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.

Full text

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Co‑use of MDMA with psilocybin/
LSD may buer against challenging
experiences and enhance positive
experiences
Richard J. Zeifman
1,2*, Hannes Kettner
2,3, Broc A. Pagni
1, Austin Mallard
1,
Daniel E. Roberts
1, David Erritzoe 2, Stephen Ross
1 & Robin L. Carhart‑Harris
2,3
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 eects 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 dierences 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 identied 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 signicantly 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 dierences in mystical‑type experiences or compassion. Findings suggest co‑use of
MDMA with psilocybin/LSD may buer 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 eects 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 recep-
tor agonists with therapeutic potential for treating psychiatric disorders and mental health concerns (for a
review, see1). Classic psychedelics show a fairly strong safety prole, including minimal adverse eects, toxicity,
and potential for abuse2–5. A primary concern associated with classic psychedelics relates to their alteration of
consciousness3, which can range from highly positive ‘peak’ experiences6,7 to psychologically challenging experi-
ences (oen referred to as “bad trips”8,9), such as grief, paranoia, and fear10.
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.,11–19). 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 ve most psycho-
logically challenging experiences of their life and 25% of individuals described it as the single most psychologi-
cally challenging experience of their life13. Furthermore, across their two psilocybin experiences in this clinical
trial13, 92% of individuals reported that they felt like crying (although note that catharsis-related responses such
OPEN
1NYU Langone Center for Psychedelic Medicine, Department of Psychiatry, NYU Grossman School of Medicine, 1
Park Avenue, New York, NY 10016, USA. 2Centre for Psychedelic Research, Department of Brain Sciences, Faculty
of Medicine, Imperial College London, London, UK. 3Psychedelics Division, Neuroscape, University of California,
San Francisco, USA. *email: richard.zeifman@nyulangone.org
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as crying are more likely to be regarded as therapeutically useful, e.g., see20), 79% of individuals reported expe-
riencing sadness, 56% reported experiencing anxiousness, and 77% reported experiencing emotional or physical
suering. Among healthy individuals that were administered psilocybin, 31% of individuals reported experi-
encing strong or extreme fear and 22% reported that a signicant portion or their entire psilocybin experience
was characterized by anxiety or unpleasant psychological struggle15. Within a nationally representative sample,
40.9% of individuals with lifetime psychedelic use reported having a challenging psychedelic experience19. Cross-
sectional surveys of psychedelic-induced challenging experiences12 and so-called “God encounter experiences”21
have also found that for some individuals (11% and 15%, respectively) these were the single most psychologically
challenging experience of their life.
Although challenging experiences are sometimes described as ultimately benecial or therapeutic9,10,12,17,20,22,
these experiences can sometimes contribute to post-acute distress, functional impairment, and medical atten-
tion seeking (e.g.,11,18,23–27). For instance, among individuals with lifetime use of a classic psychedelic, 8.9%
of individuals reported experiencing functional impairment for longer than one day, and 2.6% of individuals
reported seeking medical or psychological assistance, following a challenging psychedelic experience19. ere
are also reports of the emergence of psychiatric diagnoses, suicidality, and harm to self and others during and
aer challenging psychedelic experiences4,11,12. Importantly, concerns about challenging experiences and their
eects are commonly noted as a reason that health care providers28–30 and users31–33 are reluctant to suggest or
receive treatment with classic psychedelics.
Several factors likely contribute to the intensity of challenging psychedelic experiences, including trait level
neuroticism, preparedness for the psychedelic experience, and the setting in which the psychedelic is used34–37.
Co-use of other pharmacological agents may also intensify or buer against challenging experiences. For instance,
relative to use of classic psychedelics alone, co-use of classic psychedelics with lithium and other mood stabilizers
was associated with greater intensity of challenging experiences19 (in addition to medical complications, such as
seizures38,39). Another study found a quadratic relationship between co-use of cannabis and classic psychedelics,
such that (relative to use of a classic psychedelic alone) co-use of low dose cannabis was associated with less
intense challenging experiences and co-use of large dose cannabis was associated with more intense challenging
experiences40.
Co-use of 3,4-methylenedioxymethamphetamine (MDMA) with psilocybin (referred to as “hippy ipping”)
and LSD (referred to as “candy ipping”) is one method that is reportedly used to reduce challenging experiences
and enhance positive experiences41,42. MDMA, a potent serotonergic entactogen/empathogen, induces the release
of serotonin, norepinephrine, dopamine, vasopressin, and oxytocin; dampens amygdala blood ow43; decreases
feelings of fear and sadness44,45; and may increase positive feelings43, including love46,47, compassion48,49, and
self-compassion50,51.
Several studies have reported on co-use of LSD/psilocybin and MDMA, with prevalence rates ranging from
8 to 52% among recreational drug users with lifetime LSD/psilocybin use41,42,52–54. Among polydrug users in the
United Kingdom, participants reported co-using LSD and MDMA to improve the eect of LSD and to ease its
aereects41. As one anecdotal report noted, “…when taken in conjunction…[MDMA] acts as a safety buer
and allows you to go a lot further than you normally would”55. Importantly, to date, only a single study has exam-
ined the eects of co-using MDMA alongside LSD in humans (with no studies on co-use alongside psilocybin).
is was a recent double-blind placebo-controlled study56 that did not observe signicant dierences in acute
experiences between LSD (100µg) plus placebo relative to LSD (100µg) plus MDMA (100mg). Importantly,
this study was conducted in a controlled setting and excluded individuals with a personal or family history of
psychiatric disorders, which reduce the potential for LSD-related challenging experiences10,12,22 and thereby may
have resulted in oor eects. Furthermore, the study examined only a single (medium–high) dose of MDMA and
did not measure certain positive experiences (e.g., self-compassion, compassion, love, and gratitude) that may
be impacted by MDMA. Finally, the study sample was small (N = 24), which increases the likelihood of Type II
errors. erefore, in an observational study, we further examined whether (relative psilocybin/LSD use alone)
co-use of psilocybin/LSD and MDMA was associated with lower acute challenging experiences and increased
acute positive experiences.
Results
Demographics and identication of covariates. e nal sample included 698 individuals. For par-
ticipant demographics, see Table1. 342 individuals reported using LSD and 356 individuals reported using psil-
ocybin 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 signicantly associated with: (a) conscientiousness
(F = 3.20, p = 0.041; individuals who co-used low dose MDMA were signicantly 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
signicantly lower than those who did not co-use MDMA); and psilocybin/LSD use in the following contexts (c)
recreational/social (χ2 = 18.80, p < 0.001; more common among co-users of low and medium–high dose MDMA);
(d) live singing (χ2 = 9.81, p = 0.007), (e) emotional support (χ2 = 9.38, p = 0.009), and (f) strangers (χ2 = 15.88,
p < 0.001; higher among co-users of low dose MDMA relative to those who did not co-use MDMA). Correlation
coecients and VIFs were all below cutos (i.e., all r < 0.4 and all VIF < 5), indicating that multicollinearity was
not of signicant concern. ese 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.
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Primary analyses. Challenging experiences. Co-use of MDMA with psilocybin/LSD was associated with
signicant dierences in total challenging experience (F(2,672) = 3.62, p = 0.031). Relative to psilocybin/LSD
use alone, psilocybin/LSD + low dose MDMA was associated with signicantly lower levels of total challenging
experience, t(672) = 2.54, p = 0.011. ere was no signicant dierence between psilocybin/LSD use alone and
psilocybin/LSD + medium–high dose MDMA use, t(672) = − 0.68, p = 0.498.
Examining group dierences on CEQ subscales, co-use of MDMA with psilocybin/LSD was associated with
signicant dierences in experiences of grief (F[2,672] = 4.64, p = 0.012) and fear (F[2,672] = 33.80, p = 0.023), but
not physical distress (F[2,672] = 0.43, p = 0.654), insanity (F[2,672] = 1.30, p = 0.273), isolation (F[2,672] = 1.25,
p = 0.287), death (F[2,672] = 2.42, p = 0.090), or paranoia (F[2,672] = 1.64, p = 0.196). Relative to psilocybin/
LSD use alone, psilocybin/LSD + low dose MDMA was associated with signicantly lower levels of grief and
fear (t[672] = 2.83, p = 0.005; t[672] = 2.21, p = 0.027, respectively). ere was no signicant dierence between
psilocybin/LSD use alone and psilocybin/LSD + medium–high dose MDMA use for grief and fear (t[672] = 1.02,
p = 0.310; t[672] = − 1.61, p = 0.108, respectively).
Positive experiences. Co-use of MDMA with psilocybin/LSD was associated with higher levels of self-com-
passion, feelings of love, and experiences of gratitude (F(2,256) = 3.62, p = 0.028; F(2,256) = 3.97, p = 0.020;
F(2,256) = 3.92, p = 0.021, respectively). Relative to psilocybin/LSD use alone, psilocybin/LSD + low dose MDMA
was associated with greater feelings of self-compassion, love, and gratitude (t(256) = − 2.61, p = 0.010; t(256) =
− 2.69, p = 0.008; t(256) = − 2.12, p = 0.035, respectively), while psilocybin/LSD + medium–high dose MDMA
was not (t(256) = 0.59, p = 0.557; t(256) = 0.79, p = 0.431; t(256) = 1.78, p = 0.076, respectively). Co-use of MDMA
with psilocybin/LSD was not associated with signicant dierences in compassion (F(2,256) = 2.67, p = 0.071) or
Table 1. Demographics. # Data available for 675 individuals.
Demographic Category N(%) M(SD)
Age#30.18 (10.68)
Sex#
Female 199 (29.5)
Male 467 (69.2)
Other 9 (1.3)
Nationality
United States 184 (26.4)
United Kingdom 183 (26.2)
Canada 41 (5.9)
Germany 34 (4.9)
Denmark 19 (2.7)
Other 237 (34.0)
Employment
Full-time employment 281 (40.3)
Part-time employment 85 (12.2)
Retired 14 (2.0)
Student 223 (31.9)
Unemployed 72 (10.3)
Education
Le school before age 16 without qualications 15 (2.1)
Some high school/GCSE level (in UK) 46 (6.6)
High school diploma/A-level education (in UK) 110 (15.8)
Some university (or equivalent) 160 (22.9)
Bachelor’s degree (or equivalent) 197 (28.2)
Post-graduate degree (e.g., masters or doctorate) 147 (21.1)
Lifetime psychiatric diagnosis (Yes)#188 (26.9)
Lifetime prescribed psychiatric medication (Yes)#230 (34.1)
Currently prescribed psychiatric medication (Yes)#66 (9.8)
Currently prescribed antidepressants (Yes)#40 (6.1)
Lifetime psychedelic use (Yes)#607 (89.9)
Lifetime psychedelic use (frequency)#
Never 68 (10.1)
Once 49 (7.3)
2–5 times 162 (24.0)
6–10 times 114 (16.9)
11–20 times 103 (15.3)
21–50 times 99 (14.7)
51–100 times 41 (6.1)
More than 100 times 39 (5.8)
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Var iable Sample Mean ( SD)Statistic p
Challenging experiences
Challenging experience total (CEQ-Total)
Main eect 6.98 0.030
No MDMA 18.83 (15.50) – –
Low dose MDMA 9.18 (5.93) 2.59 0.010
Medium–high dose MDMA 19.10 (12.06) − 0.49 0.627
CEQ subscales
Grief
Main eect 13.04 0.001
No MDMA 22.60 (21.87) – –
Low dose MDMA 6.44 (8.68) 3.28 0.001
Medium–high dose MDMA 14.44 (19.30) − 1.58 0.114
Fear
Main eect 7.62 0.022
No MDMA 20.63 (22.57) – –
Low dose MDMA 7.47 (8.12) 2.19 0.028
Medium–high dose MDMA 27.00 (18.14) − 1.64 0.102
Physical distress
Main eect 1.29 0.525
No MDMA 20.92 (17.77) – –
Low dose MDMA 19.47 (12.18) – –
Medium–high dose MDMA 25.67 (16.84) – –
Insanity
Main eect 2.66 0.265
No MDMA 16.77 (22.76) – –
Low dose MDMA 8.44 (11.12) – –
Medium–high dose MDMA 22.78 (22.65) – –
Isolation
Main eect 3.56 0.168
No MDMA 20.11(24.27) – –
Low dose MDMA 8.89 (13.25) – –
Medium–high dose MDMA 17.22 (24.20) – –
Death
Main eect 6.01 0.050
No MDMA 10.73 (23.21)
Low dose MDMA 0.00 (0.00) 2.36 0.018
Medium–high dose MDMA 6.67 (9.85) − 0.63 0.531
Paranoia
Main eect 0.97 0.065
No MDMA 6.99 (14.42) – –
Low dose MDMA 6.67 (15.89) – –
Medium–high Dose MDMA 6.67 (14.98) – –
Positive experiences
Self-compassion*
Main eect 4.12 0.128
No MDMA 58.34 (34.71) – –
Low dose MDMA 79.00 (36.23) – –
Medium–high dose MDMA 49.43 (23.20) – –
Compassion*
Main eect 3.66 0.161
No MDMA 60.24 (33.49) – –
Low dose MDMA 82.57 (26.57) – –
Medium–high dose MDMA 69.00 (21.57) – –
Gratitude*
Main eect 11.35 0.003
No MDMA 58.06 (34.56) – –
Low dose MDMA 91.43 (11.86) − 2.80 0.005
Medium–high dose MDMA 34.43 (29.65) 1.81 0.070
Love*
Main eect 6.50 0.039
No MDMA 59.38 (35.04) – –
Low dose MDMA 90.43 (18.17) − 2.53 0.011
Medium–high dose MDMA 59.00 (33.28) 0.25 0.804
Mystical-type experience total (MEQ-30)
Main eect 1.94 0.378
No MDMA 57.76 (22.41) – –
Low dose MDMA 53.37 (12.56) – –
Medium–high dose MDMA 50.04 (23.40) – –
MEQ-30 subscales
Continued
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mystical-type experience (total score F[2,577] = 0.65, p = 0.524; mystical F[2,556] = 0.49, p = 0.613; positive mood
F[2,577] = 2.13, p = 0.120; t ranscendence F[2,577] = 0.35, p = 0.703; and ineability F[2,577] = 0.87, p = 0.421).
Discussion
Psilocybin/LSD experiences can range from being profoundly positive to overwhelmingly challenging. Anecdotal
reports indicate that individuals sometimes co-use MDMA to buer against challenging experiences and enhance
positive experiences associated with psilocybin/LSD55. To date, only a single study had examined the association
between co-use of MDMA and psilocybin/LSD and acute subjective drug eects. erefore, 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 (specically 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). ese reductions in total challenging experience, fear, and grief are in line with
research indicating that MDMA reduces experiences of sadness and fear44,45 and anecdotal reports regarding the
eects of “hippy ipping” and “candy ipping”41,55. Although death-related challenging experiences were also
signicantly 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 signicant dierences in death-related or other
aspects of challenging experiences (i.e., physical distress, insanity, isolation, and paranoia). ese non-signicant
results may be explained by: (1) co-MDMA use targeting aective/emotional systems over cognitive systems,
explaining why emotions like fear and grief were altered, while having limited inuence on more cognitively-
dependent states like death and paranoia; (2) oor eects 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 eects in non-parametric analyses.
Regarding positive experiences, co-use of low dose MDMA (but not medium–high dose MDMA) with psilo-
cybin/LSD was associated with enhanced feelings of self-compassion, love, and gratitude relative to psilocybin/
LSD alone. ese ndings are in line with previously reported motivations for co-using MDMA with psilocybin/
LSD41, as well as research indicating that MDMA (alone) may increase acute positive experiences (e.g.,46,47). We
did not nd signicant dierences between groups for mystical-type experiences (MEQ-30 total score or subscale
scores) and compassion (single-item measure) suggesting that these experiences may be unaected. 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 ineability) 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 signicant dierences between co-use of medium–high dose MDMA and the psilocy-
bin/LSD alone groups for acute challenging or positive experiences. is dose-dependent relationship is similar
to that previously observed for co-use of cannabis with classic psychedelics40, which found that while co-use of
low dose cannabis was associated with lower challenging experiences, co-use of high dose cannabis was associ-
ated with greater total challenging experiences, fear, and grief. ese null ndings are also in line with a recently
conducted placebo-controlled study in which (relative to LSD [100µg] and placebo) co-administration of LSD
Table 2. Descriptive data and comparison of dependent variables by MDMA use. * = Data only collected
in Study 1. Bold text indicates p < 0.05. Eects for Low Dose MDMA and Medium–High Dose MDMA are
relative toNo MDMA.
Var iable Sample Mean ( SD)Statistic p
Mystical
Main eect 4.58 0.101
No MDMA 60.03 (22.48) – –
Low dose MDMA 45.93 (21.76) – –
Medium–high dose MDMA 52.17 (20.41) – –
Positive mood
Main eect 3.35 0.187
No MDMA 64.69 (22.56) – –
Low dose MDMA 75.56 (13.44) – –
Medium–high dose MDMA 58.15 (24.89) – –
Transcendence
Main eect 0.70 0.706
No MDMA 47.64 (28.09) – –
Low dose MDMA 39.26 (15.07) – –
Medium–high dose MDMA 46.67 (28.87) – –
Ineability
Main eect 0.81 0.667
No MDMA 65.71 (30.14) – –
Low dose MDMA 74.81 (18.49) – –
Medium–high dose MDMA 57.78 (35.43) – –
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with a medium–high dose of MDMA (100mg) was not associated with signicant dierences in challenging
or positive experiences56. While neither found statistically signicant eects 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 psilo-
cybin/LSD experience (i.e., the analyses fail to reject the null but do not provide evidence for the null hypothesis;
for discussions, see57–59), especially given the relatively small sample sizes. Further studies with larger samples will
remain necessary. Nonetheless, these ndings 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 buer against
negative or challenging experiences and enhance certain positive experiences. ese ndings 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 ndings 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 experiences11,18,23–27).
Provided that pharmacokinetic and larger controlled studies conrm the present preliminary ndings and
establish the safety and feasibility of co-administering MDMA with psilocybin/LSD, individuals with elevated
anxiety about challenging experiences and clinical presentations/proles (e.g., individuals with elevated
neuroticism34, avoidant attachment style60, borderline personality disorder61,62, poor therapeutic alliance63) at a
greater risk of challenging experiences may benet 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 benecial in specic therapeutic contexts, including couples-based treatment (e.g., see64),
positive psychology interventions (which are oen gratitude focused; e.g., see65), and group-based treatment/
sessions66,67.
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 providers28–30 and users31–33. Considering the unique mechanisms of action of MDMA and psilocybin/LSD
and the growing preliminary support for their ecacy for specic psychiatric diagnoses (posttraumatic stress
disorder68 and depression, anxiety, and alcohol use1, respectively), it is also possible co-administration might
potentiate the potential ecacy of either compound alone. Contrarily, it remains unclear if challenging experi-
ences are integral to the therapeutic process and mental health improvements–as has been reported by some9,22,
leaving open the possibility that co-administration of MDMA may interfere with the therapeutic process.
Limitations and future directions. e present study has considerable limitations including a small
sample size, convenience sampling method, and uncontrolled design. e small sample size and potential oor
eects may have contributed to null ndings 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. Follow-
up conrmatory studies are therefore needed to establish condence in the replicability of the present ndings.
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 benet to generalizability, as it is likely
more reective of “hippy-ipping” and “candy-ipping” in Western recreational users. e prospective recruit-
ment and consistency in post-co-use data collection (day aer use) are superior to other retrospective studies,
which may be more confounded by time and memory-related eects. 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 eects 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 ndings generalize to those who are psychedelic-naive and of
other demographic status (e.g., minoritized individuals69,70). Additionally, the majority of the positive experi-
ences (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 identi-
es low dose MDMA as 50–75 mg71, other research identies low dose MDMA as 30–49 mg68), which will be
important for designing future controlled studies on co-administration of psilocybin/LSD and MDMA. Future
studies are needed to conrm these ndings 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 adminis-
tered, as well as interactions with individual traits and psychiatric diagnoses, may benet clinical application
and precision-based medicine.
Methods
Design and procedure. e 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 natural-
istic setting. Data unrelated to co-use of MDMA has previously been published from Study 136,40,72 and Study
273–76. Study designs were nearly identical and therefore data were collapsed across the two studies. e studies
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were approved by the Imperial College London’s Research Ethics Committee and Joint Research Compliance
Oce and were conducted in accordance with principles of Good Clinical Practice.
Eligibility criteria for both studies were as follows: (1) 18years or older; (2) ability to read/write English;
and (3) intention to use a psychedelic substance (e.g., psilocybin/magic mushrooms/trues, MDMA, LSD/
1-propionyl-lysergic acid diethylamide (1P-LSD), ayahuasca, N,N-Dimethyltryptamine (DMT), 5-methoxy-
N,N-dimethyltryptamine (5-MeO-DMT), mescaline, 2,5-dimethoxy-4-bromophenethylamine (2C-B), salvia
divinorum, iboga/ibogaine). Individuals were included in the present manuscript if they used psilocybin or LSD
alone or co-used psilocybin or LSD and MDMA during their experience. Individuals were excluded from the
present analyses if they used substances other than (a) psilocybin/LSD alone or (b) psilocybin/LSD and MDMA
during their experience.
Participants were recruited using online advertisements, postings on Facebook, Twitter, and email newslet-
ters, and online forums (e.g., Reddit). Interested participants reviewed study details and provided informed
consent online along with their email address. Surveys were subsequently sent via email depending upon the
date the participant intended to use a psychedelic. Surveys relevant to the present manuscript were administered
seven days prior to the planned psychedelic experience and 1day aer the planned psychedelic experience. e
following data was collected prior to participants’ psychedelic experience: demographics (age, sex, nationality,
employment, and education); personality (Extraversion, Agreeableness, Conscientiousness, Emotional Stability,
and Openness to Experiences; measured via the Ten Item Personality Measure [TIPI]77); self-reported psychiat-
ric history (previous and/or current use of psychiatric medications, lifetime psychiatric disorder); and lifetime
psychedelic use (frequency).
Following their psychedelic experience, participants identied the psychedelic they used and the dose they
used: (1) Low dose (e.g., < 50μg LSD); (2) Moderate dose (e.g., 51–100μg LSD); (3) High dose (e.g., 101–200μg
LSD); (4) Very high dose (e.g., 201–300μg LSD); and (5) Extremely high dose (> 300μg LSD) (Fig.1). Partici-
pants were also asked whether they co-used MDMA during their experience and the dose of MDMA they used:
(1) None; (2) Low; (3) Medium; and (4) High. Participants were asked to identify (yes/no) whether they had
their psychedelic experience in specic settings (retreat, reactional/social, and/or therapeutic) and whether their
experience featured the following elements: music; live singing; emotional support; sense of threat; strangers,
and/or disruption. Finally, relating to their psychedelic use 1day prior, participants completed measures of acute
challenging and positive experiences (see ‘Measures’ section below). All data was collected using the online
‘Psychedelic Survey’ platform (https:// www. psych edeli csurv ey. com).
Measures. Challenging experiences. Challenging experiences were measured using the Challenging Expe-
rience Questionnaire (CEQ10), a 26-item scale developed to characterize acute adverse experiences occasioned
by psychedelic substances10. Subscales of the CEQ measure grief (6 items), fear (5 items), physical distress (5
items), insanity (3 items), isolation (3 items), death (2 items), and paranoia (2 items). Reecting on a particular
psychedelic experience, items are rated on a six-point Likert scale ranging from 0 (none; not at all) to 5 (extreme
[more than ever before in my life]). In line with past research20, total challenging experiences were scored by
calculating the mean of all 26 items multiplied by 20 to provide a score ranging from 0 to 100. Similarly, subscales
were scored by calculating the mean for each subscale multiplied by 20. e CEQ has been utilized in both non-
clinical10,12,20,36 and clinical7,21 studies of classic psychedelic experiences.
Positive experiences. Self-compassion, compassion, love, and gratitude. Positive experiences of self-compas-
sion, compassion, gratitude, and love were each measured using individual self-constructed items. Reecting
on their psychedelic experience, participants rated each item on a visual analogue scale from 0 (No/not more
than usual) to 100 (Yes/very much more than usual). Items were as follows: (1) self-compassion (“I felt compas-
sion towards myself”); (2) compassion (“I felt compassion towards others”); (3) gratitude (“I felt a great sense
of gratitude”); and (4) love (“I felt a great sense of love”). ese items were only collected in Study 1 (n = 282).
Mystical experience. Mystical-type experiences were measured using the revised Mystical Experience Ques-
tionnaire (MEQ-3078). e MEQ-30 is a 30-item measure of mystical eects of classic psychedelics composed
of four factors: (1) mystical (i.e., unity, noetic quality, and sacredness; 15 items); (2) deeply felt positive mood
(6 items); (3) transcendence of time and space (6 items); and (4) ineability/paradoxicality (3 items). Items are
rated on a six-point Likert scale ranging from 0 (none/not at all) to 5 (extreme [more than any other time in my
life]). Total mystical experience was scored by calculating the mean of all 30 items multiplied by 20 to provide a
score ranging from 0 to 100. Subscale scores were similarly calculated using the relevant items. e MEQ-30 has
been used widely in both non-clinical (e.g.,36,79,80) and clinical samples (e.g.,81–83).
Figure1. Categorization by psilocybin/LSD and co-use of MDMA by dose.
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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 ineability subscales]) experiences. All depend-
ent 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). erefore, we conducted a series of preliminary Kruskal–Wallis tests (without covari-
ates). When these main eects were signicant 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 research36,40,84,85, the following variables were examined as potential confounding variables:
age, sex, lifetime previous psychedelic use (yes/no), lifetime previous psychedelic use (frequency), lifetime psy-
chiatric 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 (Extra-
version, Agreeableness, Conscientiousness, Emotional Stability, and Openness to Experiences; measured via
the TIPI77), 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 independ-
ent variable and potential confounds were included as the dependent variable. Variables that were signicantly
associated with MDMA dose (p < 0.05) were identied as potential confounds and were included as covariates in
the primary analyses. Multicollinearity among the selected confounders were examined by calculating Pearson
correlation coecients (cut-o: r > 0.4) and variance ination factors (VIFs; cut-o ≥ 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. Post-
hoc analyses were performed for signicant group dierences to determine if low dose and/or medium–high
dose MDMA were responsible for signicant eects. All analyses were conducted in SPSS (Version 28) and the
threshold for statistical signicance was set at p < 0.05, two-tailed.
Data availability
e data that support the ndings of this study are available from the corresponding author, RJZ, upon reason-
able request.
Received: 18 May 2023; Accepted: 17 August 2023
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Author contributions
R.J.Z., H.K., D.E., and R.C.H. contributed to the design of the study. R.J.Z. conducted the analyses and draed
the introduction and results. R.J.Z. and A.M. draed the Methods. R.J.Z., B.A.P., and D.R. draed the discussion.
All authors contributed to the writing and reviewed the manuscript.
Content courtesy of Springer Nature, terms of use apply. Rights reserved

11
Vol.:(0123456789)
Scientic Reports | (2023) 13:13645 | https://doi.org/10.1038/s41598-023-40856-5
www.nature.com/scientificreports/
Funding
RJZ received funding from the Canadian Institutes of Health Research (Grant Number: 202110MFE-472921-
HTB-272687). RJZ and BAP received funding from the NYU Langone Psychedelic Medicine Research Training
program funded by MindMed.
Competing interests
RJZ and BAP are postdoctoral fellows in the NYU Langone Psychedelic Medicine Research Training program
funded by MindMed. HK is a scientic advisor to Maya Health. DER has received compensation as an independ-
ent contractor from Fluence. RCH is a scientic advisor to Usona Institute, Maya Health, Osmind, Beckley Psy-
chtech, TRYP therapeutics, Journey Collab and MindState Design Lab. DE is a paid advisor for Aya Biosciences,
Clerkenwell Health, and Mindstate Design Lab. None of the aforementioned organizations were involved in the
design, execution, interpretation, or communication of ndings from present study.
Additional information
Supplementary Information e online version contains supplementary material available at https:// doi. org/
10. 1038/ s41598- 023- 40856-5.
Correspondence and requests for materials should be addressed to R.J.Z.
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