4-Methyl-2-hexanamine hydrochloride (DMAA) is a drug made synthetically in a laboratory. It was originally used as a nasal decongestant. Today, 4-Methyl-2-hexanamine hydrochloride is sold as a dietary supplement used for attention deficit-hyperactive disorder (ADHD), weight loss, improving athletic performance, and body building.

The Alkylamine Stimulant 4-Methyl-2-hexanamine hydrochloride

The alkylamine stimulant 4-Methyl-2-hexanamine hydrochloride (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. There is scant research describing the mechanism of action of 4-Methyl-2-hexanamine hydrochloride, making it difficult to gauge risks or therapeutic potential. An important molecular target of structurally related phenethylamines, such as amphetamine, for regulating mood, cognition, movement, and the development of substance use disorder is the dopamine transporter, which limits the range and magnitude of dopamine signaling via reuptake from the extracellular space. The present studies were therefore initiated to characterize the effects of DMAA on dopamine transporter function. Specifically, we tested the hypothesis that DMAA exhibits substrate-like effects on dopamine transporter function and trafficking. In transport assays in human embryonic kidney cells, 4-Methyl-2-hexanamine hydrochloride inhibited dopamine uptake by the human dopamine transporter in a competitive manner.[1]

Docking analysis and molecular dynamics simulations supported these findings, revealing that 4-Methyl-2-hexanamine hydrochloride binds to the S1 substrate binding site and induces a conformational change from outward-facing open to outward-facing closed states, similar to the known substrates. Further supporting substrate-like effects of DMAA, the drug stimulated dopamine transporter endocytosis in a heterologous expression system via cocaine- and protein kinase A-sensitive mechanisms, mirroring findings with amphetamine. Together, these data indicate that 4-Methyl-2-hexanamine hydrochloride elicits neurologic effects by binding to and regulating function of the dopamine transporter. Furthermore, pharmacologic distinctions from amphetamine reveal structural determinants for regulating transporter conformation and add mechanistic insight for the regulation of dopamine transporter endocytosis. SIGNIFICANCE STATEMENT: The alkylamine stimulant DMAA is used as an appetite suppressant and athletic performance enhancer and is structurally similar to amphetamine, but there is scant research describing its mechanism of action. Characterizing the effects of 4-Methyl-2-hexanamine hydrochloride on dopamine transporter function supports evaluation of potential risks and therapeutic potential while also revealing mechanistic details of dynamic transporter-substrate interactions.

Physiological and pharmacokinetic effects of oral 4-Methyl-2-hexanamine hydrochloride

4-Methyl-2-hexanamine hydrochloride (DMAA) has been a component of dietary supplements and is also used within "party pills," often in conjunction with alcohol and other drugs. Ingestion of higher than recommended doses results in untoward effects including cerebral hemorrhage. To our knowledge, no studies have been conducted to determine both the pharmacokinetic profile and physiologic responses of 4-Methyl-2-hexanamine hydrochloride. To conclude on the safety profile of DMAA based solely on case reports would be problematic, in particular when accepting testimony from patients in uncontrolled environment, potentially under the influence of alcohol and other drugs. This is especially true in light of the fact that no prospective studies have shown these effects. Hence, the intent of the present study was to determine the pharmacokinetic profile of a single 25 mg oral dosage of 4-Methyl-2-hexanamine hydrochloride alone through 24 hours post-ingestion. The results of this study, along with current available information, may provide a more comprehensive view of the effects of oral administration of this ingredient in humans.[2]

The most important finding in this investigation is the relatively low plasma concentrations of 4-Methyl-2-hexanamine hydrochloride corresponding to the 25 mg oral dose, and the lack of meaningful physiologic effects associated with the single dose. Since data from a standardized and verified dose of DMAA was not previously available, our findings shed light on the possible reason for the adverse outcomes noted in prior case reports citing DMAA use (i.e., highly abusive dosages of this ingredient). Our data show a consistent pattern of increase across subjects with regards to peak plasma DMAA concentration, with peak values approximately 15–30 times lower than those reported in the case studies—strongly questioning the accuracy of reporting by patients in the case reports. It is hypothesized that patients in the case reports may have ingested dosages of 4-Methyl-2-hexanamine hydrochloride that were approximately 15–30 times higher than what our subjects ingested (i.e., 375 mg-750 mg). In fact, based on the time course of our peak response data (~5 hours post-ingestion), coupled with the times provided by Gee et al. for blood sample collection from their patients (i.e., before or after our noted peak concentration time), it is possible that our “15-30 times higher” estimation is quite low. The conclusions from our data are based on the assumption of linearity of 4-Methyl-2-hexanamine hydrochloride PK, and that no previous DMAA was ingested by the participants. Also, no assumption of linearity can be made from our data since only one dose was used.

Scientists report for the first time the pharmacokinetic profile of oral DMAA. Based on our data, it appears that the concern over adverse health-related effects of 4-Methyl-2-hexanamine hydrochloride is specific to the dosage ingested by the individual. When ingested at recommended doses (e.g., 25 mg), our data indicate minimal to no change in heart rate, blood pressure, or body temperature, and no adverse effects were noted. We also note a consistent pattern of increase across subjects concerning peak DMAA concentration, with mean peak values being <77 ng?mL-1. This is approximately 15–30 times lower than plasma values reported by other investigators citing adverse outcomes following 4-Methyl-2-hexanamine hydrochloride use. However, due to the case-study format of some of these adverse events, one cannot ignore possible drug interaction, errors in bioanalytical methods, differing bioavailability, or variability in exposure that might make this comparison difficult. Interpretation of our data would lead one to hypothesize that the adverse outcomes associated with 4-Methyl-2-hexanamine hydrochloride use are simply due to the blatant abuse of this ingredient. Future research on DMAA may consider pharmacokinetic characterization of each individual diastereoisomer.

Analysis and Confirmation of 4-Methyl-2-hexanamine hydrochloride in Geranium Plants

There has been significant discussion of 4-Methyl-2-hexanamine hydrochloride (1,3-DMAA) in the literature concerning the presence of 1,3-DMAA in geranium plants (Pelargonium graveolens). 1,3-DMAA, also known as 4-methyl-2-hexaneamine (MHA), 1,3-dimethylpentylamine, or 2-amino-4-methylhexane can be labeled as geranium extract in dietary supplements. The World Anti-Doping Agency requires that compounds with chemical structure and biological activity similar to banned substances must be analyzed by anti-doping laboratories. 4-Methyl-2-hexanamine hydrochloride and 2-aminoheptane (a banned stimulant) have similar chemical structures and physiological stimulant effects. The laboratory of Saudan developed a high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for detection of 1,3-DMAA in urine samples. The method was calibrated over the range of 50 to 700 ng/mL with excellent intraday precision and accuracy of less than 6%. The results from the Saudan laboratory found that 4-Methyl-2-hexanamine hydrochloride could be detected in urine samples up to 105 hours after administration of a 40 mg dose.[3]

The published research to date includes a substantial amount of geranium plant and oil analysis. However, until now, none of the samples analyzed have been identical or reported as from the same region. Thus, regional environmental variations could explain the presence of 4-Methyl-2-hexanamine hydrochloride in the Changzhou S11, Changzhou March 2012, and Changzhou May 2012 samples and the absence of 4-Methyl-2-hexanamine hydrochloride concentrations in Kunming and Guiyang geranium samples reported here; the Indian and Mississippi samples reported by ElSohly et al, the France, Egypt, and New Zealand samples reported by Lisi et al, and the China and Egypt samples reported by Zhang et al. A possible solution to this discrepancy would be a multiple laboratory and blind analysis of identical samples expected to have 1,3-DMAA (such as Changzhou region samples) as well as samples that are not expected to contain 4-Methyl-2-hexanamine hydrochloride. Using this approach, a satisfactory answer for the national regulatory agencies as well as the commercial interests could be provided.

References

[1]Small C, Cheng MH, Belay SS, Bulloch SL, Zimmerman B, Sorkin A, Block ER. The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization. J Pharmacol Exp Ther. 2023 Aug;386(2):266-273.

[2]Schilling BK, Hammond KG, Bloomer RJ, Presley CS, Yates CR. Physiological and pharmacokinetic effects of oral 1,3-dimethylamylamine administration in men. BMC Pharmacol Toxicol. 2013 Oct 4;14:52.

[3]Fleming HL, Ranaivo PL, Simone PS. Analysis and Confirmation of 1,3-DMAA and 1,4-DMAA in Geranium Plants Using High Performance Liquid Chromatography with Tandem Mass Spectrometry at ng/g Concentrations. Anal Chem Insights. 2012;7:59-78.