA has previously been published from Study 1 36,40,72 and Study 2 [73][74][75][76] .Study designs were nearly identical and therefore data were collapsed across the two studies.The studies Statistical analyses.Only one individual reported co-using psilocybin/LSD with high dose MDMA, therefore medium and high dose were collapsed into one category.Co-use of MDMA was categorized as either none (0), low (1), or medium-high (2), as shown in Fig. 2. We examined whether co-use of MDMA (none, low dose, and medium-high dose) with psilocybin/LSD predicted the intensity of participants' challenging (total challenging experience [CEQ Total], grief, fear, physical distress, insanity, isolation, death, and paranoia [CEQ subscales]) and positive (love, gratitude, compassion, self-compassion, and mystical-type experience [MEQ-30 total score and mystical, positive mood, transcendence, and ineffability subscales]) experiences.All dependent variables were examined via Q-Q plots, histograms, and statistical analyses (i.e., Kolmogorov-Smirnov and Shapiro Wilk tests) and were found to be non-normally distributed (e.g., all Kolmogorov-Smirnov and Shapiro Wilk tests were p < 0.001).Therefore, we conducted a series of preliminary Kruskal-Wallis tests (without covariates).When these main effects were significant we then conducted Dunn's post-hoc tests to compare psilocybin/ LSD without MDMA against: (a) psilocybin/LSD + low dose MDMA; and (b) psilocybin/LSD + medium-high dose MDMA.
Based on past research 36,40,84,85 , the following variables were examined as potential confounding variables: age, sex, lifetime previous psychedelic use (yes/no), lifetime previous psychedelic use (frequency), lifetime psychiatric diagnosis, previous use of psychiatric medications, current use of psychiatric medications, current use of antidepressant medication, psilocybin or LSD use for experience, psilocybin/LSD dose, personality (Extraversion, Agreeableness, Conscientiousness, Emotional Stability, and Openness to Experiences; measured via the TIPI 77 ), and setting (retreat, recreational/social, or therapeutic, presence of music, live singing, emotional support, a threat, strangers, and/or disruption).A series of statistical tests (ANOVAS for continuous variables and chi-squared tests for binary variables) were performed where MDMA dose was treated as the independent variable and potential confounds were included as the dependent variable.Variables that were significantly associated with MDMA dose (p < 0.05) were identified as potential confounds and were included as covariates in the primary analyses.Multicollinearity among the selected confounders were examined by calculating Pearson correlation coefficients (cut-off: r > 0.4) and variance inflation factors (VIFs; cut-off ≥ 5).
Quade nonparametric ANCOVAs were conducted wherein MDMA dose was the independent variable, acute experience measures were the dependent variable, and potential confounds were included as covariates.Posthoc analyses were performed for significant group differences to determine if low dose and/or medium-high dose MDMA were responsible for significant effects.All analyses were conducted in SPSS (Version 28) and the threshold for statistical significance was set at p < 0.05, two-tailed.

Table 2 .
Descriptive data and comparison of dependent variables by MDMA use.* = Data only collected in Study 1. Bold text indicates p < 0.05.Effects for Low Dose MDMA and Medium-High Dose MDMA are relative to No MDMA.