Submission Science KO Round 2

DMAA (1,3-dimethylamylamine)

DMAA (1,3-dimethylamylamine, methylhexanamine) is a synthetic stimulant that constricts blood vessels and raises blood pressure. It has been sold in pre-workout and weight-loss supplements and as a recreational stimulant¹.

DMHA (2-aminoisoheptane, octodrine) and DMBA

DMHA, also labelled 2-aminoisoheptane or octodrine (2-amino-6-methylheptane), is a synthetic aliphatic amine stimulant found in pre-workout and weight-loss supplements, sometimes alongside the related compound DMBA².

Higenamine

Higenamine is a plant alkaloid that stimulates β2-adrenergic receptors, the same receptor family targeted by asthma bronchodilators. It is found in plants such as Nandina domestica³.

Yohimbine (yohimbe bark, rauwolscine)

Yohimbine is an alkaloid from the bark of the African tree Pausinystalia yohimbe. It blocks α2-adrenergic receptors, which increases noradrenaline release. Rauwolscine (alpha-yohimbine) is a closely related alkaloid.

Caffeine

Caffeine is a stimulant that blocks adenosine receptors in the brain, reducing perceived effort and fatigue. It is found in coffee, tea and energy drinks and is a common ingredient in pre-workout products⁴.

Dicaffeine malate (sold as Infinergy®) is caffeine bonded to malic acid. Its caffeine adds to the total caffeine in a product, but labels do not always state the caffeine equivalent.

Synephrine (bitter orange, Citrus aurantium)

p-Synephrine is the main protoalkaloid of bitter orange (Citrus aurantium). It is structurally related to adrenaline and is used in weight-loss and pre-workout products⁵.

L-tyrosine

L-tyrosine is an amino acid that the body uses to make the neurotransmitters dopamine and noradrenaline. It is found in protein-rich foods; N-acetyl-L-tyrosine is a related form⁶.

Theacrine (TeaCrine®) and theobromine

Theacrine is a purine alkaloid related to caffeine, found in some tea plants; theobromine is the related methylxanthine in cocoa. Both are used in stimulant products.

L-citrulline and citrulline malate

L-citrulline is an amino acid that the body converts to arginine, a precursor of nitric oxide, which widens blood vessels. Citrulline malate combines citrulline with malic acid⁷.

Vitamin B12 (cobalamin)

Vitamin B12 is needed for red blood cell formation and nerve function. EFSA set an adequate intake of 4 µg a day for adults⁸. It is found almost only in animal foods, so vegans need a supplement or fortified foods.

Vitamin D3 (cholecalciferol)

Vitamin D is made in the skin in sunlight and is found in a few foods. It is needed for calcium absorption and bone health. EFSA set an adequate intake of 15 µg (600 IU) a day for adults⁹. 1 µg equals 40 IU.

DMAA (1,3-dimethylamylamine)

No controlled trials show that DMAA improves athletic performance or weight loss. A pharmacokinetic study of a single 25 mg dose did not find meaningful changes in resting heart rate, blood pressure or body temperature¹⁰.

DMHA (2-aminoisoheptane, octodrine) and DMBA

There are no controlled human trials showing that DMHA improves exercise performance or weight loss.

Higenamine

There are no controlled human trials showing that higenamine improves exercise performance or weight loss. Analyses of US supplements found up to about 62 mg per serving, with labels that often did not state the amount³.

Yohimbine (yohimbe bark, rauwolscine)

A small trial in professional soccer players found reduced body fat with yohimbine but no change in body mass, muscle mass or performance¹¹. Larger, independent trials are lacking.

Caffeine

The International Society of Sports Nutrition concludes that caffeine consistently improves exercise performance when consumed in doses of about 3–6 mg per kg of body mass, with benefits for muscular endurance, movement velocity, strength, sprinting, jumping and aerobic exercise⁴.

Synephrine (bitter orange, Citrus aurantium)

A review of human clinical studies reported small increases in energy expenditure and modest weight loss with bitter orange extract or p-synephrine products over 6–12 weeks, many in combination with other ingredients⁵.

L-tyrosine

A review found that tyrosine may support cognitive performance in short-term stressful or cognitively demanding situations, when these neurotransmitters are temporarily depleted, but found no consistent effect on physical exercise performance⁶.

Theacrine (TeaCrine®) and theobromine

An 8-week study of daily theacrine (TeaCrine®) up to 300 mg a day reported no safety concerns and no tolerance effect¹². Evidence for performance benefits is limited.

L-citrulline and citrulline malate

A review of human studies found that citrulline supplementation raises plasma arginine, and that several studies report improved exercise performance or recovery, but the results are inconsistent⁷.

Vitamin B12 (cobalamin)

Authorised EU claims include that vitamin B12 contributes to normal red blood cell formation, normal functioning of the nervous system and the reduction of tiredness and fatigue¹³.

Vitamin D3 (cholecalciferol)

Authorised EU claims include that vitamin D contributes to the maintenance of normal bones, muscle function and immune function¹³.

In the large VITAL trial, 2000 IU (50 µg) a day of vitamin D3 did not lower the incidence of invasive cancer or major cardiovascular events compared with placebo¹⁴. A meta-analysis found that vitamin D supplements did not prevent fractures or falls, or have clinically meaningful effects on bone density¹⁵.

DMAA (1,3-dimethylamylamine)

The single-dose study does not reflect repeated use, higher doses or combination with other stimulants and exercise¹⁰. Analyses of sports and weight-loss supplements have repeatedly found stimulants that were not declared, or quantities different from the label²¹⁶.

DMHA (2-aminoisoheptane, octodrine) and DMBA

The research concerns detection of these stimulants in supplements, not their effects. Analyses of sports and weight-loss supplements have repeatedly found stimulants that were not declared, or quantities different from the label²¹⁶.

Higenamine

Published research concerns supplement analysis rather than effects in humans³.

Yohimbine (yohimbe bark, rauwolscine)

Evidence for fat loss or performance is limited to small studies. Supplement labels are often inaccurate: of 49 US yohimbine supplements tested, only 2 gave accurate information on both the quantity and the known adverse effects¹⁷.

Caffeine

Responses vary widely between people, partly because of genetics and habitual caffeine use. Many studies use pure caffeine, so results do not automatically apply to multi-ingredient products⁴.

Synephrine (bitter orange, Citrus aurantium)

Most studies are small, short and use multi-ingredient products, and longer studies are needed to establish efficacy and safety⁵.

L-tyrosine

Most studies are small and use single doses in laboratory settings⁶.

Theacrine (TeaCrine®) and theobromine

Studies are few, small and often industry-funded¹².

L-citrulline and citrulline malate

Studies differ in dose, form (citrulline or citrulline malate, often with an unverified ratio) and exercise test, and many are small. The mechanism behind any performance effect is not established⁷.

Vitamin B12 (cobalamin)

Extra benefit beyond correcting low status is not established.

Vitamin D3 (cholecalciferol)

Benefits are clearest for correcting deficiency. Trials in people with adequate vitamin D status show little benefit for bone, cancer or heart outcomes¹⁴¹⁵.

DMAA (1,3-dimethylamylamine)

DMAA is a potent pressor agent. Cases of cerebral haemorrhage have been reported in adults after using DMAA¹.

DMHA (2-aminoisoheptane, octodrine) and DMBA

Human safety data are lacking. As a sympathomimetic amine, DMHA may raise heart rate and blood pressure; avoid combining it with other stimulants. Contaminated supplements have caused positive doping tests¹⁶.

Higenamine

As a β2-agonist, higenamine may raise heart rate and cause palpitations, and its safety at supplement doses has not been established³.

Yohimbine (yohimbe bark, rauwolscine)

A review of poison-centre cases found that adverse events with yohimbine products had more serious outcomes than average exposures, including rapid heart rate, anxiety, high blood pressure and agitation¹⁸. People with heart conditions, high blood pressure, anxiety disorders or taking antidepressants should not use yohimbine.

Caffeine

EFSA concluded that single doses of up to 200 mg, and daily intakes of up to 400 mg from all sources, do not raise safety concerns for healthy adults. For pregnant and breastfeeding women, daily intakes up to 200 mg do not raise concerns for the foetus or infant¹⁹.

Higher intakes can cause anxiety, sleep disturbance, raised heart rate and blood pressure, and digestive upset. Combining several caffeine sources (coffee, energy drinks, pre-workouts) raises total intake¹⁹⁴.

Synephrine (bitter orange, Citrus aurantium)

The reviewed studies did not report serious adverse effects at the doses tested⁵, but combining synephrine with caffeine and other stimulants increases cardiovascular stress. People with high blood pressure, heart-rhythm disorders or taking stimulant or antidepressant medication should avoid it.

L-tyrosine

People taking MAO inhibitors or thyroid medication should not use tyrosine supplements without medical advice.

Theacrine (TeaCrine®) and theobromine

Combined with caffeine and other stimulants, these compounds add to the overall stimulant load¹⁹.

L-citrulline and citrulline malate

Citrulline is generally well tolerated in the doses studied. Digestive discomfort has been reported, and people taking blood-pressure or erectile-dysfunction medication should ask a doctor, because citrulline raises arginine and nitric oxide production⁷.

Vitamin B12 (cobalamin)

No tolerable upper intake level has been set, and adverse effects of high oral intakes have not been established²⁰.

Vitamin D3 (cholecalciferol)

EFSA set a tolerable upper intake level of 100 µg (4000 IU) a day for adults, based on persistent hypercalciuria (excess calcium in the urine) as an early sign of excess vitamin D²¹. Long-term intakes above this level can raise blood calcium and harm the kidneys. High-dose products should only be used on medical advice.

Contains 1,3-dimethylamylamine (DMAA), a synthetic stimulant that is not authorised as a novel food in the EU and is on the WADA Prohibited List. Contains DMHA/DMBA, a synthetic stimulant that is not authorised as a novel food in the EU. Contains higenamine and/or octopamine, which are on the WADA Prohibited List. Contains yohimbine. Isolated yohimbine is classified as a medicinal substance in several EU member states; its legal status depends on the country of sale.

DMAA (1,3-dimethylamylamine)

DMAA is not authorised as food or as a food supplement ingredient in the EU²² and is prohibited in competition by the World Anti-Doping Agency²²³.

DMHA (2-aminoisoheptane, octodrine) and DMBA

DMHA and DMBA are not authorised as novel foods in the EU²². Octodrine and related stimulants are prohibited in competition by the World Anti-Doping Agency¹⁶²³.

Higenamine

Higenamine is not an authorised food supplement ingredient in the EU²² and is prohibited at all times by the World Anti-Doping Agency as a β2-agonist¹⁶²³.

Yohimbine (yohimbe bark, rauwolscine)

Yohimbine is a pharmacologically active substance. Its use in food is regulated under Regulation (EC) No 1925/2006 and national rules²⁴, and several EU Member States treat it as a medicinal substance²⁵.

Caffeine

Caffeine is permitted in EU foods and food supplements, subject to labelling rules. It is not on the World Anti-Doping Agency Prohibited List²³.

Synephrine (bitter orange, Citrus aurantium)

Bitter orange extracts are used in EU food supplements under national rules, which differ between Member States²⁶.

L-tyrosine

Amino acids such as L-tyrosine are used in EU food supplements under national rules. No health claim is authorised¹³.

Theacrine (TeaCrine®) and theobromine

Theacrine is not an authorised novel food in the EU²²; theobromine occurs naturally in cocoa. No health claim for this ingredient is authorised in the EU¹³; botanical ingredients are sold under national food-supplement rules²⁶.

L-citrulline and citrulline malate

L-citrulline is used in EU food supplements under national rules. No health claim for citrulline is authorised in the EU¹³.

Vitamin B12 (cobalamin)

It is a permitted nutrient in EU food supplements²⁶; authorised claims may only be used in their approved wording and when the product is at least a source of the nutrient¹³.

Vitamin D3 (cholecalciferol)

It is a permitted nutrient in EU food supplements²⁶; authorised claims may only be used in their approved wording and when the product is at least a source of the nutrient¹³.