Unauthorized ingredients in "nootropic" dietary supplements: A review of the history, pharmacology, prevalence, international regulations, and potential as doping agents.

The first nootropic prohibited in sport was fonturacetam (4-phenylpiracetam, carphedon) in 1998. Presented here 25 years later is a broad-scale consideration of the history, pharmacology, prevalence, regulations, and doping potential of nootropics viewed through a lens of 50 selected dietary supplements (DS) marketed as "cognitive enhancement," "brain health," "brain boosters," or "nootropics," with a focus on unauthorized ingredients. Nootropic DS have risen to prominence over the last decade often as multicomponent formulations of bioactive ingredients presenting compelling pharmacological questions and potential public health concerns. Many popular nootropics are unauthorized food or DS ingredients according to the European Commission including huperzine A, yohimbine, and dimethylaminoethanol; unapproved pharmaceuticals like phenibut or emoxypine (mexidol); previously registered drugs like meclofenoxate or reserpine; EU authorized pharmaceuticals like piracetam or vinpocetine; infamous doping agents like methylhexaneamine or dimethylbutylamine; and other investigational substances and peptides. Several are authorized DS ingredients in the United States resulting in significant global variability as to what qualifies as a legal nootropic. Prohibited stimulants or ß2-agonists commonly used in "pre-workout," "weight loss," or "thermogenic" DS such as octodrine, hordenine, or higenamine are often stacked with nootropic substances. While stimulants and ß2-agonists are defined as doping agents by the World Anti-Doping Agency (WADA), many nootropics are not, although some may qualify as non-approved substances or related substances under catch-all language in the WADA Prohibited List. Synergistic combinations, excessive dosing, or recently researched pharmacology may justify listing certain nootropics as doping agents or warrant additional attention in future regulations.