In 2011, Health Canada determined that 1,3-DMAA should be considered a drug and should not allowed to be included in dietary supplements [11]. In 2013, the FDA declared products containing 1,3-DMAA to be illegal and to have potential health risks [12]. 1,3-DMAA has been included on the prohibited lists of the World Anti-Doping Agency (WADA) and the U.S. Department of Defense (DoD) for over 10 years now [13].

Most of the severe adverse effects related to bitter orange are associated with its use in combination products. Hypertension and tachycardia are the most common adverse effects reported with bitter orange-containing products, particularly in combination with caffeine and/or other stimulant ingredients. Other adverse effects reported with the use of bitter orange or synephrine-containing multi-ingredient products, with or without other stimulants, include blackout, cardiac arrest, collapse, ischemic stroke, myocardial infarction, QT prolongation, tachyarrhythmia, tachycardia, variant angina, ventricular fibrillation, and death [20].

Most of the severe adverse effects related to bitter orange are associated with its use in combination products. Hypertension and tachycardia are the most common adverse effects reported with bitter orange-containing products, particularly in combination with caffeine and/or other stimulant ingredients. Other adverse effects reported with the use of bitter orange or synephrine-containing multi-ingredient products, with or without other stimulants, include blackout, cardiac arrest, collapse, ischemic stroke, myocardial infarction, QT prolongation, tachyarrhythmia, tachycardia, variant angina, ventricular fibrillation, and death [20].

Caffeine is also available alone or in combination with other ingredients in some prescription and OTC products that are approved for specific medical uses (e.g., to help restore mental alertness and wakefulness when experiencing fatigue or drowsiness). Caffeine tablets contain up to 200 mg of caffeine [25].

Caffeine has been demonstrated to improve athletic performance. It decreases perceived levels of exertion, enabling athletes to feel less tired and increase their performance. It can also improve anaerobic exercise performance [21]. National Collegiate Athletic Association (NCAA) lists caffeine as a banned substance, prohibiting urine concentrations above 15 mcg/mL during competition [26,27]., Reaching this threshold typically requires ingesting approximately 500 mg of caffeine, roughly six to eight cups of coffee, two to three hours before an event [26,28]. While the International Olympic Committee and the World Doping Agency (WADA) removed caffeine from their list of banned substances in 2004, WADA continues to monitor its use [29].

While most Ephedra species contain ephedrine alkaloids, Mormon tea (Ephedra nevadensis or Ephedra viridis) is a plant in the Ephedra genus that is devoid of ephedrine and other alkaloids [41]. Some other plants also contain ephedrine alkaloids, including Sida cordifolia and Pinellia ternate [42,43].

Senna is the fruit (pod) or leaf of the plant Senna alexandrina. Senna contains sennosides, which are high molecular weight dianthrone glycosides [58]. Because sennosides are prodrugs, they are not absorbed in the gastrointestinal (GI) tract and are instead activated by enzymes in the colon. The cathartic properties of the senna leaf are greater than the fruit. Effects usually occur within 6 to 10 hours after oral administration, primarily by increasing colon motility. This occurs through selective action on the nerve plexus of the intestinal smooth muscle, stimulating contractions and promoting bowel movements [58].

Stimulant laxatives can cause abdominal pain and discomfort, bloating, cramping, diarrhea, faintness, flatulence, fecal urgency, and nausea. Use of laxatives at high doses and for long periods might be unsafe. Abuse of laxatives can cause fluid and electrolyte, particularly potassium, losses. Theoretically, this can increase the risk for arrhythmias. There is also a risk of malabsorption as a result of intestinal hypermotility [58,60].

Several chemically related analogs of GHB, including gamma butyrolactone (GBL) and 1,4-butanediol (BD), are rapidly converted to GHB in the body and have similar effects to the parent compound [69]. Popularity of these analogs increased with the regulatory restriction of GHB as a Schedule I controlled substance. These analogs are legally available as industrial solvents, but are also sold illicitly as supplements for bodybuilding, weight loss, reversal of baldness, drug addiction, and other uses. GBL and BD are abused for the same reasons as GHB. Routine toxicologic screens do not detect the presence of these analogs, so abuse can be difficult to identify [76].

Kratom contains the mu-opioid receptor agonist, 7-hydroxymitragynine. 7-Hydroxymitragynine is estimated to be approximately 10 times as potent as morphine [99,101].