Acute subjective effects in LSD- and MDMA-assisted psychotherapy

Schmid and colleagues situate this study within the renewed clinical interest in serotonergic hallucinogens and entactogens, noting that LSD and MDMA were used as adjuncts to psychotherapy from the 1950s to the 1980s and are again being investigated for disorders such as depression, anxiety associated with life‑threatening illness, OCD, substance use disorders and PTSD. Previous clinical and experimental work has identified acute prosocial and empathogenic effects of both LSD and MDMA, and hallucinogen‑induced mystical‑type experiences have been associated with persistent positive changes; however, most experimental studies assessed subjects individually in controlled laboratory settings, and there are few objective data on acute subjective effects when these drugs are administered clinically in group psychotherapy outside formal trials. This prospectively designed study aimed to describe patient characteristics, treatment indications and acute subjective alterations of consciousness in patients receiving LSD (100–200 µg) and/or MDMA (100–175 mg) within the Swiss compassionate use programme from 2014–2018. In addition, the investigators compared these acute responses, measured with validated psychometric instruments, to pooled data from healthy volunteers and to patients treated alone in clinical trials, to explore whether acute effects differ between clinical group settings and laboratory or single‑patient therapeutic settings.

The study prospectively collected data from patients treated with LSD and/or MDMA under individual compassionate‑use authorisations issued by the Swiss Federal Office of Public Health between December 2014 and March 2018. Ethics approval was obtained from the local committee (the extracted text does not clearly report the full committee name). All participants gave written informed consent to include their data. This was an observational, open‑label assessment of acute subjective effects in a naturalistic group psychotherapy setting; there was no placebo control. Eighteen patients (12 women, six men; median age 49 years, range 29–77) treated in groups of 3–13 patients with 1–3 investigators were included. Treatment indications were mostly post‑traumatic stress disorder (PTSD) and major depression; some patients had comorbid conditions. Patients with psychotic disorders or who could not attend group meetings were excluded. In the compassionate‑use programme, dosing and choice of compound were individually determined by treating psychotherapists; LSD was given orally at 100, 150, 175 or 200 µg and MDMA at 100, 125 or 175 mg. Drug‑assisted sessions occurred repeatedly (mean 5.7 ± 0.8 sessions per patient, range 2–12) with drug‑assisted sessions roughly every 3.5 months following 3–10 non‑drug psychotherapy sessions. Medications potentially interacting with LSD or MDMA (for example some antidepressants) were paused around sessions when applicable. Acute subjective effects were measured using the 5 Dimensions of Altered States of Consciousness scale (5D‑ASC) and the Mystical Experience Questionnaire (MEQ). Both instruments were administered on the same day after effects had faded or on the next day, with participants asked to retrospectively rate peak experiences. For comparative purposes, pooled datasets from previously published studies in healthy volunteers were used: LSD data from groups receiving 100 µg and 200 µg, and MDMA data pooled from nine studies (125 mg). The LSD effects in study patients treated alone in a clinical trial were also used for comparison. Statistical analyses used one‑sample t‑tests to compare patient ratings against zero (no change from everyday life), ANOVA to compare LSD groups, t‑tests to compare MDMA groups, and chi‑square tests for categorical comparisons such as frequency of complete mystical experiences. Only the first assessment per patient was used if questionnaires were completed after multiple sessions; significance was set at p < 0.05.

Sample and treatment characteristics are reported for 18 compassionate‑use patients (12 women, six men, median age 49 years). Seven patients had limited prior experience with psychoactive drugs. Eleven patients received LSD and 11 received MDMA, with four patients receiving both substances sequentially (typically MDMA before LSD). Antidepressants, some neuroleptics and other interacting medications were paused during sessions in a minority of patients. On average drug‑assisted sessions occurred every 105 ± 51 days. LSD on the 5D‑ASC: In the compassionate‑use patients, LSD produced pronounced alterations of waking consciousness with significant increases on all five 5D‑ASC dimensions and all lower‑order subscales (all t10 > 3.0, p < 0.05). There was no clear dose‑response within the patient group—higher doses did not produce significantly greater effects than lower doses. Overall ASC global scores were comparable between patients in the compassionate‑use group and healthy volunteers, although some perceptual subscales were lower in patients when compared specifically with healthy subjects who received 200 µg LSD. In healthy subjects, 200 µg produced greater visionary and positive‑mood ratings than 100 µg. LSD on the MEQ: LSD increased all MEQ scales significantly in the compassionate‑use patients (all t10 > 4.9, p < 0.001). The proportion of complete mystical experiences (defined as ≥60% on all MEQ30 factors) was 3 of 11 patients in the compassionate‑use group, compared with 5 of 27 healthy subjects at 100 µg, 2 of 16 healthy subjects at 200 µg, and 2 of 11 study patients treated alone; these differences were not statistically significant (χ2(3) = 0.96, NS). MDMA on the 5D‑ASC: MDMA significantly increased most 5D‑ASC dimensions in compassionate‑use patients (all t8 > 2.9, p < 0.05) except for auditory alterations. MDMA effects on the 5D‑ASC were generally less pronounced than LSD. When compared with pooled healthy volunteer data (125 mg MDMA), patients showed higher ratings of anxious ego dissolution (t171 = 2.851, p = 0.005), including higher anxiety (t171 = 4.029, p < 0.001), and greater visionary restructuralization and complex imagery (t171 = 2.871, p = 0.005; t171 = 4.241, p < 0.001). Patients also reported greater spiritual experience (t171 = 3.326, p = 0.001) and insightfulness (t171 = 2.891, p = 0.004) after MDMA than healthy volunteers. MDMA on the MEQ: Compassionate‑use patients showed significant increases on most MEQ scales after MDMA (all t8 > 2.7, p < 0.05), with a trend for internal unity (t8 = 2.3, p = 0.06). MDMA produced a higher MEQ30 total score in patients than in healthy volunteers (t35 = 4.1, p < 0.001), with higher ratings across most dimensions except positive mood and internal unity. No complete mystical experiences occurred with MDMA in either patients or healthy subjects. Additional findings and safety observations: Ratings on the 5D‑ASC were similar over repeated sessions within subjects, suggesting no rapid tolerance at the intersession intervals used. No pharmacological interventions were required for acute anxiety; however, MDMA produced relatively greater anxiety and ego‑dissolution ratings in patients, which the authors note may reflect the clinical population (for example PTSD) and the predominance of female patients for MDMA. The study did not routinely record physiological course or vital signs in the compassionate‑use group; sample size was too small to draw firm safety conclusions for older patients or those with somatic comorbidities.

Schmid and colleagues interpret their findings as showing that both LSD and MDMA induce marked acute alterations of consciousness when administered within a clinical compassionate‑use group psychotherapy setting, and that these acute subjective responses are broadly comparable to those observed in healthy volunteers and patients treated alone in controlled studies. They emphasise that most compassionate‑use patients were treated for PTSD or major depression, with MDMA used more often for trauma‑related disorders and LSD more often for depression and OCD; some patients received MDMA first to prepare for the more confrontational effects of subsequent LSD therapy. The investigators note that LSD produced larger perceptual changes and more instances of complete mystical experiences than MDMA, whereas MDMA produced significant empathogenic and insightfulness ratings and, in this patient sample, greater MEQ30 total scores than in pooled healthy‑volunteer data. Differences between patient and healthy cohorts were attributed to a combination of dose differences, setting (group versus individual sessions), participant characteristics including prior drug experience and sex distribution, and the clinical nature of the patient sample. The authors argue that mystical‑type experiences appear to be influenced strongly by the pharmacology of the administered compound and less so by setting, given that LSD produced similar MEQ scores across settings, although they acknowledge that setting and preparatory practice can modulate outcomes in other studies. Key limitations acknowledged by the authors include the small sample size, which limits power to detect dose effects and safety signals; the observational, non‑randomised and unblinded design with no placebo control; the absence of efficacy or longitudinal outcome measures linking acute effects to clinical benefit; and the fact that comparative analyses used pooled data from different studies rather than within‑study randomised comparisons. Expectancy effects could have influenced results because subjects were informed about expected effects prior to administration. The authors conclude that their observational data provide an initial description of patient characteristics and acute subjective responses in a real‑world group therapy context and that these data can inform and motivate larger, controlled trials to examine efficacy, dose–response relationships and safety across indications.