Psychostimulants such as d-amphetamine and methamphetamine primarily activate dopamine and norepinephrine systems, with only minimal effects on 5-HT, and promote stimulation, wakefulness, and concentration without the MDMA-typical emotional effects. The unique emotional effects of MDMA lead to its classification as an empathogen or entactogen, referring to assumingly distinct effects from psychostimulants. Additionally, MDMA releases oxytocin, which may contribute to the mediation of its prosocial effects. MDMA acutely induces feelings of well-being, love, empathy, and prosociality, and produces mild perceptual alterations that are thought to be primarily mediated by the release of serotonin (5-HT) and norepinephrine, and the direct activation of 5-HT 2A receptors. MDMA not only exhibits some amphetamine-like properties but also shows hallucinogenic-like effects and can be considered an intermediate substance between a pure stimulant like d-amphetamine and a pure hallucinogenic drug like LSD. 3,4-Methylenedioxymethamphetamine (MDMA) is the active compound in the recreational substance ecstasy and is currently investigated as an adjunct to psychotherapy to treat post-traumatic stress disorder (PTSD). For example, greater psilocybin-induced mystical-type experiences and more pronounced and more positive acute alterations of consciousness were associated with lasting antidepressant responses in patients with depression. Recent clinical trials indicate that the quality of the acute psychedelic experience in response to psilocybin or LSD predicts long-term changes in mental health and well-being in patients and healthy persons. LSD acutely induces marked alterations of waking consciousness that have been shown to primarily depend on an interaction with the serotonin 5-hydroxytryptamine-2A (5-HT 2A) receptor, although LSD also acts on 5-HT 1 and dopamine receptors. Lysergic acid diethylamide (LSD) is a classic serotonergic hallucinogen that has been widely used recreationally and to a limited extent in psychiatric research. These results indicate clearly distinct acute effects of LSD, MDMA, and d-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. MDMA but not LSD or d-amphetamine increased plasma concentrations of oxytocin. d-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with 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. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and d-amphetamine.
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 and MDMA increased heart rate more than d-amphetamine, and d-amphetamine increased blood pressure more than LSD and MDMA. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. 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, double-blind, cross-over study in 28 healthy subjects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. All three substances induce distinct acute subjective effects. 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 are used recreationally. Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and d-amphetamine is a classic stimulant.
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