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

Abstract

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.

Annual banned‐substance review 16th edition—Analytical approaches in human sports drug testing 2022/2023

“…91 The analytes exhibited molecular masses of 3.8 and 4.2 kDa, respectively, and the extraction from plasma was shown to be particularly efficient when combining protein precipitation with subsequent mixed-mode cation-exchange SPE. LODs were determined with 0.5 ng/mL, and by means of isotope-labeled reporter ion screening using 13…”

“…More than 50% of the study participants declared the use of dietary supplements, 9,10 and data suggest that such dietary supplement use is, to some extent, also a gateway to the use of prohibited performance enhancing substances. 11,12 Besides, the issue of contaminated and adulterated dietary supplements resulting in AAFs during doping controls still exists, both in manufactured and compounded products, 13,14 which substantially increases the risk of AAFs and ADRVs as well as health issues as recently outlined by Pascali et al 15 and Tran et al 16 Advancing test methods for doping controls is vital for modern sports drug testing programs, 17 as demonstrated by attributable effects and impact 18 as well as their implementation into routine application at major sporting events. 19,20 Research aiming at facilitating such advances are commonly aligned with the World Anti-Doping Agency's (WADA's) Prohibited List 21 and its 11 classes of banned substances (S0-S9 plus P1) and three categories of prohibited methods (M1-M3) (Table 1).…”

“…More than 50% of the study participants declared the use of dietary supplements, 9,10 and data suggest that such dietary supplement use is, to some extent, also a gateway to the use of prohibited performance enhancing substances 11,12 . Besides, the issue of contaminated and adulterated dietary supplements resulting in AAFs during doping controls still exists, both in manufactured and compounded products, 13,14 which substantially increases the risk of AAFs and ADRVs as well as health issues as recently outlined by Pascali et al 15 and Tran et al 16 …”

Adulteration of Brain Health (Cognitive, Mood, and Sleep Enhancement) Food Supplements by the Addition of Pharmaceutical Drugs: A Comprehensive Review of Analytical Approaches and Trends

“…Among those, PFS advertised for cognitive enhancement, as they contain nootropic plants as ingredients, have risen in prominence worldwide, and their possible adulteration has been highlighted by different studies [ 52 ]. The direct use of nootropic substances, such as the pharmaceutical stimulant Adderall, is known to occur by a variety of consumers, including students, the military, and night-shift workers, who seek increasing concentration and focus, performance enhancement, and fatigue reduction [ 53 ]. Among college students, studies have reported the illegal use of compounds such as modafinil and methylphenidate, which were developed to treat disorders such as attention deficit, narcolepsia, and/or dementia-like diseases, and even illegal compounds, such as cocaine and amphetamines [ 54 ].…”

“…Besides PFS used for cognitive enhancement, other supplements used for different purposes but also related to brain activity, such as mood or sleep improvement, are also increasingly available in the market. Altogether, the global market for brain health supplements was estimated at USD 8.2 billion in 2022 and is expected to grow to more than USD 15 billion by 2030 [ 53 ]. As far as the literature consulted, data on the consumption prevalence of supplements to improve mood or sleep are still scarce or non-existent.…”