Journal of Alternative Complementary & Integrative Medicine Category: Medicine Type: Review Article
1,3-Dimethylamylamine (DMAA): A Brief History and Review of Anecdotal and Laboratory Findings
- Richard J Bloomer1*, Nicholas JG Smith2, Damien C Moore2, Charles R Yates3
- 1 Center For Nutraceutical And Dietary Supplement Research, School Of Health Studies, The University Of Memphis, 106 Roane Fieldhouse, Memphis, TN 38152, Tennessee, United States
- 2 Center For Nutraceutical And Dietary Supplement Research, School Of Health Studies , University Of Memphis, Memphis, Tennessee, United States
- 3 Center For Nutraceutical And Dietary Supplement Research, School Of Health Studies, University Of Memphis, Memphis, Tennessee, United States
*Corresponding Author:Richard J Bloomer
Center For Nutraceutical And Dietary Supplement Research, School Of Health Studies, The University Of Memphis, 106 Roane Fieldhouse, Memphis, TN 38152, Tennessee, United States
Received Date: Dec 07, 2018 Accepted Date: Dec 20, 2018 Published Date: Dec 28, 2018
DMAA (1,3-dimethylamylamine) was once a popular ingredient for inclusion within dietary supplements, in particular those marketed to the bodybuilding community as “pre-workouts.” Also known as methylhexanamine, and geranium extract, DMAA was not in supplements prior to the Dietary Supplement and Health Education Act of 1994 (DSHEA); hence, DMAA would be classified as a New Dietary Ingredient (NDI) by the Food and Drug Administration (FDA). In 2012, the FDA issued warning letters to manufacturers and distributors calling for cessation of DMAA sales and use within dietary supplement formulations, partly because required safety data supporting DMAA’s use was lacking. Thus, supplements containing DMAA were considered “adulterated”. Adverse event reports following DMAA ingestion prompted the FDA’s actions. Though the use of DMAA has since decreased considerably, sales of dietary supplements containing DMAA or close derivatives continue. Currently, no scientific evidence exists to support DMAA’s use as an ergogenic aid, notwithstanding widespread anecdotal reports of improved exercise performance and focus following DMAA ingestion. While reports have documented an association between DMAA ingestion and adverse events, it remains unclear as to the causal role of DMAA, in particular considering the fact that specific to the reported events, DMAA was often used in combination with other dietary ingredients, prescription medications or recreational drugs. This review discusses the history of DMAA, anecdotal and laboratory findings pertaining to its use, and its use today within the dietary supplement market.
In 2012, the United States Food and Drug Administration (FDA) issued warning letters to companies informing them that products containing DMAA should be removed from the market or reformulated without the inclusion of DMAA. Also in 2012, the United States Department of Defense removed all DMAA containing products from stores on military bases . Although most companies complied with the recommendation for removal and cessation of use, some companies continued to sell DMAA containing products. Most appeared to be newly formulated products within the sport nutrition market, as highlighted in the report of the Human Performance Resource Center Operation Supplement Safety and noted here (https://www.opss.org/docs/dietary-supplements-containing-dmaa) .
While the overall question regarding the safety of DMAA appears to be of greatest importance to most individuals, the issue of whether or not the ingredient can be legally included within dietary supplements has also been a topic of discussion. Based on guidelines regulating what is considered a New Dietary Ingredient (NDI), the FDA claims that DMAA lacks safety data to support its inclusion in dietary supplements. This point alone, the lack of adequate safety data and not the assertion that DMAA is unsafe, may have been the rationale used by the FDA to call for the removal of DMAA from dietary supplements.
Regardless of the reason for the FDA’s action, DMAA containing products still exist and it is logical to assume that such products are being regularly used. If this is the case, users should understand that this ingredient might promote an acute dose-dependent elevation in blood pressure. In addition, since some individuals may use DMAA to enhance sports performance, they should know that DMAA is a banned substance by most sporting agencies, including the World Anti-Doping Agency. As such, users may test “positive” for a banned substance and face the consequences of doing so.
This paper provides a historical overview of DMAA, a summary of the anecdotal and laboratory findings pertaining to its use, as well as the authors’ perspective concerning this ingredient.
BRIEF HISTORY OF DMAA
In 2012 following the reporting of multiple adverse events, the FDA issued warning letters to companies thought to be responsible for a high percentage of the DMAA products sold in the United States . Marketing and sales of DMAA containing products subsequently declined. However, to our knowledge and as noted here (https://www.opss.org/docs/dietary-supplements-containing-dmaa), several DMAA containing products continued to be sold. The companies responsible for the continued sales of DMAA appear to be relatively small in comparison to the market leaders. Regardless, due to the apparent demand for this ingredient, it is possible that sales volumes will be relatively significant.
PROPOSED MECHANISM OF ACTION AND RELATED CONCERNS
Our group conducted an oral PK study in order to determine the plasma concentration time profile in humans (n=7) following ingestion of a single 25 mg DMAA dose . Oral Clearance (CL) values (CL/F; F represents oral bioavailability) were found to be relatively low (20±5.0 L/hr), whereas oral Volume of distribution (V/F) was relatively high (236±38.0 L). A 25 mg single oral dose resulted in a maximum plasma concentration (Cmax) of 76.5 ng/mL, which occurred approximately 4 hours post-ingestion. Cmaxvalues were approximately 15-30 times lower than those reported in case studies linking DMAA intake with severe adverse events, suggesting that the reported adverse events were associated with a DMAA intake much higher than the 25 mg dose in our study [9,10]. Additionally, the potential impact of drug-drug interactions should be considered when interpreting DMAA adverse event reports. Because DMAA PK data suggest that a significant fraction of an orally administered DMAA dose is metabolized, concomitant administration of common ingredients that are also metabolized (e.g., caffeine), may lead to exaggerated DMAA concentrations by inhibiting DMAA clearance.
DMAA PHYSIOLOGICAL/PERFORMANCE EFFECTS
As stated above, most dietary supplements containing DMAA were manufactured or are presently being manufactured and marketed for purposes of weight/fat loss and/or improved physical performance. DMAA purportedly aids in weight/fat loss when combined with caffeine and other agents . However, since this study involved the use of a multi-ingredient formulation, there is no way to know the contribution of DMAA to these outcomes. To our knowledge, DMAA alone has not been rigorously evaluated for its potential impact on weight/fat loss using an intervention design.
Arguably the most common use of DMAA is as an ergogenic aid; specifically, as an aid that will help to improve physical performance. This may be appealing to competitive athletes and non-athletes alike, such as individuals who perform resistance or cardiovascular exercise to improve physical strength, muscle mass, cardio respiratory endurance, or enhance aesthetics. In fact, this latter category of non-competitive athletes (e.g., resistance-trained men) likely makes up the largest consumers of “pre-workout” dietary supplements that might contain DMAA.
In the lone human study conducted to determine a physical performance benefit from using DMAA, no ergogenic effect was noted . Subjects performed a 10 km outdoor run after receiving oral DMAA alone or in combination with caffeine. Performance, based on time to complete the run, was not different for subjects when receiving D¬MAA or caffeine alone, together, or when using a placebo. Heart rate, perceived exertion, and vigor was not different between conditions during the run. Specifically, heart rate was 181 bpm for placebo, 179 bpm for caffeine, 182 bpm for DMAA and 179 bpm for caffeine +DMAA. Blood pressure (systolic in particular) was similar between caffeine and DMAA during the post-exercise period, both of which demonstrated a greater blood pressure response as compared to caffeine +DMAA.
To our knowledge, all claims of an ergogenic effect of DMAA have been anecdotal and reported on various blogs and message boards, with individuals noting increased energy, enhanced mood, “laser-like” focus, and improved exercise performance. Scientific evidence to support such claims is lacking. To our knowledge, there have been no published studies to evaluate the ergogenic effects of DMAA other than that performed by Bloomer and colleagues . Perhaps future studies may be conducted which provide evidence to support the anecdotal reports. However, it is unlikely that such studies will be performed unless a more rigorous assessment of its safety is first completed.
Aside from an impact on exercise performance, Powers and colleagues examined neurocognitive performance following acute consumption of a DMAA-containing dietary supplement . The ImPACT test, a computerized neurocognitive assessment, was used to measure neurocognitive performance such as attention, verbal recognition memory and visual working memory. Results indicated that participants had significantly improved reaction time and increased scores on the cognitive-efficiency index following ingestion of the DMAA containing supplement. Although this may be promising, it should be noted that these findings cannot be directly attributed to DMAA alone, as the supplement also contained caffeine and other ingredients. It is possible that caffeine alone will have been responsible for the noted findings in this investigation. Moreover, this is only one study and included a sample size of only five men and seven women. Additional studies would be needed to fully characterize the effect of DMAA alone on cognitive performance in men and women.
SAFETY CONCERNS OF DMAA
Notable case reports have associated DMAA consumption with cerebral hemorrhaging, Myocardial Infarction (MI), liver injury and death. In two publications, Gee et al., reviewed four separate cases in which individuals reported ingesting pure DMAA in conjunction with alcohol in recreational settings [9,10]. Individuals experienced adverse outcomes, including severe headaches, vomiting and involuntary twitching. Hospitalization revealed cerebral hemorrhaging in all cases. Following post-hospitalization analysis, Gee and colleagues attributed the cerebral hemorrhages to DMAA ingestion, noting that DMAA is structurally similar to amphetamines, which can cause cerebral hemorrhaging [14-16]. The amount of DMAA ingested by individuals described in these reports was estimated to be approximately 15 to 30 times the amount provided in a usual serving of most dietary supplements containing DMAA. This hypothesis was based on the cited dosages indicated within the papers by Gee and colleagues, in conjunction with individuals’ plasma DMAA concentrations as reported by the authors, as compared to plasma DMAA concentrations obtained from subjects following a 25 mg oral dosage of DMAA within a controlled laboratory investigation [5,9,10]. In addition, as noted in the papers of Gee and colleagues [9,10], other chemicals may have been taken along with the DMAA (e.g., caffeine, phenethylamine, alcohol and cannabis). Hence, the likelihood exists that the adverse events noted by Gee et al., are linked to 1) ingestion of very high doses of DMAA and 2) confounding variables, which may have exacerbated the pressor effects of DMAA and/or promoted other untoward effects leading to the noted outcomes.
Another individual, a 36-year-old man, also suffered a cerebral hemorrhage . He was drinking alcoholic beverages at a public bar and decided to purchase a legal party drug called “Cocaine Party Powder”. The authors cite a listed composition of 50 mg of DMAA and state that the individual “took one quarter of the packet with a drink” . An online review (https://www.pills4party.com/dex-party-powder.html) noted that such powder packets often contain multiple dosages, with one advertisement claiming, “…each bag contains a mind blowing 40 doses”. If consuming one quarter of the packet and assuming that said packet contained multiple dosages, it is possible that this individual consumed a very high quantity of DMAA. When coupled with alcohol and nicotine, this indeed presents a potentially harmful combination.
A 41-year-old man was also highlighted in the Gee et al. report . The man was supposedly, “offered a white powder dissolved in water as a pick-me-up in a bar” . He collapsed 30 minutes later with a severe headache and upon analysis, it was noted that he also suffered a cerebral hemorrhage. His blood DMAA levels were extremely high (2.31 µg/mL), which is a DMAA level associated with ingestion of at least 30 times the dose reported in our DMAA PK study, viz., 25 mg . At such a high dosage of DMAA, it is not surprising that the individual experienced an adverse outcome.
Finally, Gee and coworkers reported on a patient who was claimed to ingest two “tablets” containing DMAA (later confirmed by analysis to contain 278 mg of DMAA per “capsule”: total dosage=556 mg), along with 150 mg of caffeine and one can of beer . The following day the patient reported to the ER and was found to suffer from a large hemorrhage in the region of the left basal ganglia.
Considering the above information presented by Gee and colleagues, one issue is clear and needs to be understood: individuals ingesting DMAA at extremely high dosages are subject to adverse outcomes likely involving elevated blood pressure and associated problems. Gee and colleagues  comment within their paper that, “The stated doses of DMAA in party pills sold in New Zealand range between 50 and 300mg per pill.” The products are often combined with caffeine. Considering that our work demonstrated a clear dose-dependent increase in blood pressure following DMAA use , with a mean increase in systolic blood pressure of 16 mmHg with a 75 mg dosage of DMAA, it is not surprising that adverse events are noted when individuals consume doses that are several fold higher. Couple this with caffeine ingestion and the intake of alcohol and other drugs, and adverse events are likely. Individuals considering DMAA use, as well as healthcare providers, who may be providing care to such individuals, should understand the potential risks of using DMAA. Like all stimulants, caution needs to be used as related to the total dosage ingested.
MYOCARDIAL INFARCTION AND CARDIAC ARREST
In a similar situation, Karnatovskaia et al., reported the case of a 21-year-old male who suffered cardiac arrest while exercising . Again, the individual examined presented none of the typical risk factors for heart disease. However, the individual had consumed for the first time an unnamed pre-workout supplement that reportedly contained DMAA. With a lack of other risk factors present, Karnatovskaia and coworkers attributed the arrest to the consumption of DMAA. No data were presented as to how much of the dietary supplement was consumed by the individual, including the quantity of DMAA. Moreover, no information was presented as to which other ingredients were contained within the supplement. In almost all cases, pre-workout dietary supplements containing DMAA are formulated with multiple ingredients, including caffeine and additional stimulants. The caffeine content of these products is typically 8-10 times that of DMAA (e.g.,25 mg DMAA and 250 mg caffeine). This should be considered in the case analyses.
A report composed by Roytman et al., described eight previously healthy overweight and obese individuals who developed hepatitis after prolonged consumption of OxyELITE Pro . The cases were severe, with one individual dying and two requiring liver transplants. While six of the eight individuals highlighted in this paper had used the original OxyELITE Pro product containing DMAA, the authors focused more heavily on the potential cause of liver injury being an ingredient known as aegeline, contained within a reformulated version of the OxyELITE Pro, rather than DMAA. Clearly, it is unknown what ingredient (s) may have been associated with the cases noted above. As with all multi-component products, it is difficult to determine the direct contribution of DMAA to the outcomes, as multiple other ingredients are contained within the OxyELITE Pro.
Another case of death associated with physical exercise was documented in 2012, when a 30-year-old woman died prior to completing the London Marathon in 2012 . It was reported that the woman ingested a DMAA containing dietary supplement mixed in her water bottle. No additional information is available in the scientific literature pertaining to this case. Therefore, it is difficult to draw conclusions specific to the role that the supplement may have played in this situation.
SCIENTIFIC AND CONTROLLED
DMAA AS A STAND-ALONE INGREDIENT
With acute ingestion, caffeine elevates both systolic and diastolic blood pressure, typically in a dose dependent manner, which persists for up to three hours following ingestion. For example, Karatzis and coworkers reported a 4 mmHg increase in both systolic and diastolic blood pressure when 80 mg of caffeine was ingested within coffee [37,38]. Robertson et al., provided a dosage of 250 mg caffeine to healthy men and women and noted an increase in systolic and diastolic blood pressure of 14 mmHg and 10 mmHg, respectively (one hour after caffeine ingestion) . In a review and meta-analysis, it was determined that when analyzing data from five trials, the administration of 200-300 mg caffeine produced an average increase of 8.1 mmHg in systolic blood pressure and 5.7 mmHg in diastolic blood pressure . Collectively, these data indicate that DMAA at dosages up to50 mg promotes a similar increase in mean blood pressure than does caffeine when ingested at a dosage of 250 mg or the amount contained within approximately two cups of coffee.
Aside from acute ingestion of DMAA as a stand-alone ingredient, one multi-week study was conducted to assess the safety of DMAA ingestion. We investigated the safety profile of DMAA and caffeine, alone or in combination, when ingested for a period of 12 weeks . Fifty young and healthy men (mean age of 23 years) completed 12 weeks of daily supplementation with either a placebo, caffeine at 250 mg/day, DMAA at 50 mg/day, or caffeine at 250 mg/day + DMAA at 50 mg/day. Before and after 6 and 12 weeks of supplementation, the following variables were measured in the morning following an overnight fast: body mass/composition, respiratory rate, blood pressure, 12-lead ECG, complete urinalysis, complete blood count, metabolic panel, lipid panel, oxidative stress, inflammatory and cardiac biomarkers. Results indicated that little to no change occurred across time for subjects in any of the four conditions, with no interaction effects noted (p>0.05). An increase in heart rate (~5 bpm) was observed for subjects in the DMAA condition, as well as an increase in respiratory rate for subjects in the caffeine +DMAA condition (~3 breaths per minute). Apart from urinary pH (Pre [6.5±0.1] higher than week 6 [6.1±0.1]) and blood CO2 (week 12 [25.9±0.3 mmol/L] higher than week 6 [24.8±0.3 mmol/L]), no time effect was noted for any variable (p>0.05).
STUDIES INVOLVING DMAA WITHIN FINISHED DIETARY SUPPLEMENTS
In a longer-term study of Jack 3D, 25 healthy men (mean age of 23 years) were randomly assigned to either a placebo (n=13) or to Jack 3D (n=12) for a period of 10 weeks . Subjects were instructed to consume 1-3 servings on each workout day. The mean number of workout days per week for subjects was four and the mean number of servings of the supplement consumed on workout days was 2.4±0.3 (approximately 50 mg DMAA and 300 mg caffeine). Before and after the intervention, resting blood pressure and heart rate were measured, and blood samples were collected for determination of complete blood count, metabolic panel and lipid panel. It was found that no significant differences were detected between conditions for blood pressure (p>0.05), although systolic blood pressure increased approximately 6 mmHg with Jack 3D, while diastolic blood pressure decreased approximately 4 mmHg. Heart rate was noted to decrease slightly from pre-to post-intervention. There were significant main effects for time for creatinine (increased from pre-to post-intervention; p=0.043) and alkaline phosphatase (decreased from pre-to post-intervention; p=0.009), with no condition differences noted (p>0.05). There was a significant interaction noted for low density lipoprotein cholesterol (p=0.043), with values decreasing for subjects assigned to Jack 3D by approximately 7 mg/dL. An approximate 5% reduction was also noted in total cholesterol for subjects assigned to Jack 3D. No other effects of significance were noted for blood parameters. It was concluded that Jack 3D does not result in a statistically significant increase in resting heart rate or blood pressure (although systolic blood pressure was increased approximately 6 mmHg with supplement use). The supplement did not negatively impact bloodborne markers of health but may improve the blood lipid profile, as evidenced by the noted reduction in total and LDL cholesterol.
Studies have also been conducted using the product OxyELITE Pro, containing a blend of DMAA, caffeine, Bauhinia purpurea, Bacopa monniera, Cirsium oligophyllum and Rauwolscine Extract. In one such study, 4 men and 2 women (22.5±1.8 yrs) ingested two servings (two capsules) per day of OxyELITE Pro for two weeks . On days 1 and 15, resting heart rate and blood pressure were measured and fasting blood samples were analyzed for complete blood count, comprehensive metabolic panel and lipid panel. On days 1 and 15 following blood collection, subjects ingested two servings of the supplement and heart rate and blood pressure were recorded at 30-minutes intervals for two hours. No change was noted in the measured variables following 15 days of supplementation. In response to acute intake, heart rate and diastolic blood pressure were increased approximately 6 bpm and 6 mmHg, respectively. Systolic blood pressure was increased approximately 15 mmHg with acute treatment of two capsules of OxyELITE Pro.
Using an acute study design, twelve subjects (men 24.8±4.3 yrs; women 22.8±0.4 yrs) ingested OxyELITE Pro or a placebo, on two separate days in a double blind, crossover design . Breath samples were collected immediately before ingestion and at 30, 60, 90 and 120 minutes post ingestion, for a measure of energy expenditure. Heart rate and blood pressure were recorded at all times. Acute ingestion of two capsules of the supplement increased energy expenditure, heart rate and blood pressure above pre-ingestion values; values were greater than observed for placebo. Specifically, heart rate was stable for men (~ 60 bpm at all measurement times) but increased 7 bpm for women. Systolic blood pressure increased approximately 20 mmHg for men and 12 mmHg for women, while diastolic blood pressure increased approximately 8-10 mmHg for both men and women. We concluded that, “These latter findings (increased SBP in particular) may warrant caution, in particular in those with pre-hypertension or hypertension. The use of a lower dosage may attenuate this response.”
In another study to investigate OxyELITE Pro, exercise-trained subjects between the ages of 19 and 36 years were randomly assigned in double-blind manner to ingest either OxyELITE Pro (n=16; aged 22.8±0.7) or a placebo (n=16; 22.5±0.5) every day for eight weeks . Subjects were provided the option to use either 1 or 2 capsules per day. This was done to duplicate the conditions in which individuals would use this dietary supplement in a non-laboratory setting. For both conditions, capsules were taken with water on an empty stomach in the early morning, and if taking a second dosage, this was to be taken during the early to mid afternoon. Body weight, body composition, complete blood count, comprehensive metabolic panel, resting heart rate and blood pressure were measured (pre-andpost-intervention). When comparing pre-and post-intervention values for the supplement, significant decreases were noted in body weight and body fat percentage, while an increase was noted for resting heart rate (approximately 6 bpm). Blood pressure was increased slightly with the supplement (approximately 3 mmHg) but not with placebo. Of the 16 subjects assigned to OxyELITE Pro, 11 ingested two capsules per day and five ingested only one capsule per day. These five subjects indicated that the ingestion of two capsules was associated with increased feelings of jitters and sleeplessness. None of the remaining 11 subjects assigned to the supplement noted any adverse effects of treatment.
ABUSE LIABILITY OF DMAA
IMPACT OF DMAA ON BODY TEMPERATURE
For example, one study conducted by investigators at the Army Research Institute of Environmental Medicine used a sample of 10 men who exercised in the heat (104°F) . The authors noted that even when caffeine was provided at an extremely high dosage of 9 mg/kg body weight (585-855 mg caffeine for 65 to 95 kg individuals), heat production was only marginally higher for caffeine as compared to placebo and likely due to the increase in oxygen consumption. The authors concluded, “The magnitude of the increase in heat production was small and heat losses appeared unaffected. As a result, elevations in mean body temperature were marginal, physiologically unimportant, and unlikely to predispose athletes or military personnel to an increased risk of heat illness” . Roti et al., concluded that acute caffeine ingestion, in chronically consuming subjects (3 and 6 mg/kg per day), did not alter fluid-electrolyte, exercise endurance or thermoregulatory responses during 90 minutes of walking in the heat (100°F) when compared with no caffeine . In addition, Del Coso and colleagues reported that caffeine ingestion at 6 mg/kg body mass was not thermogenic and did not impair heat dissipation when men exercised in the heat (97°F) for two hours .
Aside from caffeine alone, investigators from the Canadian Defense and Civil Institute of Environmental Medicine provided a dosage of 5 mg/kg caffeine + 1 mg/kg ephedrine to 10 men who exercised in a hot environment (104°F) . The authors noted no increase in internal body temperature during exercise, despite the high dosage of stimulant provided. Collectively, these studies indicate that well-known stimulants fail to increase internal body temperature, even when provided at very high dosages.
Considering the minimal effects of DMAA and caffeine on human body temperature, there is no scientific basic to claim that DMAA at a dosage of 25-50 mg would lead to a significant increase in body temperature [5,44]. Such a suggestion is mere speculation and fails to consider the available science.
NATURAL VERSUS SYNTHETIC DMAA
In one study by Fleming and colleagues in which DMAA was detected in small quantities in cultivars of Pelargonium graveolens, the authors report, “The results reported here provide evidence that 1,3-DMAA naturally occurs in geranium plants” but go on to state that their work disagrees with other previous articles by well-respected chemists . The authors follow by stating that, “…this may not be a case of right or wrong. In analytical chemistry, the critical review of data is important for explaining differences in reported results. These differences can also provide insight into why analysis of seemingly identical plant species can result in very different outcomes” .
In short, scientists continue to disagree on whether DMAA can be identified in plant species. Regardless, it is obvious that despite its claimed existence in plants or the plant oils, since the quantities of detection are very small, dietary supplements using dosages of 20-30 mg of DMAA per serving must include synthetic DMAA in these preparations. It would be difficult for a manufacturer to provide support to the contrary. As such, labeling the product as “natural” is misleading to the consumer, as many may believe that the entirety of the product is natural when in fact, it is not.
Assuming that DMAA is of natural origin, the question arises as to whether or not use of a synthetic version of the ingredient within dietary supplement preparations would be of concern. For some individuals, the answer is likely yes, as they believe that all dietary supplements should be natural and contain no synthetic components. Other might argue, no; they are fine with the use of synthetic ingredients as long as said ingredient does exist in nature. The rationale for the latter might be the simple fact that the use of synthetic ingredients within dietary supplements is common. A quick review of many off the shelf multi-vitamin/mineral supplements will confirm this. For example, synthetic vitamin E (dl-alpha-tocopherol) has been used for many years, although well-documented to be inferior to the natural form of this vitamin. The same is true for many other agents that are naturally occurring but are used in synthetic form within dietary supplements. Synthetic when it comes to dietary supplements does not necessarily equate to harm, which is often the implication. It simply means different and in some cases, inferior. In other cases, such as with vitamin C, “different” may not matter at all .
SHOULD DMAA DOSING BE CONSIDERED?
As mentioned above, in many of the case reports noting significant adverse outcomes from DMAA ingestion, quantities of use appeared to be far greater than what would be recommended by the manufacturer or tolerated by human consumption. Based on a review of product labels and anecdotal reports, most DMAA containing dietary supplements are thought to include approximately 25 mg of DMAA per serving. We know from our prior controlled studies using DMAA that blood pressure increases in a dose-dependent manner with treatment. That is, at 25 mg we observe essentially no change in blood pressure, with a 7 mmHg mean increase at a dosage of 50 mg and a 16 mmHg mean increase at a dosage of 75 mg . If our calculations are accurate and certain individual cases as reported in the papers of Gee and colleagues were consuming 15+ times the recommended dosage, these individuals may have ingested 375 mg of DMAA (on the low end), in addition to other stimulants [9,10]. If this was the case, it is not surprising that adverse effects were noted. Such activity is extremely unwise and should be strongly discouraged.
The above would be akin to an individual ingesting 3,750 mg of caffeine in the morning rather than the usual 250 mg found in two cups of coffee; or perhaps drinking 15-20 glasses of wine with dinner rather than an acceptable, one or two glasses. Likewise, it would be similar to the cardiologist prescribing 375 mg of Atenolol to their patient rather than a more typical dosage of 25 mg of this beta-blocker. No rational person would consider doing such things, as they know the results could be devastating. Yet, this is the sort of practice that appeared commonplace with DMAA, in particular when used within “party pills”. The outcome is dependent on more than the agent; it is also dependent on the dosage of agent being delivered and this should always be taken into account.
GROUNDS FOR DMAA REMOVAL
What we know at present is that multiple adverse event reports have been filed which cite the involvement of DMAA. These events may be linked to the well-described pressor actions of DMAA and the resulting dose-dependent rise in blood pressure with use. It only follows that the FDA would need to investigate these reports and take the appropriate action. While their decision of removing DMAA from the marketplace is not popular with many, they must have believed it was the correct and responsible action in this case. Unfortunately, many individuals are prone to reckless behavior and it may have been the FDA’s belief that reckless behavior involving the ingestion of high quantities of DMAA needed to be stopped. Just as a protective parent steps in to regulate the activities of their children, the FDA may have believed that their actions helped to regulate the activity of would-be DMAA users. In such a case, protecting individuals who refuse to protect themselves seems appropriate. Whether this is right or wrong and/or whether this infringes on individuals’ rights to make their own choices remains a topic of debate.
Beyond the above, the overarching question is whether DMAA qualified for inclusion within dietary supplements in the first place. This is based on the issue of NDI status. Unlike the Dietary Supplement Health and Education Act of 1994, which places the burden of proof on the FDA, the NDI guidelines require that the company provide the FDA with information pertaining to the overall safety of the ingredient of interest. If this was never done and if DMAA was considered A NDI, this presents a separate topic for discussion.
CONCLUSION AND SUGGESTIONS FOR MOVING FORWARD
It is apparent that consumer education is needed, including instruction as to how to report adverse events. While this is specific to DMAA in our current discussion, it certainly should not end with this one ingredient. There are many dietary ingredients being sold and used today by consumers for which we know little about in terms of efficacy, dosing, and safety. Rather than constantly battling over so many issues, the medical community, FDA and dietary supplement community need to come together to develop a comprehensive plan of action that will serve to help the people who need it most the consumers. Without this, more confusion will arise and people across groups will continue to be frustrated.
First sentence should read:
Since some companies continue to manufacture products containing DMAA, strict adherence to current Good Manufacturing Practice should be adhered to by all contract manufacturers. While most companies selling dietary supplements do not manufacture the products on their own, they should make certain that they have an excellent working relationship with their contract manufacturer and can assure customers that they can trust label claims for product purity and potency. If a company continues to use DMAA in their formulas, it would be wise to limit the amount contained in the product, to avoid the elevated blood pressure that is well documented with DMAA use.
If DMAA continues to be sold, long-term safety studies should be initiated in order to expand on our understanding of DMAA. These studies should include men and women, as well as those of various ages and fitness levels. Since many overweight/obese individuals may opt to use products containing DMAA to lose body weight/fat, such individuals should be included in the subject pool. Using DMAA within the context of exercise stress should also be done, as most users will ingest the supplements prior to acute exercise. Moreover, since DMAA is typically used in conjunction with other ingredients (e.g., caffeine), the combination of ingredients should be considered in study designs.
If people continue to use this agent, it is imperative that they understand the potential harm of doing so, in particular when using DMAA in high quantities. Specifically, blood pressure will likely be elevated acutely with use and this may pose a problem for those who may already be hypertensive and/or are using DMAA in the context of strenuous, high force resistance exercise. Companies who continue to market and sell DMAA containing products should focus efforts on educating the consumers of the potential safety concerns of using DMAA. This should extend to the issue of DMAA being banned by most sporting agencies, raising the possibility of athletes testing positive on mandatory drug tests and subsequently being ineligible to compete.
As with all stimulants, the potential for elevated heart rate and blood pressure exists. Additional complications may arise based on an individual’s sensitivity to the agent. For example, some subjects who have used DMAA and other stimulants note feeling jittery and anxious, while sometimes having difficulty falling asleep at night. These are undesirable outcomes for many individuals. Users need to understand that, not unlike medications, when using certain dietary supplements, some degree of risk is involved. This is the reality, and companies who market such products need to specify what these risks might be in order to better educate potential consumers.
AUTHOR DISCLOSURE STATEMENT (DECLARATION OF INTERESTS)
- Lattman P, Singer N (2012) Army studies workout supplements after deaths. The New York Times, New York, USA.
- US Food and Drug Administration (2013) DMAA in Products Marketed as Dietary Supplements. US Food and Drug Administration, Silver Spring, Maryland, USA.
- Bloomer RJ, Harvey IC, Farney TM, Bell ZW, Canale RE (2011) Effects of 1,3-dimethylamylamine and caffeine alone or in combination on heart rate and blood pressure in healthy men and women. Phys Sportsmed 39: 111-120.
- Schilling BK, Hammond KG, Bloomer RJ, Presley CS, Yates CR (2013) Physiological and pharmacokinetic effects of oral 1,3-dimethylamylamine administration in men. BMC Pharmacol Toxicol 14: 14:52.
- MacDougall JD, Tuxen D, Sale DG, Moroz JR, Sutton JR (1985) Arterial blood pressure response to heavy resistance exercise. J Appl Physiol 58: 785-790.
- Perrenoud L, Saugy M, Saudan C (2009) Detection in urine of 4-methyl-2-hexaneamine, a doping agent. J Chromatogr B Analyt Technol Biomed Life Sci 877: 3767-3770.
- Lisi A, Hasick N, Kazlauskas R, Goebel C (2011) Studies of methylhexaneamine in supplements and geranium oil. Drug Test Anal 3: 873-876.
- Gee P, Jackson S, Easton J (2010) Another bitter pill: a case of toxicity from DMAA party pills. N Z Med J 123: 124-127.
- Gee P, Tallon C, Long N, Moore G, Boet R. et al. (2012) Use of recreational drug 1,3 Dimethylamylamine (DMAA) [corrected] associated with cerebral hemorrhage. Ann Emerg Med 60: 431-434.
- McCarthy CG, Canale RE, Alleman RJ Jr, Reed JP, Bloomer RJ (2011) Biochemical and anthropometric effects of a weight loss dietary supplement in healthy men and women. Nutr Metab Insights 5: 13-22.
- Bloomer RJ, McCarthy CG, Farney TM, Harvey IC (2011) Effect of caffeine and 1,3-dimethylamylamine on exercise performance and blood markers of lipolysis and oxidative stress in trained men and women. J Caffeine Res 1: 169-177.
- Powers ME (2015) Acute stimulant ingestion and neurocognitive performance in healthy participants. J Athl Train 50: 453-459.
- Buxton N, McConachie NS (2000) Amphetamine abuse and intracranial haemorrhage. J R Soc Med 93: 472-477.
- Chaudhuri C, Salahudeen AK (1999) Massive intracerebral hemorrhage in an amphetamine addict. Am J Med Sci 317: 350-352.
- McGee SM, McGee DN, McGee MB (2004) Spontaneous intracerebral hemorrhage related to methamphetamine abuse: autopsy findings and clinical correlation. Am J Forensic Med Pathol 25: 334-337.
- Smith TB, Staub BA, Natarajan GM, Lasorda DM, Poornima IG (2014) Acute myocardial infarction associated with dietary supplements containing 1,3-dimethylamylamine and Citrus aurantium. Tex Heart Inst J 41: 70-72.
- Forrester M (2013) Exposures to 1,3-dimethylamylamine-containing products reported to Texas poison centers. Hum Exp Toxicol 32: 18-23.
- Karnatovskaia LV, Leoni JC, Freeman ML (2015) Cardiac arrest in a 21-year-old man after ingestion of 1,3-DMAA-containing workout supplement. Clin J Sport Med 25: 23-25.
- Foley S, Butlin E, Shields W, Lacey B (2014) Experience with OxyELITE Pro and acute liver injury in active duty service members. Dig Dis Sci 59: 3117-3121.
- Roytman MM, Pörzgen P, Lee CL, Huddleston L, Kuo TT, et al. (2014) Outbreak of severe hepatitis linked to weight-loss supplement OxyELITE Pro. Am J Gastroenterol 109: 1296-1298.
- Eliason MJ, Eichner A, Cancio A, Bestervelt L, Adams BD, et al. (2012) Case reports: death of active duty soldiers following ingestion of dietary supplements containing 1,3-Dimethylamylamine (DMAA). Mil Med 177: 1455-1459.
- Mayo Clinic (2017) Heatstroke. Mayo Clinic, Rochester, Minnesota, USA
- Yankelson L, Sadeh B, Gershovitz L, Werthein J, Heller K, et al. (2014) Life-threatening events during endurance sports: is heat stroke more prevalent than arrhythmic death? J Am Coll Cardiol 64: 463-469.
- Zeller L, Novack V, Barski L, Jotkowitz A, Almog Y (2011) Exertional heatstroke: clinical characteristics, diagnostic and therapeutic considerations. Eur J Intern Med 22: 296-299.
- Casa DJ, Armstrong LE, Ganio MS, Yeargin SW (2005) Exertional heat stroke in competitive athletes. Curr Sports Med Rep 4: 309-317.
- BBC News (2013) Claire Squires inquest: DMAA was factor in marathon runner’s death. BBC News, London, UK.
- Bloomer RJ, Farney TM, Harvey IC, Alleman RJ (2013) Safety profile of caffeine and 1,3-dimethylamylamine supplementation in healthy men. Hum Exp Toxicol 32: 1126-1136.
- Farney TM, McCarthy CG, Canale RE, Allman Jr, Bloomer RJ (2011) Hemodynamic and hematologic profile of healthy adults ingesting dietary supplements containing 1,3-dimethylamylamine and caffeine. Nutr Metab Insights 5: 1-12.
- McCarthy CG, Farney TM, Canale RE, Alleman RJ Jr, Bloomer RJ (2011) A finished dietary supplement stimulates lipolysis and metabolic rate in young men and women. Nutr Metab Insights 5: 23-31.
- Whitehead PN, Schilling BK, Farney TM, Bloomer RJ (2012) Impact of a dietary supplement containing 1,3-dimethylamylamine on blood pressure and bloodborne markers of health: a 10-week intervention study. Nutr Metab Insights 5: 33-39.
- Frary CD, Johnson RK, Wang MQ (2005) Food sources and intakes of caffeine in the diets of persons in the United States. J Am Diet Assoc 105: 110-113.
- Branum AM, Rossen LM, Schoendorf KC (2014) Trends in caffeine intake among U.S. children and adolescents. 133: 386-393.
- Heckman MA, Weil J, Gonzalez de Mejia E (2010) Caffeine (1, 3, 7-trimethylxanthine) in foods: a comprehensive review on consumption, functionality, safety, and regulatory matters. J Food Sci 75: 77-87.
- Nawrot P, Jordan S, Eastwood J, Rotstein J, Hugenholtz A, et al. (2003) Effects of caffeine on human health. Food Addit Contam 20: 1-30.
- McCusker RR, Goldberger BA, Cone EJ (2003) Caffeine content of specialty coffees. J Anal Toxicol 27: 520-522.
- Nurminen ML, Niittynen L, Korpela R, Vapaatalo H (1999) Coffee, caffeine and blood pressure: a critical review. Eur J ClinNutr 53: 831-839.
- Karatzis E, Papaioannou TG, Aznaouridis K, Karatzi K, Stamatelopoulos K, et al. (2005) Acute effects of caffeine on blood pressure and wave reflections in healthy subjects: should we consider monitoring central blood pressure? Int J Cardiol 98: 425-430.
- Robertson D, Frölich JC, Carr RK, Watson JT, Hollifield JW, et al. (1978) Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 298: 181-186.
- Mesas AE, Leon-Muñoz LM, Rodriguez-Artalejo F, Lopez-Garcia E (2011) The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis. Am J Clin Nutr 94: 1113-1126.
- Eichner S, Maguire M, Shea LA, Fete MG (2016) Banned and discouraged-use ingredients found in weight loss supplements. J Am Pharm Assoc 56: 538-543.
- Pawar RS, Grundel E (2017) Overview of regulation of dietary supplements in the USA and issues of adulteration with phenethylamines (PEAs). Drug Test Anal 9: 500-517.
- Dolan SB, Gatch MB (2015) Abuse liability of the dietary supplement dimethylamylamine. Drug Alcohol Depend 146: 97-102.
- Ely BR, Ely MR, Cheuvront SN (2011) Marginal effects of a large caffeine dose on heat balance during exercise-heat stress. Int J Sport Nutr Exerc Metab 21: 65-70.
- Bell DG, Jacobs I, McLellan TM, Miyazaki M, Sabiston CM (1999) Thermal regulation in the heat during exercise after caffeine and ephedrine ingestion. Aviat Space Environ Med 70: 583-588.
- Roti MW, Casa DJ, Pumerantz AC, Watson G, Judelson DA, et al. (2006) Thermoregulatory responses to exercise in the heat: chronic caffeine intake has no effect. Aviat Space Environ Med 77: 124-129.
- Del Coso J, Estevez E, Mora-Rodriguez R (2009) Caffeine during exercise in the heat: thermoregulation and fluid-electrolyte balance. Med Sci Sports Exerc 41: 164-173.
- Fleming HL, Ranaivo PL, Simone PS (2012) 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 7: 59-78.
- Li JS, Chen M, Li ZC (2012) Identification and quantification of dimethylamylamine in geranium by liquid chromatography tandem mass spectrometry. Anal Chem Insights 7: 47-58.
- Ping Z, Jun Q, Qing L (1996) A study on the chemical constituents of geranium oil. J Guizhou Inst Technol 25: 82-85.
- Austin KG, Travis J, Pace G, Lieberman HR ( 2014) Analysis of 1,3 dimethylamylamine concentrations in Geraniaceae, geranium oil and dietary supplements. Drug Test Anal 6: 797-804.
- Zhang Y, Woods RM, Breitbach ZS, Armstrong DW (2012) 1,3-Dimethylamylamine (DMAA) in supplements and geranium products: natural or synthetic? Drug Test Anal 4: 986-990.
- Gauthier TD (2013) Evidence for the presence of 1,3-Dimethylamylamine (1,3-DMAA) in geranium plant materials. Anal Chem Insights 8: 29-40.
- Mangels AR, Block G, Frey CM, Patterson BH, Taylor PR, et al. (1993) The bioavailability to humans of ascorbic acid from oranges, orange juice and cooked broccoli is similar to that of synthetic ascorbic acid. J Nutr 123: 1054-1061.
Citation: Bloomer RJ, Smith NJC, Moore DC, Yates CR (2018) 1,3-Dimethylamylamine (DMAA): A Brief History and Review of Anecdotal and Laboratory Findings. J Altern Complement Integr Med 4: 057.
Copyright: © 2018 Richard J Bloomer, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.