Effects of the psychedelic amphetamine MDA (3, 4-methylenedioxyamphetamine) in healthy volunteers

This double-blind, placebo-controlled study (n=12) investigated the effects of the MDMA-related compound, MDA. It found the duration to be longer (8 vs 6 hours) and with various characteristics more similar to classical psychedelics.

Abstract

“Entactogens such as 3,4-Methylenedioxymethamphetamine (MDMA, “molly”, “ecstasy”) appear to have unusual, potentially therapeutic, emotional effects. Understanding their mechanisms can benefit from clinical experiments with related drugs. Yet the first known drug with such properties, 3,4-Methylenedioxyamphetamine (MDA), remains poorly studied and its pharmacokinetics in humans are unknown. We conducted a within-subjects, double-blind, placebo-controlled study of 1.4 mg/kg oral racemic MDA and compared results to those from our prior similar studies with 1.5 mg/kg oral racemic MDMA. MDA was well-tolerated by participants. MDA induced robust increases in heart rate and blood pressure and increased cortisol and prolactin to a similar degree as MDMA. MDA self-report effects shared features with MDMA as well as with classical psychedelics. MDA self-report effects lasted longer than those of MDMA, with MDA effects remaining elevated at 8 h while MDMA effects resolved by 6 h. Cmax and AUC0-∞ for MDA were 229 ± 39 (mean ± SD) and 3636 ± 958 µg/L for MDA and 92 ± 61 and 1544 ± 741 µg/L for the metabolite 4-hydroxy-3-methoxyamphetamine (HMA). There was considerable between-subject variation in MDA/HMA ratios. The similarity of MDA and MDMA pharmacokinetics suggests that the greater duration of MDA effects is due to pharmacodynamics rather than pharmacokinetics.”

Authors: Matthew J. Baggott, Kathleen J. Garrison, Jeremy R. Coyle, Gantt P. Galloway, Allan J. Barnes, Marilyn A. Huestis & John E. Mendelson

Notes

“Thus, it may be useful to think about these and related drugs as having potential effects within three main dimensions: entactogen, stimulant, and classical psychedelic. The current results point to MDMA having strong entactogen effects, modest stimulant effects, and weak psychedelic effects, and MDA having significant effects in all three dimensions.”

The current study provides a sort of bridge or framework through which to see how MDMA compares to classical psychedelics.

The MDMA comparison data comes from an earlier paper by Baggot and colleagues (2016).

Summary

Entactogens such as 3,4-Methylenedioxymethamphetamine (MDMA) appear to have unusual, potentially therapeutic, emotional effects. A study of 3,4-Methylenedioxyamphetamine (MDA) found that it was well-tolerated and that it induced robust increases in heart rate and blood pressure and increased cortisol and prolactin to a similar degree as MDMA.

Introduction

MDA (3,4-methylenedioxyamphetamine) is an illicit drug with a long history of experimental medical and nonmedical use. It was scheduled as a controlled substance in the United States in 1970.

MDA is sometimes described as an amphetamine or hallucinogen, but it also shares the unusual social-emotional effects of MDMA, such as feeling emotionally close to others. It also has complex pharmacological mechanisms that overlap with classical psychedelics, such as LSD, and psychostimulants.

We conducted a placebo-controlled study administering MDA to healthy volunteers in a laboratory setting to determine the pharmacokinetics of MDA in humans. The results suggest that MDA may have similar kinetics to MDMA.

Material and methods

This double-blind, placebo-controlled, within-subjects crossover study was conducted at the UCSF Clinical Research Center at San Francisco General Hospital with participants admitted for a single three-evening stay.

Source of MDMA comparison data

For drug comparisons, we used data from two placebo-controlled studies of 1.5 mg/kg oral racemic MDMA in healthy volunteers.

Participants

Participants were 12 healthy individuals with self-report experience with MDMA, or with MDMA and a classical serotonin psychedelic, such as LSD. They were asked to practice effective contraception during the study.

Drugs and dosing

Racemic MDA was synthesized by the researchers and administered after a two-hour fast to minimize individual variance in drug absorption.

Measures

Timed measurements included blood samples, physiological measures, self-report measures, and computerized tasks. The visual analog items were previously unreported.

Self-report drug effects

We used the 66-item Altered States of Consciousness visual analog scale to measure psychedelic-like self-report effects. The original three main scales and 11 lower-order factors were identified by Studerus, Gamma, and Vollenweider (2010).

We used visual analog scales to measure three main areas: general drug effects, stimulant or entactogen (MDMA-like) effects, and psychedelic-like (LSD-like) effects. Questions about time distortions and closed-eye imagery were asked immediately after the participants closed their eyes for a computer-timed 30-sec.

We administered the Affect Valuation Index (AVI) and Interpersonal Adjectives Scale-Revised (IASR) before and 2.5 h after drug administration to measure self-report affect and social feelings.

Physiological, endocrine, and pharmacokinetic effects

We measured heart rate and blood pressure before and after drug administration, and then collected blood samples to measure prolactin and cortisol. We measured concentrations of MDA and its major metabolite 4-hydroxy-3-methoxyamphetamine using two-dimensional GC/MS.

Statistical analysis

We analyzed data using mixed-effects models in R with drug condition as a fixed effect and participant as a random effect. Pharmacokinetic parameters were estimated in NONMEM using a noncompartmental model using linear trapezoidal calculations and linear weighing of lambdas.

Participants

Twelve participants were enrolled, two were Hispanic or Latino, 10 were not Hispanic or Latino, and the absolute MDA doses administered were 83 to 128 mg.

Checking for sequence effects

We used a compact study design in which MDA and placebo occurred on consecutive days. We checked for differences between the placebo-MDA sequence, MDA-placebo sequence, and MDMA placebo sessions, but found no significant effects of sequence.

Affect and social functioning (AVI and IASR)

MDA and MDMA showed partly overlapping profiles, but MDA had longer duration of effects. MDA produced significant elevations in all five general drug effects items at 6 h and in all except bad drug effect at 8 h.

Physiological changes

MDA and MDMA both increased heart rate and blood pressure, but MDA increased heart rate less than MDMA did, and MDMA increased blood pressure more than MDA did.

Endocrine changes

Both MDA and MDMA increased serum prolactin and cortisol, with MDMA producing higher peak prolactin than MDA.

Pharmacokinetics

MDA and HMA had a similar elimination half-life and a similar clearance/F, but there was noticeable between-subject variation in HMA formation.

Discussion

We conducted the first controlled study of MDA in humans in over 35 years, and found that it produced a mixture of MDMA-like and psychedelic-like self-report effects, as well as a sympathomimetic syndrome of increased heart rate and blood pressure.

MDA induced robust acute increases in heart rate and blood pressure in healthy participants, and was well-tolerated, although these effects could be of concern in individuals with cardiovascular disease.

Our results provide insights into the pharmacological relationships between MDMA-like drugs, stimulants, and classical psychedelics. MDMA has strong entactogen effects, modest stimulant effects, and weak psychedelic effects, while MDA has significant effects in all three dimensions.

This is consistent with hypothesized mechanisms of entactogens, stimulants, and classical psychedelics, including noradrenergic effects, balance of dopaminergic and serotonergic effects, and ability to stimulate 5-HT2A receptors.

MDA’s kinetics were similar to MDMA’s, with the exception of a possibly longer half-life for MDA at this dose level. The difference in duration of effects between these drugs may be due to the difference in half-life.

HMA is a minor metabolite of MDMA and its elimination half-life was previously estimated after administration of MDMA. However, our study found that the elimination half-life is lower and has less variance than these past estimates.

This report has several limitations, including administering MDA and placebo on consecutive days, comparing MDA data with MDMA data from separate studies, and administering racemic MDA and MDMA because these are the forms that are used nonmedically.

The present study was the first modern human experiment with MDA and the first characterization of MDA pharmacokinetics. It confirms earlier reports that MDA has significant MDMA-like effects as well as LSD-like effects.

Study details

Compounds studied
MDMA

Topics studied
Safety Healthy Subjects

Study characteristics
Placebo-Controlled Double-Blind Within-Subject

Participants
12 Humans

Authors

Authors associated with this publication with profiles on Blossom

Matthew Baggott
Matthew Baggott is a PhD neuroscientist and data scientists that has published various papers about psychedelics and is the CEO of Tactogen.