Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic that is widely used recreationally and increasingly investigated in patients who suffer from psychiatric conditions, such as anxiety and depression [1, 2]. LSD acutely produces mostly positive experiences of alterations of consciousness but may also produce negative subjective effects, including acute anxiety [3,4,5,6,7,8]. Acute negative psychological effects are also considered the main risk of psychedelic substance use in humans [9]. Clinical trials showed that positive psychedelic-induced experiences are associated with more positive long-term therapeutic improvements in patients in psychedelic-assisted therapy [1, 10,11,12,13]. Additionally, low ratings of acute anxiety induced by a psychedelic predicted positive long-term clinical outcomes in patients [10]. Thus, the induction of a positive acute psychedelic experience may be desirable to enhance treatment outcome, although challenging experiences may also have therapeutic potential [14, 15].

3,4-Methylenedioxymethamphetamine (MDMA) is investigated in MDMA-assisted therapy [16]. MDMA acutely induces mostly positive subjective effects, including increases in well-being, empathy, trust, and closeness to others [3, 17,18,19]. The combined administration of MDMA and LSD is known as “candyflipping” among recreational substance users [20,21,22,23,24] and reportedly induces synergistic acute positive mood effects [24]. However, no controlled study has investigated the combined administration of MDMA and LSD. Therefore, the present study investigated whether MDMA can be used to optimize the acute effects profile of LSD by inducing more positive mood and less anxiety compared with LSD alone.

The primary hypothesis was that the co-administration of MDMA and LSD results in higher acute “good drug effects,” well-being, openness, and trust and lower “bad drug effects” and anxiety compared with LSD administration alone.

Methods and materials

Study design

The study used a double-blind, placebo-controlled, crossover design with four experimental test sessions to investigate responses to (i) placebo, (ii) 100 mg MDMA, (iii) 100 µg LSD, and (iv) 100 µg LSD + 100 mg MDMA. Block randomization was used with counter-balanced treatment order. The washout periods between sessions were at least 10 days. The study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Guidelines in Good Clinical Practice and approved by the Ethics Committee of Northwest Switzerland (EKNZ) and Swiss Federal Office for Public Health. The study was registered at ClinicalTrials.gov (NCT04516902).

Participants

Twenty-four healthy participants (12 men and 12 women; mean age ± SD: 30 ± 7 years; range: 25–54 years) were recruited by word of mouth or from a pool of volunteers who had contacted our research group because they were interested in participating in a clinical trial on psychedelics. All of the subjects provided written informed consent and were paid for their participation. Exclusion criteria were age <25 years or >65 years, pregnancy (urine pregnancy test at screening and before each test session), personal or family (first-degree relative) history of major psychiatric disorders (assessed by the Semi-structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Axis I disorders by a trained psychologist), the use of medications (e.g., antidepressants, antipsychotics, and sedatives) that may interfere with the study medications, chronic or acute physical illness (e.g., abnormal physical exam, electrocardiogram, or hematological and chemical blood analyses), tobacco smoking (>10 cigarettes/day), lifetime prevalence of hallucinogens or MDMA use >20 times, illicit drug use within the last 2 months (except for Δ⁹-tetrahydrocannabinol), and illicit drug use during the study period (determined by urine drug tests). The participants were asked to consume no more than 20 standard alcoholic drinks/week and have no more than one drink on the day before the test sessions. Twelve participants had previously used a psychedelic, including LSD (6 participants, 1–3 times), psilocybin (9 participants, 1–2 times), N,N-dimethyltryptamine (DMT; one participant, one time), and mescaline (one participant, 1 time). Nine participants had used MDMA (1–13 times), 12 participants had used a stimulant, including methylphenidate (5 participants, 1–10 times), amphetamine (3 participants, 1–7 times), and cocaine (4 participants, 2–10 times), one participant had used 4-bromo-2,5-dimethoxyphenethylamine (2C-B; 1 time), and one participant had used ketamine (1 time). Four participants had never used any illicit drugs with the exception of cannabis.

Study drugs

LSD base (Lipomed AG, Arlesheim, Switzerland) was administered as an oral solution that was produced according to good manufacturing practice in units that contained 100 µg LSD base in 1 ml of 96% ethanol [25]. The exact analytically confirmed LSD base content (mean ± SD) was 92.5 ± 1.89 µg (n = 10 samples). Placebo consisted of identical units that were filled with ethanol only. MDMA (ReseaChem, Burgdorf, Switzerland) was administered in opaque capsules that contained a 25 mg dose of MDMA hydrochloride and an exact analytically confirmed actual MDMA content of 25.40 ± 0.48 mg (n = 9 samples). Placebo consisted of identical opaque capsules that were filled with mannitol. A double-dummy method was used. The subjects received four capsules and one solution in each session: (i) four placebo capsules and one placebo solution, (ii) four 25 mg MDMA capsules and one placebo solution, (iii) four placebo capsules and one 100 µg LSD solution, and (iv) four 25 mg MDMA capsules and one 100 µg LSD solution. Then, 2.5 h after administration, at the end of each session, and at the end of the study, the participants guessed their treatment assignment to evaluate blinding.

Study procedures

The study included a screening visit, four 13-h test sessions with follow-up measurements 24 h after drug intake, and an end-of-study visit which took place on average 31 days after the last test session. Test days were separated by at least 10 days. The sessions were conducted in a calm hospital room. Only one research subject and one investigator were present during each test session. The test sessions began at 8:00 AM. A urine sample was taken to verify abstinence from drugs of abuse, and a urine pregnancy test was performed in women. The subjects then underwent baseline measurements. A standardized breakfast (two croissants) was served. Substances were administered at 9:00 AM. The outcome measures were repeatedly assessed for 12 h. Standardized lunches and dinners were served at 1:30 PM and 6:00 PM, respectively. The subjects were never alone during the acute effect phase. The subjects were sent home at 9:15 PM and returned the next day for follow-up measurements at 9:00 AM.

Subjective drug effects and effect durations

Subjective effects were assessed repeatedly using visual analog scales (VASs) [3, 6] 0.5 h before and 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 24 h after drug administration. The Adjective Mood Rating Scale (AMRS) [26] was used 0.5 h before and 3, 6, 9, 12, and 24 h after drug administration. The 5 Dimensions of Altered States of Consciousness (5D-ASC) scale [27, 28] was used as the primary outcome measure and was administered 12 h after drug administration to retrospectively rate peak drug effects. Mystical experiences were assessed 12 h after drug administration using the States of Consciousness Questionnaire (SOCQ) [29, 30] that includes the 43-item Mystical Effects Questionnaire (MEQ43) [29], 30-item Mystical Effects Questionnaire (MEQ30) [31], and subscales for “aesthetic experience,” “connectedness,” “distressing experience,” and negative “nadir” effects. Subjective effect measurements are described in detail in the Supplementary Methods online.The time to onset, time to maximal effect, time to offset, and effect duration were assessed in Phoenix WinNonlin 8.3 (Certara, Princeton, NJ, USA) using the “any drug effect” VAS effect-time plots and an onset/offset threshold of 10% of the maximum individual response as described previously in detail [7, 25].

Autonomic and adverse effects

Blood pressure, heart rate, and tympanic body temperature were repeatedly measured at baseline and 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 24 h after drug administration [32]. Pupil size was assessed at baseline and 1, 2.5, 4, 7, 11, and 24 h after drug administration [6]. Adverse effects were assessed 0.5 h before and 12 and 24 h after drug administration using the List of Complaints [33].

Circulating oxytocin and brain-derived neurotrophic factor

Plasma concentrations of oxytocin were measured before and 1.5, 3, and 6 h after drug administration and were determined as previously described [3, 6, 7, 34]. Serum BDNF levels were measured at baseline and 3, 6, 9, 12, and 24 h after drug administration (Supplementary Methods).

Plasma LSD and MDMA concentrations

Plasma concentrations of LSD and MDMA and their metabolites were measured before and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 9, 10, 11, 12, and 24 h after drug administration. Blood was collected into lithium heparin tubes. The blood samples were immediately centrifuged, and the plasma was subsequently stored at −80°C until analysis. Plasma concentrations of LSD and its metabolite 2-oxo-3-hydroxy-LSD (O-H-LSD) were determined by ultra-high-performance liquid chromatography tandem mass spectrometry with a lower limit of quantification of 10 pg/ml [25].MDMA and its metabolites 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) were analyzed in human plasma using high-performance liquid chromatography tandem mass spectrometry as previously described. HMMA concentration was determined after enzymatic deglucuronidation [35].

Pharmacokinetic analyses

Pharmacokinetic parameters were estimated using non-compartmental methods as described previously [25]. Analyses were conducted using Phoenix WinNonlin 8.3 (Certara, Princeton, NJ, USA).

Data analysis

Peak (E_max and/or E_min) or peak change from baseline (ΔE_max) values were determined for repeated measures. The values were then analyzed using repeated-measures analysis of variance (ANOVA), with drug as the within-subjects factor, followed by the Tukey post hoc tests using R 4.2.1 software (RStudio, PBC, Boston, MA, USA) and Statistica 12 software (StatSoft, Tulsa, OK, USA). The criterion for significance was p < 0.05.

Results

Subjective drug effects

Subjective effects over time on the VAS are shown in Fig. 1 and Supplementary Fig. S1. Statistics are summarized in Table 1 and Supplementary Table S1. Alteration of mind and mystical-type effects are shown in Fig. 2 and Supplementary Fig. S2. Statistics are summarized in Supplementary Tables S2 and S3. Effects on mood over time on the AMRS are shown in Supplementary Fig. S3. The corresponding peak responses and statistics are presented in Supplementary Table S4. Characteristics of subjective responses are shown in Supplementary Table S5.

Fig. 1: Acute subjective effects of 100 µg lysergic acid diethylamide (LSD), 100 mg 3,4-methylenedioxymethamphetamine (MDMA), and the LSD + MDMA combination over time on the Visual Analog Scale (VAS).

_{LSD and the LSD + MDMA combination produced comparable subjective effects with no significant differences in Emax values (Table 1). However, the co-administration of MDMA and LSD prolonged the psychedelic experience compared with LSD alone (Supplementary Table S5). Overall, effects of LSD and LSD + MDMA were significantly stronger and longer compared with MDMA alone. There was no significant difference in peak “drug high” between the substances alone and the combination. The substances were administered at t = 0 h. The data are expressed as the mean ± SEM percentage of maximally possible scores in 24 subjects. The corresponding maximal responses and statistics are shown in Table 1.}

Table 1 Mean values and statistics for the acute effects of LSD, MDMA, LSD + MDMA and placebo, N = 24.

Fig. 2: Acute mystical-type experiences on the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale.

The combination of LSD (100 µg) and MDMA (100 mg) induced comparable effects to LSD (100 µg) alone. MDMA (100 mg) alone only significantly induced mystical-type effects on the lower-order “blissful state” scale. The data are expressed as the mean ± SEM percentage of maximally possible scale scores in 24 subjects. Statistics are shown in Supplementary Table S2.

The LSD + MDMA combination did not induce significantly different subjective responses on the VASs, 5D-ASC, MEQ, or AMRS compared with LSD alone (Figs. 1 and 2, Supplementary Figs. S1–3, Table 1, Supplementary Tables S1–4). LSD and the LSD + MDMA combination produced overall greater psychedelic effects compared with MDMA alone. LSD and the LSD + MDMA combination induced greater “any drug effects,” “good drug effects,” “ego dissolution,” “alteration of vision,” and “audio-visual synesthesia” compared with MDMA alone (Fig. 1). In contrast, ratings of “drug high” were comparable for MDMA, LSD, and the LSD + MDMA combination (Fig. 1). LSD and LSD + MDMA induced increased ratings in all main dimensions and subscales of the 5D-ASC with the exception of the subscale anxiety which only showed a trend wise increase with LSD (p = 0.073). MDMA only increased the subscale blissful state (Fig. 2.). LSD and the LSD + MDMA combination induced more emotional excitation, introversion, anxiety and depression compared to MDMA on the AMRS (Supplementary Fig. S3).

Subjective “any drug effects” lasted an average of 1.5 h longer after the LSD + MDMA combination (mean = 9.9 h) compared with LSD alone (mean = 8.4 h; p < 0.05; Fig. 1, Supplementary Table S5).

Autonomic and adverse effects

Autonomic effects over time and respective peak effects are shown in Fig. 3 and Table 1, respectively. MDMA and the LSD + MDMA combination induced higher increases in blood pressure, heart rate, and pupil size compared with LSD alone (Fig. 3, Supplementary Fig. S4, Table 1). Body temperature increased similarly for LSD and the LSD + MDMA combination but less when MDMA was administered alone (Fig. 3). The LSD + MDMA combination and LSD alone produced similar total acute and subacute adverse effects scores on the List of Complaints, exceeding those of MDMA (Table 1). Frequently reported adverse effects on the List of Complaints are presented in Supplementary Table S6. Headache, lack of energy, loss of appetite, and dry mouth were similarly often reported with MDMA, LSD, and LSD + MDMA. Acute nausea was more frequent with MDMA than LSD. No severe adverse events were observed.

Fig. 3: Acute autonomic effects of 100 µg lysergic acid diethylamide (LSD), 100 mg 3,4-methylenedioxymethamphetamine (MDMA), and the LSD + MDMA combination (100 µg+100 mg) over time.

Effects on circulating oxytocin and BDNF

Effects of MDMA, LSD, and the LSD + MDMA combination on plasma levels of oxytocin and BDNF are shown in Supplementary Fig. S5 and Table 1. MDMA alone and the LSD + MDMA combination robustly increased oxytocin, with greater peak increases compared with LSD alone. LSD alone produced only minimal increases in oxytocin. Effects of MDMA and LSD on oxytocin were additive when the two substances were combined. MDMA, LSD, and the LSD + MDMA combination had no significant effects on serum BDNF concentrations (Supplementary Fig. S5, Table 1).

Plasma drug concentrations

The concentration-time curves for LSD, MDMA, and their metabolites are shown in Supplementary Figs. S6 and S7. Table 2 and Supplementary Table S7 show the corresponding pharmacokinetic parameters. MDMA slightly altered the pharmacokinetics of LSD. Specifically, the peak plasma concentration of LSD was higher in the LSD + MDMA condition (2.1 ng/mL) compared with LSD alone (1.9 ng/ml; T = 2.09; p < 0.05). The plasma LSD elimination half-life was longer in the LSD + MDMA condition (5.2 h) compared with LSD alone (3.9 h; T = 5.00; p < 0.001). The area under the concentration time curve (AUC_∞) also increased to 19 ng∙h/ml in the LSD + MDMA condition compared with LSD alone (14 ng∙h/mL; T = 3.53; p < 0.01; Table 2).

Table 2 Pharmacokinetic parameters based on non-compartmental analyses [geometric mean (95% CI), range], N = 24.

Blinding

Data on the participants’ retrospective identification of their substance condition after the session and after the study are shown in Supplementary Table S8. During and after receiving LSD + MDMA, 50% and 46% of the participants, respectively, thought they received LSD alone. During and after receiving LSD alone, 25% and 38% of the participants, respectively, thought they received LSD + MDMA. When asked at the end of the study, 25% of the participants mistook LSD for LSD + MDMA and vice versa.

Discussion

The main finding of the present study was that MDMA co-administration did not relevantly alter acute psychedelic effects of LSD while producing greater autonomic effects compared with LSD alone. However, LSD + MDMA co-administration prolonged acute subjective effects compared with LSD alone. The prolonged LSD response is consistent with a higher plasma concentration of LSD (C_max and AUC) and a longer plasma elimination half-life of LSD when it was co-administered with MDMA and as determined in the present study. Acute effects of LSD and MDMA alone have previously been compared in healthy participants [3], but the present study was the first to investigate the combined use of MDMA and LSD in a controlled laboratory setting and using defined doses of both substances. Synergistic discriminative effects of LSD and MDMA were previously reported in rats [24]. However, the rats were trained to discriminate MDMA (1.5 mg/kg) alone from saline, and then the co-administration of a low MDMA dose (0.15 mg/kg) with LSD (0.04 mg/kg) produced a full MDMA-like response [24]. Acute subjective effects of LSD are primarily positive. However, there are also negative subjective effects (e.g., anxiety) of LSD, depending on the dose of LSD used, personality traits of the person using LSD, their life circumstances, and the setting [1, 3,4,5,6,7, 9, 36]. Acute negative psychological effects are the main adverse events that are associated with LSD when it is used in psychedelic-assisted therapy [1]. In contrast to LSD, MDMA induces fewer psychedelic effects with little anxious ego-dissolution [3]. MDMA typically produces robust positive subjective effects, including enhanced feelings of positive mood, well-being, empathy, trust, and closeness to others [3, 16,17,18,19].Therefore, we hypothesized that adding MDMA to LSD would enhance positive mood effects and decrease anxiety that is associated with the LSD response. The same approach is also used by recreational substance users when combining MDMA and LSD in “candyflipping.” Contrary to our expectation, the present controlled study showed that the co-administration of LSD and MDMA and administration of LSD alone produced overall very similar subjective effects on the VAS, 5D-ASC, and MEQ. However, although no significant differences were seen, the addition of MDMA tended to nonsignificantly increase ratings of “happy,” “open,” and “trust” on the VAS and “well-being” on the AMRS, especially in the beginning of the experience compared with LSD alone. Additionally, ratings of “well-being” on the AMRS increased at the beginning of the drug response but dropped at 6 h when the MDMA effect ended. This may indicate some enhanced MDMA-typical subjective effects with the combination compared with LSD alone. Furthermore, we only tested single dose levels of both LSD and MDMA and co-administration at the same time. An LSD base dose of 100 µg has previously been used in several studies in healthy participants [3, 8, 36, 37] and could be considered a moderately high dose. LSD at a dose of 100 µg mainly induces high acute positive effects and nominally less anxiety compared with a higher dose of 200 µg [7, 36]. Thus, we cannot exclude the possibility that MDMA may reduce negative mood effects, including anxiety, of higher LSD doses than the dose that was used in the present study. The MDMA dose of 100 mg was lower than the 120–125 mg doses that were mostly used in healthy research participants [19] and patients [16]. A 100 mg dose of MDMA that is administered in women is equivalent to 120–125 mg in men and can be considered a fully psychoactive dose in women when given alone [19, 38] and not co-administered with LSD. Nevertheless, we cannot exclude different interactive effects of MDMA and LSD at different dose levels and administration time-points than those that were used herein. The duration of the acute LSD response is longer than the MDMA response, as confirmed in the present study. Future studies may test the administration of MDMA 1–4 h after LSD or use a prolonged MDMA release formulation or pro-drug of MDMA to better align its effects with the time course of the LSD effect. Moreover, the combination of MDMA and psilocybin may be interesting because of their similar durations of action [3, 36]. However, average peak effects of MDMA and LSD were reached at similar times in the present study, indicating a good match of the two subjective effect-time curves over the first 4 h. The potential drop in positive MDMA effects might have resulted in more negative mood states from 5 to 12 h in some participants, indicated by the trend-wise lower “well-being” ratings on the AMRS and higher “depression” ratings on the AMRS toward the end of the LSD response when it was co-administered with MDMA. Notably, recreational users reportedly often take MDMA after LSD when “candyflipping.”LSD, MDMA, and their combination produced significant autonomic stimulant effects as reported previously [3, 9, 39]. The LSD + MDMA combination induced greater increases in blood pressure and heart rate compared with LSD alone. Body temperature increased similarly after LSD + MDMA co-administration and LSD administration alone and more after LSD + MDMA co-administration compared with MDMA administration alone.MDMA had no relevant effects on the quality of the acute response to LSD, whereas the LSD + MDMA combination resulted in a longer effect duration compared with LSD and MDMA alone. This can be explained by higher plasma concentrations (both C_max and AUC) and a longer plasma elimination half-life of LSD when it was co-administered with MDMA. Thus, MDMA and LSD primarily interact pharmacokinetically and not pharmacodynamically. Additionally, the higher plasma exposure to LSD could be explained by metabolic P450 enzyme CYP2D6 inhibition by MDMA [38, 40]. MDMA is a strong inhibitor of CYP2D6, turning any CYP2D6 extensive or rapid metabolizer into a poor metabolizer within approximately 2 h [41]. Additionally, CYP2D6 poor metabolizers exhibited higher plasma concentrations and a longer elimination half-life of LSD compared with extensive metabolizers [42]. Thus, the present study further confirms a role for CYP2D6 in the metabolism of LSD. A similar or substantial increase in plasma LSD concentrations could be expected when patients who are on antidepressants that inhibit CYP2D6 (e.g., fluoxetine, paroxetine, duloxetine, and bupropion) and are treated with LSD-assisted therapy. This interaction warrants further study.We also evaluated selected interactive endocrine effects of LSD and MDMA. The marked release of oxytocin may mediate some of subjective effects of MDMA [17, 43, 44]. LSD also increased circulating oxytocin, although not robustly and to a lower extent than MDMA [3, 6, 7]. In the present study, effects of MDMA and LSD on plasma oxytocin concentrations were additive. Neither MDMA nor LSD altered serum concentrations of BDNF, adding further data to several inconclusive studies [3, 7, 8, 45].The present study also provided insights into the ways in which neurotransmitters mediate subjective effects of psychoactive substances. LSD directly activates the serotonin 5-hydroxytryptamine-2A (5-HT_2A) receptor [46], which primarily mediates its acute psychedelic effects [7, 8, 47]. MDMA induces the release of endogenous norepinephrine, serotonin, and oxytocin [44, 48, 49]. The present study indicates that stimulating serotonin and norepinephrine with the empathogen MDMA, in addition to the direct activation of 5-HT_2A receptors by the psychedelic LSD, does not relevantly alter the subjective effects profile of a psychedelic alone. This finding is also consistent with the observation that LSD alone strongly exerts several MDMA-like empathogenic effects, including similar ratings of well-being, happiness, closeness to others, openness, and trust, as previously reported [3, 6] and confirmed in the present study. Interestingly, the additional release of serotonin and oxytocin by MDMA does not appear to result in relevant additional psychoactive effects of LSD. The additional release of norepinephrine by MDMA explains the greater cardiovascular stimulation after the co-administration of LSD and MDMA compared with LSD alone.We found no indication of greater serotonin toxicity when MDMA and LSD were co-administered. MDMA did not increase thermogenic effects of LSD alone. Nausea was similarly frequent after the co-administration of LSD and MDMA and the administration of either substance alone.The role of dopamine in subjective effects of LSD remains unclear [50, 51]. LSD binds to dopamine D₁ and D₂ receptors [46]. We consider direct dopamine receptor stimulation irrelevant for psychedelic properties of LSD because subjective effects of LSD can be fully antagonized by blocking 5-HT₂ receptors [7, 8] and are very comparable to subjective effects of psilocybin [36] (a psychedelic with no relevant effects on D₁ or D₂ receptors) [46]. MDMA also induces the release of dopamine [52], and this may explain the nominally greater well-being ratings after the co-administration of MDMA and LSD compared with LSD alone.The present study has several strengths. We used a relatively large study sample (n = 24) and powerful within-subject comparisons in a randomized double-blind design. The LSD and MDMA doses were pharmacologically well characterized. We included equal numbers of male and female participants and used internationally established psychometric outcome measures. Plasma LSD and MDMA concentrations were determined at close intervals in all participants and analyzed with validated analytical methods.Notwithstanding these strengths, the present study also has limitations. We used only one dose of LSD and MDMA. The study used a highly controlled hospital setting and included only healthy volunteers. Thus, people in different environments and patients with psychiatric disorders may respond differently to these substances. Finally, the outcome measures may not have been sufficiently sensitive to capture all aspects of a psychedelic experience and/or very subtle differences between acute effects of LSD + MDMA compared with LSD alone.

Conclusion

MDMA co-administration did not alter acute psychedelic effects of LSD. However, MDMA acted as a blocker of the metabolism of LSD to prolong its presence in the body and acute effects. The LSD + MDMA combination produced more autonomic effects compared with LSD alone. There is likely little benefit in combining MDMA and LSD in psychedelic-assisted therapy.

Introduction

Lysergic acid diethylamide (LSD) is a classical psychedelic compound from the serotonergic class. It is widely used for recreational purposes and is increasingly being investigated as a potential treatment for psychiatric conditions, such as anxiety and depression. While LSD typically induces positive changes in consciousness, it can also lead to negative subjective experiences, including acute anxiety. Such acute negative psychological effects are considered a primary risk in the therapeutic application of psychedelic substances. Clinical studies have indicated that positive psychedelic-induced experiences correlate with more favorable long-term therapeutic outcomes in patients undergoing psychedelic-assisted therapy. Conversely, low levels of acute anxiety induced by a psychedelic have also predicted positive long-term clinical improvements. Therefore, fostering a positive acute psychedelic experience may enhance treatment efficacy, though challenging experiences can also hold therapeutic value.

3,4-Methylenedioxymethamphetamine (MDMA) is another compound currently being investigated in MDMA-assisted therapy. MDMA typically produces positive subjective effects, including heightened well-being, empathy, trust, and feelings of closeness. The combined use of MDMA and LSD, known recreationally as "candyflipping," is reported to induce synergistic positive mood effects. However, no controlled studies have investigated the combined administration of these two substances. The present study therefore aimed to determine if MDMA could optimize the acute effects profile of LSD by inducing more positive mood and reducing anxiety compared to LSD administration alone.

Primary Hypothesis

The primary hypothesis was that co-administration of MDMA and LSD would result in a greater experience of "good drug effects," well-being, openness, and trust, alongside a reduction in "bad drug effects" and anxiety, when compared with LSD administration alone.

Methods and materials

Study design

The study utilized a double-blind, placebo-controlled, crossover design, involving four experimental test sessions. These sessions investigated responses to placebo, 100 mg MDMA, 100 µg LSD, and the combination of 100 µg LSD + 100 mg MDMA. A block randomization method was employed to counterbalance the treatment order. A minimum 10-day washout period was maintained between sessions. The study adhered to the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice, receiving approval from the Ethics Committee of Northwest Switzerland (EKNZ) and the Swiss Federal Office for Public Health. The study was registered at ClinicalTrials.gov (NCT04516902).

Participants

Twenty-four healthy participants, comprising 12 men and 12 women, with a mean age of 30 ± 7 years (range: 25–54 years), were recruited through word-of-mouth or from a volunteer pool interested in psychedelic clinical trials. All participants provided written informed consent and received compensation. Exclusion criteria included age outside 25-65 years, pregnancy, a personal or first-degree family history of major psychiatric disorders, use of interfering medications, chronic or acute physical illness, heavy tobacco smoking, extensive prior lifetime use of hallucinogens or MDMA, or recent illicit drug use. Participants were also asked to limit alcohol consumption. The cohort displayed a varied history of prior illicit drug use, with some participants having used psychedelics, MDMA, stimulants, or other substances, while four had used only cannabis.

Study drugs

LSD base was administered as an oral solution containing 100 µg LSD base in 1 ml of 96% ethanol, produced according to good manufacturing practice. Placebo solutions contained only ethanol. MDMA was administered in opaque capsules, each containing 25 mg of MDMA hydrochloride. Placebo capsules contained mannitol. A double-dummy method was implemented, where participants received four capsules and one solution in each session, corresponding to the specific treatment condition. Participant blinding was assessed at various points.

Study procedures

The study protocol included a screening visit, four 13-hour test sessions with 24-hour follow-up measurements, and a final end-of-study visit approximately 31 days after the last session. Test days were separated by at least 10 days. Sessions were conducted in a calm hospital room with one research subject and one investigator present. Sessions began at 8:00 AM, involving urine drug and pregnancy tests, followed by baseline measurements and a standardized breakfast. Substances were administered at 9:00 AM. Outcome measures were assessed repeatedly over 12 hours. Standardized lunches and dinners were provided, and participants were never left unattended during the acute effects phase. Participants returned the following day for follow-up measurements.

Subjective drug effects and effect durations

Subjective effects were assessed repeatedly using Visual Analog Scales (VASs) and the Adjective Mood Rating Scale (AMRS). The 5 Dimensions of Altered States of Consciousness (5D-ASC) scale was the primary outcome measure, administered retrospectively at 12 hours to rate peak drug effects. Mystical experiences were assessed using the States of Consciousness Questionnaire (SOCQ), which includes the Mystical Effects Questionnaires (MEQ43 and MEQ30) and subscales for aesthetic experience, connectedness, distressing experience, and negative nadir effects. Time to onset, maximal effect, offset, and overall effect duration were determined from VAS effect-time plots.

Autonomic and adverse effects

Physiological parameters, including blood pressure, heart rate, and tympanic body temperature, were measured repeatedly. Pupil size was also assessed at specific intervals. Adverse effects were evaluated using the List of Complaints.

Circulating oxytocin and brain-derived neurotrophic factor

Plasma concentrations of oxytocin and serum levels of brain-derived neurotrophic factor (BDNF) were measured at baseline and various time points following drug administration.

Plasma LSD and MDMA concentrations

Plasma concentrations of LSD, MDMA, and their respective metabolites were measured before and at numerous time points post-administration. Blood samples were collected, centrifuged, and plasma stored for later analysis using ultra-high-performance liquid chromatography tandem mass spectrometry.

Pharmacokinetic analyses

Pharmacokinetic parameters were estimated using non-compartmental methods.

Data analysis

Peak or peak change from baseline values were determined for repeated measures. These values were analyzed using repeated-measures analysis of variance (ANOVA), with drug as the within-subjects factor, followed by Tukey post hoc tests. A significance criterion of p < 0.05 was applied.

Results

Subjective drug effects

LSD and the LSD + MDMA combination produced comparable subjective effects, with no significant differences in maximal effect values. However, the co-administration of MDMA and LSD prolonged the psychedelic experience compared with LSD alone. Overall, the effects of LSD and LSD + MDMA were significantly stronger and longer-lasting than those of MDMA alone. "Drug high" ratings were comparable across all substances and the combination. The LSD + MDMA combination did not induce significantly different subjective responses on the VASs, 5D-ASC, MEQ, or AMRS compared with LSD alone. Both LSD and the LSD + MDMA combination induced greater "any drug effects," "good drug effects," "ego dissolution," "alteration of vision," and "audio-visual synesthesia" compared with MDMA alone. While MDMA alone only increased the "blissful state" subscale of the 5D-ASC, LSD and the combination increased ratings across most main dimensions. Additionally, LSD and the LSD + MDMA combination induced more emotional excitation, introversion, anxiety, and depression on the AMRS compared to MDMA alone. Subjective "any drug effects" lasted approximately 1.5 hours longer with the LSD + MDMA combination (mean = 9.9 h) compared with LSD alone (mean = 8.4 h).

Autonomic and adverse effects

MDMA and the LSD + MDMA combination induced greater increases in blood pressure, heart rate, and pupil size compared with LSD alone. Body temperature increased similarly for LSD and the LSD + MDMA combination, but less with MDMA administered alone. The LSD + MDMA combination and LSD alone produced similar total acute and subacute adverse effects scores, which exceeded those of MDMA. Frequently reported adverse effects included headache, lack of energy, loss of appetite, and dry mouth, which were similarly common across MDMA, LSD, and the combination. Acute nausea was more frequent with MDMA than LSD. No severe adverse events were observed during the study.

Effects on circulating oxytocin and BDNF

MDMA alone and the LSD + MDMA combination robustly increased oxytocin plasma levels, with greater peak increases compared to LSD alone, which produced only minimal increases. The effects of MDMA and LSD on oxytocin were additive when combined. Neither MDMA nor LSD, nor their combination, had significant effects on serum BDNF concentrations.

Plasma drug concentrations

MDMA slightly altered the pharmacokinetics of LSD. Specifically, the peak plasma concentration of LSD was higher in the LSD + MDMA condition (2.1 ng/mL) compared with LSD alone (1.9 ng/ml). The plasma elimination half-life of LSD was longer in the LSD + MDMA condition (5.2 h) compared with LSD alone (3.9 h). The area under the concentration-time curve (AUC∞) also increased with the LSD + MDMA condition (19 ng∙h/ml) compared with LSD alone (14 ng∙h/mL).

Blinding

Data on participant's retrospective identification of their substance condition indicated that during and after receiving LSD + MDMA, 50% and 46% of participants, respectively, believed they had received LSD alone. Conversely, during and after receiving LSD alone, 25% and 38% of participants, respectively, thought they had received LSD + MDMA. When asked at the end of the study, 25% of participants mistook LSD for LSD + MDMA and vice versa.

Discussion

The primary finding of the present study was that MDMA co-administration did not significantly alter the acute psychedelic effects of LSD, though it did lead to greater autonomic effects compared with LSD alone. Notably, the LSD + MDMA co-administration prolonged acute subjective effects compared with LSD alone. This extended LSD response aligns with the observed higher plasma concentrations of LSD (Cmax and AUC) and a longer plasma elimination half-life of LSD when co-administered with MDMA. While acute effects of LSD and MDMA alone have been previously compared in healthy participants, this study was the first to investigate their combined use in a controlled laboratory setting with defined doses.

Contrary to the initial hypothesis, the controlled study demonstrated that the co-administration of LSD and MDMA produced overall very similar subjective effects on various scales (VAS, 5D-ASC, MEQ) compared to LSD alone. This might be partly explained by the already high acute positive effects and nominally less anxiety associated with the 100 µg dose of LSD used. Although not statistically significant, there was a tendency for MDMA addition to increase ratings of "happy," "open," and "trust," particularly in the early phase of the experience. The differing duration of effects for MDMA and LSD, with MDMA's effects concluding earlier, might also influence later mood states in the combination group. Future research could explore different dose levels or administration timings, such as administering MDMA later in the LSD experience or using a prolonged-release MDMA formulation.

The observed prolongation of LSD's effects due to MDMA co-administration is attributed to higher plasma concentrations and a longer elimination half-life of LSD. This suggests a pharmacokinetic interaction where MDMA acts as a blocker of LSD metabolism. Specifically, MDMA is a strong inhibitor of the P450 enzyme CYP2D6, which is implicated in LSD metabolism. This finding further supports the role of CYP2D6 in LSD's metabolic breakdown. The implication is significant for clinical settings, as patients undergoing LSD-assisted therapy who are also taking CYP2D6-inhibiting antidepressants might experience similar increases in plasma LSD concentrations, warranting further investigation.

Regarding neurotransmitter mechanisms, LSD directly activates the serotonin 5-HT2A receptor, mediating its psychedelic effects. MDMA, in contrast, induces the release of endogenous norepinephrine, serotonin, and oxytocin. The present study indicated that the additional stimulation of serotonin and norepinephrine by MDMA, alongside LSD's direct 5-HT2A activation, did not substantially alter the subjective effects profile of LSD alone. This may be because LSD itself already exerts empathogenic effects similar to MDMA, such as feelings of well-being, happiness, and closeness. The increased cardiovascular stimulation observed with the LSD + MDMA combination, however, can be attributed to MDMA's additional release of norepinephrine. The study also found no indication of increased serotonin toxicity or thermogenic effects when MDMA and LSD were co-administered.

The study's strengths include a relatively large sample size, powerful within-subject comparisons, and a randomized double-blind design. The LSD and MDMA doses were pharmacologically well-characterized, and participant sex was balanced. Plasma concentrations were determined with validated analytical methods at close intervals. However, the study used only one dose of each substance and was conducted in a highly controlled hospital setting with healthy volunteers, which may limit the generalizability of findings to different environments or patient populations. Furthermore, the outcome measures may not have been sufficiently sensitive to capture all aspects or subtle differences in the psychedelic experience.

Conclusion

MDMA co-administration did not alter the acute psychedelic effects of LSD. Instead, MDMA acted as a metabolic blocker of LSD, prolonging its presence in the body and extending its acute effects. The LSD + MDMA combination produced more pronounced autonomic effects compared with LSD alone. Based on these findings, there is likely limited benefit in combining MDMA and LSD for the purpose of optimizing psychedelic-assisted therapy.

Introduction

Lysergic acid diethylamide (LSD) is a well-known psychedelic substance used recreationally and studied for its potential in treating mental health conditions such as anxiety and depression. While LSD often leads to positive changes in consciousness, it can also cause negative experiences, including acute anxiety. In clinical trials, positive experiences during psychedelic therapy have been linked to better long-term treatment outcomes for patients. Additionally, low levels of anxiety during a psychedelic experience have predicted positive long-term results. Therefore, promoting a positive initial experience may improve treatment effectiveness, although challenging experiences can also have therapeutic value.

3,4-Methylenedioxymethamphetamine (MDMA) is another substance being investigated for use in therapy. MDMA typically produces positive subjective effects, such as increased well-being, empathy, trust, and feelings of closeness to others. The combination of MDMA and LSD, known recreationally as "candyflipping," is thought to create stronger positive mood effects. However, no controlled studies have previously examined the combined use of MDMA and LSD. This study aimed to determine if MDMA could enhance the positive effects of LSD and reduce anxiety compared to LSD taken alone.

The primary prediction was that taking MDMA with LSD would lead to more "good drug effects," increased well-being, openness, and trust, and fewer "bad drug effects" and less anxiety compared to taking LSD alone.

Methods and Materials

Study Design

The study utilized a double-blind, placebo-controlled, crossover design, meaning participants received all treatments in a random order over different sessions, and neither participants nor researchers knew which substance was being given at the time. There were four experimental sessions: placebo, 100 mg MDMA, 100 µg LSD, and the combination of 100 µg LSD + 100 mg MDMA. A period of at least 10 days separated each session to allow substances to clear the body. The study adhered to ethical guidelines and was approved by relevant health authorities.

Participants

Twenty-four healthy adults (12 men, 12 women) with an average age of 30 were recruited. All participants provided informed consent and were compensated. Exclusion criteria ensured participant safety and study integrity, including age limits, pregnancy, history of major psychiatric disorders (personal or family), use of interfering medications, chronic physical illness, heavy tobacco use, and recent or ongoing illicit drug use. Participants were also asked to limit alcohol consumption. The group had varied histories of previous drug use, with some having tried psychedelics or MDMA before, while a few had only used cannabis or no illicit drugs.

Study Drugs

LSD was given as an oral solution, precisely measured at 100 µg per dose. The placebo solution contained only ethanol. MDMA was provided in opaque capsules containing 25 mg doses. The placebo capsules contained mannitol. To maintain blinding, a double-dummy method was used: in each session, participants received four capsules and one solution, ensuring they always received a combination of active drug and placebo forms depending on the treatment condition. Participants were asked to guess their treatment assignment to assess blinding effectiveness.

Study Procedures

The study involved a screening visit, four 13-hour test sessions with follow-up measurements 24 hours after drug intake, and a final end-of-study visit. Sessions were held in a calm hospital room, with only one participant and one investigator present. Participants arrived at 8:00 AM, underwent baseline measurements, and consumed a standardized breakfast. Substances were administered at 9:00 AM. Outcome measures were taken repeatedly for 12 hours. Standardized meals were provided, and participants were supervised throughout the acute effect phase. They returned the following day for follow-up.

Measurements and Data Analysis

Subjective drug effects were assessed at multiple time points using various scales, including Visual Analog Scales (VAS), the Adjective Mood Rating Scale (AMRS), the 5 Dimensions of Altered States of Consciousness (5D-ASC) scale (for peak effects), and the States of Consciousness Questionnaire (SOCQ), which includes mystical experience subscales. The duration of effects was also calculated. Physiological measures, such as blood pressure, heart rate, body temperature, and pupil size, were taken repeatedly, and adverse effects were recorded using a checklist. Plasma levels of oxytocin and brain-derived neurotrophic factor (BDNF) were measured at specific intervals. Blood samples were collected to determine plasma concentrations of LSD, MDMA, and their metabolites over time. Pharmacokinetic parameters (how the body processes the drugs) were estimated. Statistical analysis involved comparing peak drug effects and changes from baseline across different drug conditions using repeated-measures analysis of variance (ANOVA) and post-hoc tests.

Results

Subjective Drug Effects

The combination of LSD and MDMA produced subjective effects generally comparable to LSD alone, with no significant differences in their maximal effects. However, the combined administration of MDMA and LSD extended the duration of the psychedelic experience compared to LSD alone. Overall, the effects of LSD and the LSD + MDMA combination were stronger and lasted longer than MDMA alone. "Drug high" ratings were similar across MDMA, LSD, and the combination. While MDMA alone increased "blissful state" ratings, LSD and the combination led to greater "any drug effects," "good drug effects," "ego dissolution," "alteration of vision," and "audio-visual synesthesia." LSD and the combination also increased ratings across most dimensions of altered consciousness, with LSD showing a trend toward increased anxiety. Subjective "any drug effects" lasted approximately 1.5 hours longer with the LSD + MDMA combination (9.9 hours) compared to LSD alone (8.4 hours).

Autonomic and Adverse Effects

MDMA and the LSD + MDMA combination led to greater increases in blood pressure, heart rate, and pupil size compared to LSD alone. Body temperature increased similarly for LSD and the combination, but less with MDMA alone. The LSD + MDMA combination and LSD alone produced similar total adverse effects scores, which were higher than those for MDMA alone. Common adverse effects like headache, lack of energy, loss of appetite, and dry mouth were reported similarly across MDMA, LSD, and the combination. Acute nausea was more frequent with MDMA than LSD. No severe adverse events occurred during the study.

Effects on Hormones and Proteins

MDMA alone and the LSD + MDMA combination significantly increased oxytocin levels, with the combination showing an additive effect of the two substances. LSD alone caused only minimal increases in oxytocin. Neither MDMA nor LSD, nor their combination, had a significant impact on serum BDNF concentrations.

Plasma Drug Concentrations

MDMA slightly altered how LSD was processed by the body. Specifically, the peak plasma concentration of LSD was higher when co-administered with MDMA (2.1 ng/mL) compared to LSD alone (1.9 ng/mL). The plasma elimination half-life of LSD was also longer with the combination (5.2 hours) than with LSD alone (3.9 hours). The total exposure to LSD (measured as Area Under the Curve) also increased significantly when MDMA was co-administered.

Blinding Assessment

When asked to identify their substance condition after each session, and again at the end of the study, participants showed some confusion. For example, 50% of participants thought they received LSD alone when they had received the LSD + MDMA combination, and 25% thought they received the combination when they had received LSD alone. This indicates that the blinding was not always perfectly maintained, as the effects could sometimes be distinguished or misattributed.

Discussion

The primary finding of this study was that MDMA co-administration did not significantly change the acute psychedelic effects of LSD in a meaningful way. However, the combination did prolong the acute subjective effects of LSD. This extended effect aligns with the observed higher plasma concentration and longer elimination half-life of LSD when MDMA was co-administered, suggesting a direct interaction in how the body processes the drugs.

Contrary to the initial hypothesis and recreational reports of "candyflipping," the controlled study showed that the combined use of LSD and MDMA did not significantly enhance positive mood or decrease anxiety compared to LSD alone. While the addition of MDMA showed a non-significant tendency to increase feelings of happiness, openness, and trust, particularly early in the experience, these effects were not strong enough to be statistically significant. The study used a moderate dose of LSD (100 µg) and a standard dose of MDMA (100 mg); therefore, different doses or administration timings might yield different results. For example, recreational users often take MDMA after LSD, which was not tested here, or MDMA might be more effective at reducing anxiety at higher LSD doses.

The combination of LSD and MDMA resulted in greater increases in blood pressure, heart rate, and pupil size compared to LSD alone, indicating increased autonomic stimulation. Body temperature increases were similar for LSD alone and the combination. No serious adverse events were observed, and common adverse effects were generally similar across conditions.

The prolonged LSD effect when combined with MDMA can be attributed to MDMA's influence on LSD's pharmacokinetics. MDMA is known to inhibit the enzyme CYP2D6, which plays a role in breaking down LSD. This inhibition likely led to higher LSD concentrations and a longer presence in the body. This finding suggests a potential drug-drug interaction when LSD is taken with certain antidepressants that also inhibit CYP2D6, which warrants further investigation in a therapeutic context.

In terms of how these substances affect the brain, LSD directly activates serotonin 5-HT2A receptors, which are primarily responsible for its psychedelic effects. MDMA releases norepinephrine, serotonin, and oxytocin. This study's findings suggest that the additional release of serotonin and oxytocin by MDMA does not substantially alter the core subjective psychedelic profile of LSD, as LSD itself already produces several MDMA-like empathogenic effects such as well-being, happiness, and closeness. The increased cardiovascular effects with the combination are likely due to MDMA's additional release of norepinephrine. This study found no indication of greater serotonin toxicity when MDMA and LSD were co-administered. While both substances can affect dopamine, this study did not clarify dopamine's role in the combined subjective effects.

The study's strengths include a relatively large sample size, a rigorous randomized double-blind crossover design, well-characterized drug doses, balanced male and female participants, and comprehensive measurement of drug concentrations. However, limitations include the use of only one dose for each substance, the highly controlled hospital setting which may not reflect real-world experiences, and the fact that only healthy volunteers were included, meaning patients with psychiatric conditions might respond differently. It is also possible that the outcome measures were not sensitive enough to capture very subtle differences in the psychedelic experience.

Conclusion

Co-administering MDMA did not significantly change the acute psychedelic effects of LSD. Instead, MDMA prolonged LSD's effects by altering its metabolism and increasing its concentration in the body. The LSD + MDMA combination also led to more pronounced autonomic effects compared to LSD alone. Based on these findings, there appears to be little additional benefit in combining MDMA and LSD in psychedelic-assisted therapy for enhancing the subjective psychedelic experience.

Lysergic acid diethylamide (LSD) is a well-known psychedelic substance used by some for recreation. It is also being studied more often for its potential to help people with mental health conditions like anxiety and depression. While LSD usually creates positive changes in perception, it can also cause negative feelings, such as strong anxiety. These negative psychological effects are seen as the main risk when using psychedelics. Studies have shown that when patients have positive experiences during psychedelic-assisted therapy, they tend to see better long-term improvements. Also, experiencing less anxiety while under the influence of a psychedelic has been linked to better patient outcomes. This suggests that creating a positive experience with psychedelics could lead to better treatment results, though challenging experiences might also offer some benefits.

MDMA is another substance being researched for use in therapy. When taken, MDMA typically causes positive feelings like increased well-being, empathy, trust, and a sense of connection with others. Users sometimes combine MDMA and LSD, a practice known as “candyflipping,” believing it creates an even stronger positive mood. However, until this study, no controlled research had looked into combining MDMA and LSD. This study aimed to find out if MDMA could make the effects of LSD better by increasing positive mood and reducing anxiety when compared to taking LSD alone.

The main idea explored was that taking MDMA and LSD together would lead to more “good drug effects,” better well-being, increased openness, and more trust, while at the same time causing fewer “bad drug effects” and less anxiety, compared to taking LSD by itself.

Methods and materials

This study used a controlled research design where neither the participants nor the researchers knew who received which substance (double-blind). Each participant attended four separate sessions, receiving a placebo, MDMA, LSD, or a combination of LSD and MDMA. The order of treatments was varied to ensure fairness, with at least 10 days between sessions. All procedures followed ethical guidelines and were approved by relevant authorities.

Twenty-four healthy adults, equally split between men and women, participated. They were recruited from volunteers interested in psychedelic research. Participants had to be between 25 and 54 years old, without major mental health issues, not pregnant, and not taking interfering medications. They were also screened for drug use habits, with limits on past psychedelic or MDMA use. Before each session, drug tests were conducted, and participants were asked to limit alcohol.

The study used 100 µg of LSD and 100 mg of MDMA. Placebo versions of both were also used. The substances were given orally. During the 13-hour test sessions, participants were constantly monitored. Researchers measured their subjective experiences (how they felt), vital signs like blood pressure and heart rate, and looked for any negative side effects. Blood samples were taken at various times to measure levels of certain hormones (oxytocin and BDNF) and the concentrations of LSD, MDMA, and their breakdown products in the participants’ blood. This helped researchers understand how the body processed the substances. The information collected was then analyzed to see if there were significant differences between the different treatments.

Results

The study found that the combination of LSD and MDMA generally led to similar subjective effects as LSD taken alone. However, taking MDMA with LSD made the psychedelic experience last about 1.5 hours longer than LSD by itself. Overall, the effects of LSD, whether alone or combined with MDMA, were stronger and lasted longer compared to taking MDMA alone. Interestingly, the feeling of a "drug high" was similar across MDMA, LSD, and the combination. While MDMA alone mostly increased a "blissful state," LSD and the combination produced a wider range of psychedelic effects, including changes in vision and ego dissolution. The combination did not significantly increase positive mood or reduce anxiety compared to LSD alone, but there was a slight tendency for more positive feelings like happiness and trust early on.

Regarding physical effects, MDMA and the LSD + MDMA combination caused a greater rise in blood pressure, heart rate, and pupil size compared to LSD alone. Body temperature increased similarly for LSD and the combination, but less so with MDMA alone. Side effects like headache, low energy, loss of appetite, and dry mouth were common across all active treatments. Nausea was reported more often with MDMA than with LSD. No severe negative events occurred during the study.

The study also looked at substances in the blood. MDMA alone and the LSD + MDMA combination significantly increased levels of oxytocin, a hormone linked to bonding, much more than LSD alone. This effect was strongest when MDMA and LSD were combined. Levels of brain-derived neurotrophic factor (BDNF), a protein important for brain health, were not significantly affected by any of the substances. Analyzing blood samples showed that MDMA slightly changed how LSD was processed by the body. Specifically, when MDMA was taken with LSD, the peak level of LSD in the blood was higher, and LSD stayed in the body longer before being eliminated. This explains why the effects of LSD lasted longer when combined with MDMA. Participants' guesses about which substance they received showed that blinding was not perfect, especially for the combination.

Discussion

The main finding of this study was that adding MDMA did not significantly change the psychedelic effects of LSD itself. However, the combination did make the acute subjective effects of LSD last longer. This longer effect is likely due to MDMA increasing the amount of LSD in the blood and slowing down its removal from the body. This study was the first controlled laboratory investigation of combining MDMA and LSD at specific doses, building on previous comparisons of LSD and MDMA alone. While recreational users often combine these substances hoping for more positive effects, this research did not find a major difference in the overall subjective experience of LSD when MDMA was added.

The researchers had expected that MDMA, known for its positive mood-enhancing effects, would improve the LSD experience by making it more positive and reducing anxiety. This was based on how MDMA works and how recreational users report “candyflipping” effects. However, this controlled study found that the combined administration of LSD and MDMA produced very similar subjective effects to LSD alone. Although there were slight trends of increased happiness, openness, and trust with the combination, these were not significant. It's possible that the specific doses used or the timing of administration might influence the effects differently; for example, if MDMA was given later during the LSD experience, or if higher LSD doses, which might induce more anxiety, were used, the results could vary.

The study confirmed that MDMA and LSD both stimulate the body’s automatic systems, like increasing blood pressure and heart rate. The combination of LSD and MDMA led to even greater increases in these physical responses compared to LSD alone. The finding that MDMA makes LSD stay in the body longer suggests that MDMA affects how the body breaks down LSD. This is important because certain antidepressant medications also affect the same body processes, meaning patients taking these drugs for therapy might experience stronger or longer LSD effects.

This research helps us understand how these substances affect the brain’s chemistry. LSD works by directly activating a specific serotonin receptor, which causes its psychedelic effects. MDMA, on the other hand, causes the release of several brain chemicals, including serotonin, norepinephrine, and oxytocin. This study suggests that adding MDMA’s effects on these chemicals to LSD’s direct receptor activation does not significantly alter the overall psychedelic experience from LSD alone. The study did not find any increased risk of serotonin toxicity or more nausea when the two substances were combined.

A strength of this study was its controlled design with a good number of participants, ensuring reliable results. However, a limitation is that it used only one dose combination in a controlled hospital setting with healthy volunteers, meaning results might differ in real-world situations or in patients with mental health conditions. Additionally, the measures used might not have captured all subtle differences in the complex psychedelic experience.

Conclusion

In summary, adding MDMA did not change the quality of LSD’s psychedelic effects. However, MDMA did cause LSD to remain in the body longer, which extended its effects. The combination of LSD and MDMA also resulted in more physical effects compared to LSD alone. Based on these findings, it is likely that combining MDMA and LSD offers little extra benefit for psychedelic-assisted therapy.

LSD is a drug that changes how people think and feel. People use it for fun, and doctors are studying it to help with problems like worry and sadness. When people take LSD, they often have good feelings and new ways of seeing things. But sometimes, it can cause bad feelings, like feeling very worried. Feeling worried right away is seen as a main risk when people use these types of drugs. Studies have shown that good feelings during a drug experience can lead to better help for patients in the long run. Also, if a drug causes less worry at first, patients often do better over time. So, having a good experience from the start might help treatment work better. Still, sometimes hard experiences can also be helpful.

MDMA is another drug being studied for therapy. It usually makes people feel good, happy, and closer to others. When people use MDMA and LSD together, it is called "candyflipping." People who do this often say it makes their good feelings even stronger. But no true study had looked at taking MDMA and LSD together in a controlled way. So, this study wanted to see if MDMA could make LSD's effects better, by causing more good feelings and less worry than LSD by itself.

The main idea tested was that taking MDMA and LSD together would lead to more good feelings, happiness, openness, and trust. It was also thought to lead to fewer bad feelings and less worry compared to taking LSD alone.

Study Details

The study was set up so that neither the participants nor the researchers knew which drug was given. Each person went through four test days. On different days, they received: a sugar pill (placebo), MDMA alone (100 mg), LSD alone (100 micrograms), or MDMA and LSD together. The order was mixed up for different people. There was at least 10 days between each test day. This study followed strict rules for medical research and was approved by health groups.

Twenty-four healthy adults took part in the study, 12 men and 12 women. Their average age was 30 years. They were found by word of mouth or had shown interest in earlier drug studies. Everyone agreed to be in the study in writing and was paid. People were not allowed to join if they were too young or too old, pregnant, had certain mental health issues in their family, used certain medicines, had serious health problems, smoked too much, or used many drugs in the past. They also had rules about drinking alcohol. Some people in the study had used drugs like LSD or MDMA before, but some had not used drugs other than cannabis.

LSD was given as a liquid, and MDMA was given in a pill. There were also fake versions of each (placebo liquid and placebo pill). This was done so that people could not tell which drug they were getting. On test days, participants came to a quiet hospital room. They had to take a drug test first. They ate breakfast, then took the study drug at 9:00 AM. For 12 hours, researchers watched them and asked about their feelings. They also checked things like blood pressure, heart rate, body temperature, and how big their pupils were. Blood samples were taken to check levels of the drugs and other body chemicals. All information was then carefully checked.

What the Study Found

People who took LSD and those who took LSD with MDMA together felt very similar effects. Taking MDMA alone caused less strong effects overall. For example, LSD and the combination made people feel more changes in their mind, clearer visions, and new ways of seeing and hearing. However, feelings of being "high" were similar for MDMA alone, LSD alone, and the combination. The study also found that taking LSD with MDMA made the effects last about 1.5 hours longer than LSD by itself.

The study looked at how the drugs affected the body. MDMA, and MDMA combined with LSD, caused bigger increases in blood pressure, heart rate, and pupil size compared to LSD alone. Body temperature went up the same amount for LSD alone and the combination, but less for MDMA alone. People had similar side effects with LSD alone and the combination, which were more than with MDMA alone. Common side effects were headache, feeling tired, not wanting to eat, and dry mouth. Feeling sick was more common with MDMA than LSD. No one had very serious side effects.

The study also checked for certain chemicals in the blood. MDMA alone and the MDMA-LSD combination caused a strong rise in a chemical called oxytocin. LSD alone caused only a small rise in oxytocin. When MDMA and LSD were taken together, the oxytocin levels added up. Another chemical, BDNF, did not change with any of the drugs. The study also found that MDMA changed how LSD levels were in the blood. When taken with MDMA, LSD reached higher levels in the blood and stayed in the body for a longer time.

The study also checked if people knew what drug they had taken. When people took LSD and MDMA together, about half of them thought they had only taken LSD. When people took LSD alone, about a quarter of them thought they had taken LSD and MDMA together. Overall, about a quarter of the people were wrong about which drug they had received at the end of the study.

What This Means

The main finding was that taking MDMA with LSD did not really change the main effects of LSD. However, the MDMA did make the LSD effects last longer. This is because MDMA made more LSD stay in the body for a longer time. People often combine MDMA and LSD hoping to make the good feelings stronger or lessen the worry that LSD can sometimes cause. But this study showed that the combination generally felt very similar to LSD alone. There was a slight trend for more happiness or trust at the start with the combination, but these feelings dropped later when the MDMA effects wore off.

This study only used one specific dose of each drug and gave them at the same time. It is possible that taking different amounts, or taking MDMA at a different time after LSD, might change the effects. For example, some people who use these drugs for fun often take MDMA after LSD. The study also found that MDMA with LSD caused more physical changes, like higher blood pressure and heart rate, than LSD alone.

The reason LSD stayed in the body longer when taken with MDMA is important. MDMA changes how the body breaks down LSD. This means that if someone takes MDMA, their body might not get rid of LSD as quickly. This is similar to how some other medicines, like certain drugs for sadness, can affect how the body handles LSD. This is something that needs more study, especially for people who might be taking LSD as part of therapy.

The study also looked at how these drugs affect brain chemicals. MDMA made a chemical called oxytocin go up a lot, which helps with feeling close to others. LSD also made oxytocin go up, but not as much. When they were taken together, the effects on oxytocin added up. However, the study did not find that MDMA made LSD's mind-altering effects stronger, even though MDMA affects many brain chemicals. This suggests that LSD already causes many of the positive feelings that MDMA does. Also, taking them together did not seem to cause more harm, like overheating or severe sickness, than taking them alone.

This study had good strengths, like having enough people, giving each person all the drugs on different days, and keeping both participants and researchers unaware of what drug was given. The drug amounts were also well-known. However, the study only used one amount of each drug. Also, it was done in a hospital with healthy people, so the results might be different for people in other places or for those with mental health problems. The ways used to measure feelings might also not have caught every small difference.

Final Thoughts

Taking MDMA with LSD did not change how LSD made people's minds feel. But MDMA did make the effects of LSD last longer by keeping more LSD in the body. The combination also caused more physical changes, like higher blood pressure, than LSD alone. Overall, it seems there is not much extra benefit to mixing MDMA and LSD for therapy.