Mexidol, Cytoflavin, and succinic acid derivatives as antihypoxic, anti-ischemic metabolic modulators, and ergogenic aids in athletes and consideration of their potential as performance enhancing drugs.

Emoxypine (ethylmethylhydroxypyridine) is a synthetic derivative of vitamin B6 . Emoxypine succinate is a registered drug in Russia and Ukraine under various trade names including Mexidol, Mexicor, and Armadin Long. Mexidol demonstrates antihypoxic and anti-ischemic effects and also modulates metabolism. The use of Mexidol by Russian athletes has been confirmed in the past. Current use by athletes is unknown as this drug is not monitored or included in drug testing protocol. Metabotropic and antihypoxic effects of Mexidol were compared to the effects of meldonium or trimetazidine, both of which are included on the World Anti-Doping Agency (WADA) Prohibited List in category S4.4. Metabolic Modulators. The conjugation of emoxypine with succinate elevates the therapeutic effectiveness of the Mexidol formulation as succinic acid itself has important impacts to consider despite being a common food additive and drug excipient. Other succinic acid salts like ammonium succinate, found as dietary supplement, have been patented as performance enhancers. Available research on healthy subjects suggests that combinations of selected 3-substituted pyridine derivatives with succinate including Mexidol and a related drug Cytoflavin can enhance the performance of athletes. Cytoflavin is a multi-component formula containing meglumine sodium succinate, nicotinamide (vitamin B3 ), inosine (riboxin), and riboflavin. Other related succinate-based drugs include Remaxol, Reamberin, and Cogitum. Mexidol and Cytoflavin and related substances exhibit similar biological effects as drugs on the WADA Prohibited List, and if they are used for performance enhancement by athletes, they could be worthy of consideration as prohibited substances in sport.

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.