Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects.

Holze and colleagues situate LSD, MDMA, and D-amphetamine as representative compounds of three pharmacological classes that are both used recreationally and being investigated clinically: LSD as a classic serotonergic hallucinogen acting principally at 5-HT2A receptors, MDMA as an empathogen/entactogen with serotonergic and noradrenergic effects and oxytocin release, and D-amphetamine as a prototypical psychostimulant acting primarily via dopamine and norepinephrine. The authors note that acute subjective experiences differ between these substances and that the magnitude and quality of psychedelic experiences (for example on measures of mystical-type experiences) have been linked in prior work with longer-term therapeutic outcomes, but that direct head-to-head, double-blind comparisons of their acute autonomic, subjective, and endocrine effects within the same participants are lacking. The primary aim of the study was to characterise and compare the acute autonomic, subjective, endocrine, and pharmacokinetic profiles of single oral doses of LSD (0.1 mg), MDMA (125 mg), and D-amphetamine (40 mg) versus placebo in a within-subject, double-blind, placebo-controlled crossover design. The investigators hypothesised that LSD would produce stronger and qualitatively different alterations of waking consciousness (measured by the 5D-ASC scale and MEQ) than MDMA and D-amphetamine, that MDMA would produce distinct emotional effects and increase plasma oxytocin more than the other drugs, and that none of the drugs would necessarily alter plasma brain-derived neurotrophic factor (BDNF) at the tested doses. The authors framed the head-to-head approach as also improving blinding compared with prior studies that used inactive placebo comparators.

This was a double-blind, placebo-controlled, four-period crossover study with at least a 10-day washout between sessions. Twenty-eight healthy volunteers (14 men, 14 women; mean age 28 ± 4 years, range 25–45; mean body weight 71.5 ± 12.0 kg) were recruited. One participant withdrew before their final LSD session; all other sessions were completed by all participants. Key exclusion criteria included age <25 or >50 years, pregnancy, personal or first-degree family history of major psychiatric disorders, use of medications that might interact with the study drugs, significant physical illness, heavy tobacco smoking (>10 cigarettes/day), and extensive lifetime illicit drug use (>10 lifetime uses, except cannabis was handled separately). Urine drug screening was performed at screening and before each session. Each participant attended four 12-hour experimental sessions conducted in a quiet hospital room. LSD (100 µg base) and D-amphetamine sulfate (40 mg salt, equivalent to 30 mg base) were administered orally at 09:00; MDMA hydrochloride (125 mg) was administered at 09:30 to align peak effects with scheduled assessments and an fMRI scan at 11:00–12:00 (fMRI results were not included in this report). Blinding used a double-dummy procedure with identical capsules and vials. At the end of each session and at study end, participants guessed which treatment they had received. Subjective effects were assessed repeatedly using visual analogue scales (VAS) at baseline and multiple post-dose time points up to 11 h (scales included any drug effect, good/bad drug effect, drug liking, drug high, stimulated, ego dissolution, talkative, open, concentration, sense of time, and speed of thinking). Additional instruments included the Adjective Mood Rating Scale (AMRS) at selected time points, the 5 Dimensions of Altered States of Consciousness scale (5D-ASC) and the Mystical Experience Questionnaire (MEQ43 and MEQ30) administered 11 h after dosing, and the Addiction Research Center Inventory (ARCI) also administered at 11 h. Duration of subjective effects was estimated from VAS "any drug effect" time–effect plots using a 10% on/off threshold. Autonomic measures (blood pressure, heart rate, tympanic body temperature) and pupil function (under standardised dark–light conditions) were recorded repeatedly up to 11 h. Adverse effects were assessed with the 66-item List of Complaints before dosing and at 11 h. Plasma oxytocin was sampled at baseline and 1.5, 2.5, 3, and 5 h after MDMA administration (and corresponding times for other drugs), using ELISA; plasma BDNF was measured at baseline and 3 and 5 h post-dose using ELISA. Plasma concentrations of LSD, its metabolite O-H-LSD, MDMA and its metabolites (MDA, HMMA), and D-amphetamine were measured at multiple time points and analysed by liquid chromatography–tandem mass spectrometry; pharmacokinetic parameters were derived by noncompartmental analysis. For repeated measures, peak effects (Emax/Emin or peak change from baseline) were extracted and analysed using repeated-measures analysis of variance with drug as the within-subject factor; significant main effects were followed by Tukey post hoc comparisons. The criterion for statistical significance was p < 0.05.

Sample and completion: Twenty-eight participants completed MDMA, D-amphetamine, and placebo sessions; one participant withdrew before their final LSD session, so LSD data reflect 27 participants for that session. Retrospective treatment identification showed high recognisability: placebo was correctly identified by all participants, LSD by 96%, and MDMA and D-amphetamine by 75% each on the day of administration. Subjective effects (VAS and mood scales): LSD produced larger overall subjective responses than MDMA and D-amphetamine. Compared with both MDMA and D-amphetamine, LSD yielded significantly higher peak ratings of "any drug effect," "good drug effect," "bad drug effect," and "ego dissolution." LSD also produced greater "drug liking," "drug high," and "stimulation" than D-amphetamine, while these scales did not differ significantly between LSD and MDMA. MDMA produced greater peak ratings than D-amphetamine on "any drug effect," "good drug effect," "drug liking," "high," and "ego dissolution." D-Amphetamine and MDMA increased ratings of "concentration" relative to placebo and to LSD, whereas LSD produced greater reductions over time and larger maximal decreases in talkativeness, concentration, sense of time, and speed of thinking compared with the other drugs. Mean durations (± SD) of the overall subjective effect (VAS "any drug effect") were 8.5 ± 2.0 h for LSD, 4.4 ± 1.7 h for MDMA, and 6.2 ± 2.0 h for D-amphetamine. Alterations of consciousness and mystical-type experiences: LSD markedly increased ratings on all subscales of the 5D-ASC and on all MEQ43/MEQ30 scales compared with placebo, MDMA, and D-amphetamine (Tukey post hoc p < 0.001 for these comparisons). MDMA produced a significant but much smaller increase on the 5D-ASC "blissful state" subscale and increased positive mood and ineffability on the MEQ compared with placebo. D-Amphetamine had minimal effects on 5D-ASC subscales and only modestly increased positive mood on the MEQ relative to placebo. Mood and personality-related effects: On the AMRS, LSD increased introversion, inactivity, emotional excitation, and anxiety compared with MDMA and D-amphetamine; conversely, MDMA and D-amphetamine increased extraversion, and D-amphetamine increased activity and concentration compared with LSD. On the ARCI, LSD elevated subscales indicating mixed hallucinogenic, sedative, and euphoriant effects, whereas D-amphetamine uniquely increased the benzedrine (stimulant) group scale. Autonomic and adverse effects: All active drugs increased systolic and diastolic blood pressure, heart rate, tympanic temperature, and pupil size relative to placebo, yielding similar overall sympathomimetic stimulation as reflected in comparable increases in the rate–pressure product. Systolic hypertension (>140 mmHg) occurred in 23 participants after D-amphetamine, 18 after MDMA, 14 after LSD, and 3 after placebo. Episodes of tachycardia (>100 beats/min) occurred in 5, 5, and 7 participants after D-amphetamine, MDMA, and LSD, respectively, and in 0 after placebo. D-Amphetamine produced significantly larger blood pressure increases than LSD and MDMA; LSD and MDMA produced greater early heart-rate increases than D-amphetamine during the first 4 h. All drugs increased pupil size, but MDMA uniquely and markedly impaired light-induced pupil constriction compared with placebo. Only LSD increased the total acute adverse-effects score on the List of Complaints compared with placebo. No severe adverse events were reported. Endocrine and neurotrophic markers: MDMA increased plasma oxytocin concentrations; LSD and D-amphetamine did not. None of the three active substances changed plasma BDNF concentrations at the sampled time points. Pharmacokinetics: Reported geometric mean maximum concentrations (Cmax) and times to maximum (Tmax) were: LSD Cmax 1.8 ng/ml (range 0.99–2.9), Tmax 1.6 h (1–3.5); O-H-LSD Cmax 0.12 ng/ml (0.07–0.2), Tmax 5.2 h (3.1–7.5). MDMA Cmax 236 ng/ml (158–357), Tmax 3.0 h (1.1–5.0); MDA Cmax 10.9 ng/ml, Tmax 7.0 h (3.0–11); HMMA Cmax 160 ng/ml (43–287), Tmax 2.8 h (1.3–6.0). D-Amphetamine Cmax 100 ng/ml (68–133), Tmax 2.6 h (1.0–5.5). Concentration–time data were analysed using noncompartmental methods.

Holze and colleagues interpret the findings as demonstrating clearly distinct acute-effect profiles for LSD, MDMA, and D-amphetamine when compared within the same participants. LSD produced the most pronounced alterations of waking consciousness, scoring substantially higher than MDMA and D-amphetamine on the 5D-ASC and MEQ, and also induced larger overall subjective effects including both positive and negative responses (for example higher ratings of anxiety and "bad drug effect"). By contrast, MDMA elicited moderate positive emotional effects (increased positive mood and ineffability on the MEQ, and increases in feelings of well-being and some VAS measures) with lower rates of adverse psychological effects compared with LSD, and it uniquely increased plasma oxytocin. D-Amphetamine produced more stimulant-typical effects, increasing activity and concentration relative to LSD and exerting the largest increases in blood pressure among the drugs tested. The authors position these results relative to prior work by noting that although MDMA and D-amphetamine share some sympathomimetic and prosocial features, MDMA produced at least some distinct empathogenic effects and oxytocin release that differentiated it from D-amphetamine. They also emphasise that the within-subject, double-blind comparison across multiple active drugs and placebo addressed limitations of earlier studies that compared each active drug only to inactive placebo, which can lead to unblinding and less informative contrasts. Key limitations acknowledged by the study team include the use of only a single dose level for each substance, precluding dose–response comparisons; the selection of an intermediate LSD dose (0.1 mg) and relatively high MDMA (125 mg) and D-amphetamine (40 mg) doses, which means that dose equivalence can only be inferred from similar autonomic stimulation rather than matched subjective potency; and the need for future studies with multiple dose levels and additional outcomes such as imaging (fMRI data were collected but reported elsewhere). The investigators also note that slightly higher measured LSD plasma concentrations in this study compared with earlier reports likely reflect analytical confirmation of a marginally higher actual dose in the administered formulation. In terms of implications, the authors suggest that the pronounced acute subjective effects of LSD, as measured here, may be relevant for dose selection and expectations in substance-assisted psychotherapy research, given prior evidence that acute psychedelic experiences predict longer-term outcomes. They further suggest that MDMA's comparatively smaller psychological adverse effects combined with empathogenic qualities and oxytocin release might make it preferable for some patients, for example those who are apprehensive about strong psychedelic effects, and that MDMA has been used in early therapy sessions in clinical practice in Switzerland. The authors call for further studies to map dose–response relationships and to extend these within-subject comparisons to clinical populations.