Multi-ingredient, caffeine-containing dietary supplements: history, safety, and efficacy

Clin Ther. 2015 Feb 1;37(2):275-301. doi: 10.1016/j.clinthera.2014.08.012. Epub 2014 Sep 26.


Purpose: Our objective was to review the history, safety, and efficacy of caffeine-containing dietary supplements in the United States and Canada.

Methods: PubMed and Web of Science databases (1980-2014) were searched for articles related to the pharmacology, toxicology, and efficacy of caffeine-containing dietary supplements with an emphasis on Ephedra-containing supplements, Ephedra-free supplements, and energy drinks or shots.

Findings: Among the first and most successful dietary supplements to be marketed in the United States were those containing Ephedra—combinations of ephedrine alkaloids, caffeine, and other phytochemicals. A decade after their inception, serious tolerability concerns prompted removal of Ephedra supplements from the US and Canadian markets. Ephedra-free products, however, quickly filled this void. Ephedra-free supplements typically contain multiple caffeine sources in conjunction with other botanical extracts whose purposes can often be puzzling and their pharmacologic properties difficult to predict. Ingestion of these products in the form of tablets, capsules, or other solid dosage forms as weight loss aids, exercise performance enhancers, or energy boosters have once again brought their tolerability and efficacy into question. In addition to Ephedra-free solid dosage forms, caffeine-containing energy drinks have gained a foothold in the world market along with concerns about their tolerability.

Implications: This review addresses some of the pharmacologic and pharmaceutical issues that distinguish caffeine-containing dietary supplement formulations from traditional caffeine-containing beverages. Such distinctions may account for the increasing tolerability concerns affiliated with these products.

Keywords: Ephedra; Ephedra-free; caffeine; dietary supplements; energy drinks.

Publication types

  • Historical Article
  • Review

MeSH terms

  • Alkaloids / adverse effects
  • Caffeine / adverse effects
  • Caffeine / pharmacology*
  • Canada
  • Central Nervous System Stimulants / adverse effects
  • Central Nervous System Stimulants / pharmacology*
  • Dietary Supplements* / adverse effects
  • Dietary Supplements* / history
  • Drug Combinations
  • Energy Drinks* / adverse effects
  • Energy Drinks* / history
  • Ephedra / adverse effects
  • Ephedra / chemistry
  • Ephedrine / chemistry
  • History, 20th Century
  • Humans
  • Safety-Based Medical Device Withdrawals
  • United States


  • Alkaloids
  • Central Nervous System Stimulants
  • Drug Combinations
  • Caffeine
  • Ephedrine