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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, double-blind, 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.

SUBMITTER: Holze F

PROVIDER: S-EPMC6969135 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Holze Friederike F Vizeli Patrick P Müller Felix F Ley Laura L Duerig Raoul R Varghese Nimmy N Eckert Anne A Borgwardt Stefan S Liechti Matthias E ME

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20191116 3

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 psyc ...[more]

PMID: 31733631

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Project description:RationaleLysergic acid diethylamide (LSD) is used in psychiatric and psychological research and investigated as a potential treatment for medical and psychiatric disorders, including depression, anxiety, and cluster headache.ObjectivesSafety data on clinical safety are available from small studies but not from larger samples. We report safety pharmacology data from a large pooled study sample on acute effects of LSD in healthy subjects.MethodsWe conducted a pooled analysis of four double-blind, randomized, placebo-controlled, crossover studies that included a total of 83 healthy subjects and 131 single-dose administrations of LSD. LSD administrations were matched to dose groups according to measured LSD peak plasma concentrations to adjust for uncertainties in the correct LSD dose in some studies. Single doses were 25, 50, 100, and 200 µg of LSD base. We investigated subjective effects (self-rated any drug effect, good drug effect, bad drug effect, and anxiety), blood pressure, heart rate, body temperature, duration of the acute LSD response, acute (12 h) and subacute (24 h) adverse effects, reports of flashbacks, and liver and kidney function before and after the studies.ResultsLSD dose-dependently increased subjective, physiologic, and adverse effects. The dose-response curves for the proportions of subjects with a certain amount of a subjective effect were steeper and reached a higher maximum for positive acute subjective effects compared with negative acute subjective effects. Maximal ratings of > 50% good drug effects were reached in 37%, 91%, 96%, and 91% of the LSD administrations at 25, 50, 100, and 200 µg. Maximal ratings of > 50% bad drug effects were reached in 0%, 9%, 27%, 31% at 25, 50, 100, and 200 µg, respectively. Mean ratings of Oceanic Boundlessness were 10%, 25%, 41%, and 44%, and mean ratings of Anxious Ego-Dissolution were 3.4%, 13%, 20%, and 22% at 25, 50, 100, and 200 µg, respectively. The physiologic effects of LSD were moderate. None of the subjects had systolic blood pressure > 180 mmHg at any time. Peak heart rate > 100 beats/min was observed in 0%, 6%, 20%, and 25% of the subjects at 25, 50, 100, and 200 µg, respectively. Maximal heart rates of 129 and 121 beats/min were observed in one subject at the 50 and 200 µg doses, respectively. Peak body temperature > 38° was observed in 0%, 11%, 7%, and 34% at 25, 50, 100, and 200 µg, respectively. Mean acute adverse effect scores on the List of Complaints were 5.6, 9.2, 12, and 13 at 25, 50, 100, and 200 µg, respectively. Kidney and liver function parameters were unaltered. Six subjects reported transient flashback phenomena.ConclusionsThe single-dose administration of LSD is safe in regard to acute psychological and physical harm in healthy subjects in a controlled research setting.

Project description:Psychostimulants such as methylphenidate and modafinil are increasingly used by healthy people for cognitive enhancement purposes, whereas the acute effect of 3,4-methylenedioxymethamphetamine (ecstasy) on cognitive functioning in healthy subjects remains unclear. This study directly compared the acute effects of methylphenidate, modafinil, and 3,4-methylenedioxymethamphetamine on the neural mechanisms underlying response inhibition in healthy subjects.Using a double-blind, within-subject, placebo-controlled, cross-over design, methylphenidate, modafinil, and 3,4-methylenedioxymethamphetamine were administrated to 21 healthy subjects while performing a go/no-go event-related functional magnetic resonance imaging task to assess brain activation during motor response inhibition.Relative to placebo, methylphenidate and modafinil but not 3,4-methylenedioxymethamphetamine improved inhibitory performance. Methylphenidate significantly increased activation in the right middle frontal gyrus, middle/superior temporal gyrus, inferior parietal lobule, presupplementary motor area, and anterior cingulate cortex compared with placebo. Methylphenidate also induced significantly higher activation in the anterior cingulate cortex and presupplementary motor area and relative to modafinil. Relative to placebo, modafinil significantly increased activation in the right middle frontal gyrus and superior/inferior parietal lobule, while 3,4-methylenedioxymethamphetamine significantly increased activation in the right middle/inferior frontal gyrus and superior parietal lobule.Direct comparison of methylphenidate, modafinil, and 3,4-methylenedioxymethamphetamine revealed broad recruitment of fronto-parietal regions but specific effects of methylphenidate on middle/superior temporal gyrus, anterior cingulate cortex, and presupplementary motor area activation, suggesting dissociable modulations of response inhibition networks and potentially the superiority of methylphenidate in the enhancement of cognitive performance in healthy subjects.

Project description:RationaleLysergic acid diethylamide (LSD) and other serotonergic hallucinogens can induce profound alterations of consciousness and mystical-type experiences, with reportedly long-lasting effects on subjective well-being and personality.MethodsWe investigated the lasting effects of a single dose of LSD (200 μg) that was administered in a laboratory setting in 16 healthy participants. The following outcome measures were assessed before and 1 and 12 months after LSD administration: Persisting Effects Questionnaire (PEQ), Mysticism Scale (MS), Death Transcendence Scale (DTS), NEO-Five Factor Inventory (NEO-FFI), and State-Trait Anxiety Inventory (STAI).ResultsOn the PEQ, positive attitudes about life and/or self, positive mood changes, altruistic/positive social effects, positive behavioral changes, and well-being/life satisfaction significantly increased at 1 and 12 months and were subjectively attributed by the subjects to the LSD experience. Five-Dimensions of Altered States of Consciousness (5D-ASC) total scores, reflecting acutely induced alterations in consciousness, and Mystical Experience Questionnaire (MEQ30) total scores correlated with changes in well-being/life satisfaction 12 months after LSD administration. No changes in negative attitudes, negative mood, antisocial/negative social effects, or negative behavior were attributed to the LSD experience. After 12 months, 10 of 14 participants rated their LSD experience as among the top 10 most meaningful experiences in their lives. Five participants rated the LSD experience among the five most spiritually meaningful experiences in their lives. On the MS and DTS, ratings of mystical experiences significantly increased 1 and 12 months after LSD administration compared with the pre-LSD screening. No relevant changes in personality measures were found.ConclusionsIn healthy research subjects, the administration of a single dose of LSD (200 μg) in a safe setting was subjectively considered a personally meaningful experience that had long-lasting subjective positive effects.Trial registrationRegistration identification number: NCT01878942.

Project description:Rationale: Lisdexamfetamine is a prodrug of D-amphetamine used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Lisdexamfetamine is thought to have a prolonged pharmacokinetic profile compared with oral D-amphetamine, possibly associated with lower drug liking and a lower risk of oral misuse. However, differences in the pharmacokinetics and pharmacodynamics of lisdexamfetamine and D-amphetamine have not been directly compared. Methods: Equimolar doses of D-amphetamine (40 mg) and lisdexamfetamine (100 mg), and placebo were administered in 24 healthy subjects in a randomized, double-blind, placebo-controlled, cross-over study. Plasma concentrations of amphetamine, subjective effects, and vital signs were repeatedly assessed. The pharmacokinetic parameters were determined using compartmental modeling. Results: The increase in plasma concentrations of amphetamine had a 0.6 ± 0.6 h (mean ± SD) longer lag time and reached peak levels 1.1 ± 1.5 h later after lisdexamfetamine administration compared with D-amphetamine administration, but no differences in maximal concentrations or total exposure (AUC) were found between the two treatments. Consistent with the pharmacokinetics, the subjective and cardiovascular stimulant effects of lisdexamfetamine also occurred later compared with D-amphetamine. However, no differences in peak ratings of potentially abuse-related subjective drug effects (e.g., drug liking, drug high, stimulation, happy, well-being, and self-confidence) were observed after lisdexamfetamine administration compared with D-amphetamine administration. Lisdexamfetamine and D-amphetamine also produced similar peak increases in mean arterial blood pressure, heart rate, body temperature, pupil size, and adverse effects. Conclusion: The pharmacokinetics and pharmacodynamics of lisdexamfetamine are similar to D-amphetamine administered 1h later. Lisdexamfetamine is likely associated with a similar risk of oral abuse as D-amphetamine. The study was registered at ClinicalTrials.gov (NCT02668926).

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

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

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