1,3-DMAA

1,3-Dimethylamylamine (1,3-DMAA; 4-methylhexan-2-amine; methylhexanamine) is a synthetic aliphatic sympathomimetic amine first introduced by Eli Lilly and Company in 1944 under the trade name Forthane as an inhaled nasal decongestant and voluntarily withdrawn from the market in 1983. The compound re-entered commercial circulation in 2006 when it was marketed as an ergogenic dietary supplement ingredient under the name Geranamine, following the regulatory removal of ephedrine alkaloids from the United States supplement market in 2004. The pharmacology of 1,3-DMAA is that of an indirect sympathomimetic: the compound acts as a norepinephrine and dopamine releasing agent, inhibits the norepinephrine transporter (NET) at low micromolar concentrations, and exhibits substrate-like regulation of the dopamine transporter (DAT) including competitive inhibition of dopamine uptake, binding at the S1 substrate site, induction of outward-facing-open to outward-facing-closed conformational transitions, and stimulation of DAT endocytosis through cocaine- and protein kinase A-sensitive mechanisms. These monoaminergic actions produce dose-dependent cardiovascular stimulation (vasoconstriction, elevation of systolic and diastolic blood pressure, tachycardia), central nervous system arousal, and thermogenic effects consistent with the broader sympathomimetic amine class that includes ephedrine, amphetamine, and phenylpropanolamine.

The sole formal human pharmacokinetic study (Schilling et al., 2013; n = 7 healthy men; single oral dose of 25 mg) reported a peak plasma concentration of approximately 70 ng/mL, time to peak of 3.57 hours, terminal elimination half-life of 8.45 hours, oral clearance of 20.02 L/hr, and volume of distribution of 236 L, indicating extensive tissue partitioning. Physiological monitoring in that study documented modest increases in heart rate and diastolic blood pressure that remained within normal clinical ranges at the 25 mg dose. However, case reports and postmarketing surveillance have associated substantially higher doses of 1,3-DMAA (often in combination with caffeine and other stimulants in multi-ingredient pre-workout and weight-loss supplements) with serious cardiovascular events including cerebral hemorrhage, myocardial infarction, cardiac arrest, hepatotoxicity, and death. The United States Food and Drug Administration has received at least 86 reports of illness and death associated with DMAA-containing supplements and has determined that 1,3-DMAA is not a dietary ingredient; its inclusion in products marketed as dietary supplements is unlawful under United States federal law. Preclinical abuse liability assessment (Dolan and Gatch, 2015) demonstrated that 1,3-DMAA fully substituted for cocaine and partially substituted for methamphetamine in drug discrimination assays, produced conditioned place preference in mice at intermediate doses, and generated dose-dependent locomotor depression, indicating psychostimulant-like abuse potential.

The compound is banned or restricted in the United States, Canada, Australia, New Zealand, the United Kingdom, Brazil, Sweden, Finland, and Switzerland, and is listed as a prohibited substance by the World Anti-Doping Agency. It is not approved as a medicine in any jurisdiction as of the date of this monograph. This monograph reviews the chemistry, synthesis, and structural classification of 1,3-DMAA; the historical development and regulatory trajectory; the molecular pharmacology at monoamine transporters and adrenergic receptors; the limited human pharmacokinetic record; preclinical pharmacology including abuse liability; the clinical and adverse-event evidence base; sourcing and analytical verification considerations; reconstitution and handling; stack interaction and combination risks; the comprehensive adverse-event and safety signal; and a comparative assessment of five sympathomimetic amine stimulants against 1,3-DMAA on five competency standards (novelty, effect size, promising potential, side-effect profile, and overall validation).