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

Abstract

Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and D-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and D-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), D-amphetamine (40 mg), and placebo in a randomized, doubleblind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than D-amphetamine, and D-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and D-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and D-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and D-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with D-amphetamine. D-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or D-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and D-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.

Comparative Untargeted Metabolomics Analysis of the Psychostimulants 3,4-Methylenedioxy-Methamphetamine (MDMA), Amphetamine, and the Novel Psychoactive Substance Mephedrone after Controlled Drug Administration to Humans

“…MDMA and amphetamine doses can be considered as "equivalent" with regard to cardiovascular effects. Both doses are in the rather high range of recreational drug use known to produce the typical psychostimulant effect, but are still considered as "safe" [5]. The chosen mephedrone dose also lies within the typical range used for recreational purposes and represented a safe dose for the participants.…”

“…The omega-6 fatty acid arachidonic acid mainly acts as an eicosanoid precursor with eicosanoids associated with inflammatory diseases [44]. For MDMA, effects on inflammation pathways were already discussed previously based on the detection of hydroxyl-eicosatetraenoic acid (5-HETE), dihydroxy-eicosatetraenoic acid (5, and oxo-octadecanedienoic acid (13-oxoODE) [24]. None of the aforementioned metabolites were detected during amphetamine or mephedrone data evaluation.…”

“…The plasma samples selected for the presented comparative, metabolic profiling study with the three psychostimulant drugs MDMA, amphetamine and mephedrone were obtained from former clinical studies initially designed for investigations of pharmacological effects [5,30] and pharmacokinetic parameters (mephedrone, unpublished data). All studies performed plasma sampling prior to drug administration (t0), and MDMA and amphetamine studies additionally included a placebo session (crossover design).…”

“…This was due to the lack of sensitivity of the Q-TOF instrument and the untargeted acquisition (data not shown). Amphetamine plasma concentrations in the initial clinical study following the 40 mg dose have been published elsewhere using targeted methods and reached a maximum plasma concentration (Cmax) of 68-133 (mean 100) ng/mL 2.6 (1.0-5.5) h after intake [5].…”

Subacute effects of the psychedelic ayahuasca on the salience and default mode networks

“…Impact of psychedelics on interoception, affect, and self-referential processes. Psychedelic substances modulate blood pressure, body temperature, and heart rate (Holze et al, 2019) by interacting with the sympathetic and parasympathetic autonomic nervous system, and have shown to impact emotional and affective functions by improving clinical symptoms in mood disorders (Carhart-Harris, Bolstridge, et al, 2016;Griffiths et al, 2016;Grob et al, 2011; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. not certified by peer review) (which was The copyright holder for this preprint this version posted February 21, 2020. .…”