As hypothesized, LSD produced stronger and more distinct subjective effects compared with MDMA and d-amphetamine. Specifically, only LSD induced significant and marked alterations of consciousness on all 5D-ASC and MEQ subscales compared with placebo, and responses were also significantly greater compared with MDMA and d-amphetamine. In contrast, MDMA only moderately increased “blissful state” on the 5D-ASC scale and “positive mood” and “ineffability” on the MEQ. d-Amphetamine only weakly increased “positive mood” on the MEQ compared with placebo. Additionally, LSD produced greater overall subjective effects, including both “good drug effects” and “bad drug effects,” on the VAS compared with both MDMA and d-amphetamine. Only LSD produced significant “bad drug effects” on the VAS, “anxiety” on the 5D-ASC scale, and “LSD group” effects and “pentobarbital-chlorpromazine-alcohol group” effects on the ARCI compared with placebo. Finally, LSD was correctly identified by 96% and 100% of the participants on the day of administration and at the end of the study, respectively. However, similarities were also observed in the effects of all compounds on scales that measured positive drug effects. All of the drugs produced comparable ratings of “open” and “talkative” on the VAS, and ratings of “drug high,” “drug liking,” and “stimulated” on the VAS did not differ between LSD and MDMA. The present findings are overall consistent with previous reports on the effects of LSD [3, 4, 38, 50, 65], MDMA [18, 25, 28], and d-amphetamine [32]. In contrast to these previous studies, however, the present study compared the subjective responses to LSD, MDMA, and d-amphetamine using a within-subjects design. Subjective effects of various substances can differ, depending on the comparator that is used. For example, marked effects of MDMA on the 5D-ASC scale compared with inactive placebo have been previously reported [18]. However, when MDMA was compared with LSD in the present study, it induced only minimal and comparatively weak alterations of consciousness.

The present findings have clinical implications. First, acute effects of the LSD-like hallucinogen psilocybin on both the 5D-ASC scale and MEQ also used in the present study have been shown to predict long-term therapeutic outcomes in patients with anxiety and depression in previous studies [6,7,8]. Similarly, 5D-ASC scale and MEQ ratings correlated with changes in well-being and life satisfaction 1 year after LSD administration in healthy subjects in a previous study [10]. Thus, stronger acute responses to LSD on the 5D-ASC scale and MEQ, as documented in the present study in healthy participants and previously in patients [37], may also predict better therapeutic outcomes in studies that evaluate the benefits of LSD-assisted psychotherapy in patients with anxiety and depression [66, 67]. However, this assumption needs to be verified in patients. Second, the present study found that MDMA produced some qualitatively similar (although less pronounced) positive effects compared with LSD, but with lower associated “bad drug effects” and anxiety. Thus, MDMA may produce less untoward effects than LSD, and this may favor its use in patients afraid to take LSD or at risk of adverse reaction (i.e., high neuroticism, high emotional lability, and young age [47]). In fact, MDMA is often used prior to LSD in substance-assisted psychotherapy in Switzerland so that patients can familiarize themselves with substance-induced states [66, 68, 69]. For example, MDMA could be used prior to LSD or psilocybin in substance-assisted psychotherapy so that patients can familiarize themselves with substance-induced states. In fact, MDMA has often been used in the first 1–3 sessions before the use of LSD in substance-assisted psychotherapy in Switzerland.

In the present study, we also directly compared the acute effects of MDMA and d-amphetamine and we hypothesized that MDMA would produce distinct subjective emotional effects compared with d-amphetamine. Previous studies have discussed the extent to which the effects of these amphetamines differ [25, 27, 28, 70]. The present study supports the view that the empathogen MDMA produces at least some clearly distinct effects compared with a pure stimulant, such as d-amphetamine. In the present study, MDMA produced greater ratings of “any drug effect,” “good drug effect,” “drug high,” and “drug liking” on the VAS, greater ratings of “positive mood” on the MEQ, and smaller “benzedrine group” effects on the ARCI than d-amphetamine. MDMA also induced greater impairments in “concentration” and “speed of thinking” compared with d-amphetamine.

In contrast and as predicted, MDMA but not d-amphetamine increased plasma oxytocin concentrations, which is thought to be attributable to the MDMA-induced release of 5-HT and 5-HT 1A receptor stimulation [23]. Interestingly, the potent 5-HT 1A and 5-HT 2A receptor agonist LSD [5] did not significantly increase plasma oxytocin levels in the present study, in contrast to a higher dose of LSD and inactive placebo as the comparator in a previous study [3]. Supporting the view of distinct effects of MDMA and d-amphetamine, 75% and 89% of the participants in the present study correctly identified MDMA and d-amphetamine on the day of administration and at the end of the study, respectively. However, MDMA and d-amphetamine also produced overlapping effects, including comparable increases in “open” and “talkative” on the VAS, “well-being” and “extraversion” on the AMRS, and a lack of significant “bad drug effects” or “anxiety” compared with placebo and in contrast to LSD. Similar partly overlapping effects of MDMA and lower doses of d-amphetamine (10–20 mg) have been previously reported [33, 71]. Interestingly, both MDMA and d-amphetamine seemed to produce relatively comparable “empathogenic” effects in the present study, whereas such effects were somewhat more unique to MDMA compared with the stimulant methylphenidate [27, 28]. Thus, MDMA and d-amphetamine are more alike than MDMA and methylphenidate, but this remains to be clarified in future studies. Pharmacologically, d-amphetamine and methylphenidate both activate the dopamine and norepinephrine systems without having relevant effects on 5-HT. However, d-amphetamine also releases monoamines similarly to MDMA, in contrast to the pure uptake inhibitor methylphenidate [29, 72].

In the present study, LSD, MDMA, and d-amphetamine produced comparable sympathomimetic activation, reflected by similar increases in the rate–pressure product, body temperature, and pupil size. Additionally, LSD, MDMA, and d-amphetamine produced comparable amounts of total adverse effects as evidenced by similar scores on the List of Complaints (Table 1), although there were some differences between the substances regarding the specific complaints (Table S2). These findings indicate that the doses of the drugs were similar with regard to sympathomimetic effects, including cardiovascular system stimulation and somatic complaints. The finding that LSD produced relatively pronounced sympathomimetic effects confirmed our previous studies [3, 38] and contradicted the assumption that LSD does not increase blood pressure [67]. On the other hand, the study findings suggest that LSD is capable of inducing greater acute psychological effects (positive and negative) than MDMA and d-amphetamine at doses that are producing comparable somatic adverse responses.

In the present study, we also determined plasma drug concentrations. Peak concentrations of MDMA and d-amphetamine were similar to previous studies that tested identical doses [32, 39, 73]. The full pharmacokinetic data for LSD derived from the present study have been published elsewhere [50]. Importantly, slightly higher plasma concentrations of LSD were documented in the present study compared with a previous study that reportedly used the same dose (0.1 mg) [49]. The higher plasma concentrations in the present study can be explained by the use of a higher dose (0.096 mg) of LSD base (analytically confirmed content and stability) compared with a lower estimated dose of 0.070 mg in previous studies [38, 49], as discussed previously [50].

The main strength and novelty of the present study was that we employed a double-blind, placebo-controlled, within-subjects design that included different active substances and validated pharmacodynamic and substance concentration measurements. The present study also has limitations. We only used one dose level of each substance. Full dose–response curves would need to be generated for each substance to achieve valid comparisons. However, we used a relatively low dose of LSD compared with the doses of MDMA and d-amphetamine and nevertheless found stronger effects of LSD compared with MDMA and d-amphetamine. Additionally, a previous study that used a higher dose of LSD (0.2 mg) showed significantly greater acute subjective effects of LSD compared with 0.1 mg LSD (the dose used in the present study), but autonomic stimulation was similar between doses [38]. Specifically, the higher dose produced both greater “good drug effect” and “bad drug effect” ratings on the VASs [38] and higher ratings of “blissful state,” “insightfulness,” and “changed meaning of percepts,” but no increase in “anxiety” on the 5D-ASC [37] compared with the lower dose of LSD. Thus, both desired and untoward drug effects were dose-dependent and future multiple dose-level studies will be needed to further define ideal dose ranges. Thus, higher doses of LSD up to 0.2 mg that are already clinically used [2, 67] can be expected to produce even greater subjective effects than the dose (0.1 mg) that was used in the present study. The dose of MDMA that was used in the present study is in the upper range of doses that are used clinically; higher doses would not likely produce stronger positive subjective effects, but would likely result in more adverse somatic responses [39]. Finally, we found that the doses of all of the active substances were equivalent with regard to autonomic stimulation. Nevertheless, there is a need for additional studies including multiple dose levels and additional outcomes such as imaging.

In conclusion, the present study found that LSD induced different and more pronounced alterations of waking consciousness compared with MDMA and d-amphetamine in the same subjects. MDMA also showed partly distinct effects compared with d-amphetamine. The acute-effect profiles of LSD and MDMA will be useful to assist the dose selection for substance-assisted psychotherapy research and to inform patients and researchers on what to expect in terms of positive and negative acute responses to these substances.