Chemical Composition and Labeling of Substances Marketed as Selective Androgen Receptor Modulators and Sold via the Internet

Key Points

Question  What types and quantity of ingredients are found in products sold through the internet and advertised to contain selective androgen receptor modulators?

Findings  Chemical analyses of 44 products sold via the internet as selective androgen receptor modulators revealed that only 52% contained selective androgen receptor modulators and another 39% contained another unapproved drug. In addition, 25% of products contained substances not listed on the label, 9% did not contain an active substance, and 59% contained substance amounts that differed from the label.

Meaning  Selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration, were available through the internet and were inaccurately labeled.

Importance  Recent reports have described the increasing use of nonsteroidal selective androgen receptor modulators, which have not been approved by the US Food and Drug Administration (FDA), to enhance appearance and performance. The composition and purity of such products is not known.

Objective  To determine the chemical identity and the amounts of ingredients in dietary supplements and products marketed and sold through the internet as selective androgen receptor modulators and compare the analyzed contents with product labels.

Design and Setting  Web-based searches were performed from February 18, 2016, to March 25, 2016, using the Google search engine on the Chrome and Internet Explorer web browsers to identify suppliers selling selective androgen receptor modulators. The products were purchased and the identities of the compounds and their amounts were determined from April to August 2016 using chain-of-custody and World Anti-Doping Association–approved analytical procedures. Analytical findings were compared against the label information.

Exposures  Products marketed and sold as selective androgen receptor modulators.

Main Outcomes and Measures  Chemical identities and the amount of ingredients in each product marketed and sold as selective androgen receptor modulators.

Results  Among 44 products marketed and sold as selective androgen receptor modulators, only 23 (52%) contained 1 or more selective androgen receptor modulators (Ostarine, LGD-4033, or Andarine). An additional 17 products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-δ agonist GW501516, and the Rev-ErbA agonist SR9009. Of the 44 tested products, no active compound was detected in 4 (9%) and substances not listed on the label were contained in 11 (25%). In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products (59%).

Conclusions and Relevance  In this limited investigation involving chemical analyses of 44 products marketed as selective androgen receptor modulators and sold via the internet, most products contained unapproved drugs and substances. Only 52% contained selective androgen receptor modulators and many were inaccurately labeled.

Quiz Ref IDAnabolic steroids are the most frequently abused appearance- and performance-enhancing drugs.^1-3 Use of these drugs was largely limited to athletes prior to the 1980s, but since then use of these substances has increased among men with the goal of building muscle and appearing lean and muscular.^1,3 Selective androgen receptor modulators (ligands that bind to the androgen receptor and exert tissue-selective effects such as muscle growth⁴) have emerged as the new appearance- and performance-enhancing substances; however, the extent of product use is unknown. Several oral nonsteroidal selective androgen receptor modulators^4,5 are under development for treating functional limitations associated with aging or muscle wasting disorders, but none has been approved by the US Food and Drug Administration (FDA).

In response to reports of increased use of nonsteroidal selective androgen receptor modulators purchased through the internet by athletes, recreational bodybuilders, and members of the US armed forces,^6,7 a systematic investigation of the availability of products marketed as selective androgen receptor modulators through the internet was conducted. In addition, the chemical identity of the products sold as selective androgen receptor modulators and the amount of the compound in the product were determined by chemical analysis and compared with the label information.

Selective androgen receptor modulator products were found by conducting web-based searches from February 18, 2016, to March 25, 2016, using the Google search engine on the Chrome and Internet Explorer web browsers and the search terms SARMs Supplements, SARMs, selective androgen receptor modulators, and buy. The products purchased were typically supplied as capsules, tablets, or syrups in sealed containers.

From time of receipt, the product samples were subjected to rigorous chain-of-custody procedures similar to those used during acquisition of biological samples from athletes being tested for banned substances. Records of the chain of custody were maintained and the samples were stored in secured areas.

The products were tested between April 2016 and mid-August 2016. The extraction, screening, and confirmation (additional details appear in the Supplement) were performed using procedures⁸ that have been approved by the World Anti-Doping Agency (WADA) for detecting the use of banned substances by athletes. Briefly, the equivalent of 1 serving of the product was extracted when that information was provided by the supplier; otherwise, 1 capsule or 1000 μL of solution was extracted.

The product contents were subjected to both targeted and untargeted analysis. In the targeted analysis, the mass-spectrometric precursor to the fragment transitions specific to the compounds of interest were monitored at the known retention times for the compounds to provide the highest degree of sensitivity in detecting their presence. In the untargeted analysis, full mass-spectrometric scans were acquired with and without molecular fragmentation across the full chromatogram to allow detection of all ionizing species (ie, without predefining which molecular masses to identify). The mass-spectrometric data were acquired with high mass accuracy (mass error of <10 ppm) and at high resolution (35 000 Da) to enable determination of the candidate molecular formulas for the detected masses.

Initially, the compounds were tested using general-purpose screenings meeting all the requirements set forth by WADA for detecting the use of performance-enhancing drugs by athletes.⁹ If no banned substances were detected in the general-purpose screening, further analyses were performed using untargeted screenings as described above. The use of general-purpose screening procedures enabled detection of additional performance-enhancing drugs other than selective androgen receptor modulators.

When the screening analysis revealed a selective androgen receptor modulator or another performance-enhancing substance, the findings were confirmed by more specific methods and reference materials for comparison of the characteristics from mass-spectral fragmentation. WADA-specified criteria were used for positive identification of compounds.^8,9 The amount of compound was estimated based on comparison of the response with those obtained from standards containing known quantities.

The analytical methods have an estimated intra-assay coefficient of variation of 20% and an interassay coefficient of variation of 20%. Label claims were considered to match the experimentally measured values when they were within the estimated uncertainty windows of the analyses. We compared the compounds found in the product and their amounts with the product label.

Internet searches yielded 210 products from 51 supplier sites offering selective androgen receptor modulators and other muscle-building compounds (Figure 1). Of these, 45 products could not be purchased due to insufficient information on the websites, and 121 products could not be obtained because they were out of stock, discontinued, or had other restrictions. Forty-four products purchased from 21 suppliers were analyzed (Figure 2 and Table). The number of products purchased from various suppliers ranged from 1 to 5.

Some companies used the term SARM in their product label or in advertising, even though the product was not a selective androgen receptor modulator (eg, growth hormone secretagogue ibutamoren) (Figure 2). Of the 44 purchased products, the following compounds were listed on the labels: Ostarine (also known as enobosarm, GTx-024, MK-2866, S-22, and S22), Andarine (also known as GTx-007), LGD-4033 (also known as Ligandrol), RAD140 (also known as Testolone), ibutamoren (also known as MK-677, L163,191), GW501516 (also known as Cardarine, Endurobol, GSK-516, and GW1516), and SR9009 (also known as Stenabolic).

Figure 2 shows the most common compounds detected in the 44 products. Selective androgen receptor modulators, peroxisome proliferator-activated receptor-δ (PPAR-δ) agonists, and growth hormone secretagogues were the 3 most frequently found classes of compounds among those tested. Selective androgen receptor modulators accounted for 23 of the 44 tested compounds (52%). Ostarine and LGD-4033 were found in more than 80% of selective androgen receptor modulator products. The PPAR-δ agonist GW501516 was the second most frequently found compound, and the growth hormone secretagogue ibutamoren was the third most common.

In only 18 of the 44 products (41%), the amount of active compound in the product matched that listed on the label. In 11 products (25%), the listed compound was detected, but in an amount that differed from the label (Table and Figure 1). In 8 products (18%), the compound listed on the label was not found; however, different compounds not listed on the label were found. Three products (7%) contained the amount listed on the label but also contained an additional compound not listed. Four products contained minimal amounts of the selective estrogen receptor modulator tamoxifen. In another 4 products (9%), no active compounds were detected.

The amount of the compounds listed on the label differed substantially from that found by analysis in 26 of 44 products (59%). Seventeen products (39%) contained another unapproved drug, including the growth hormone secretagogue ibutamoren, the peroxisome proliferator-activated receptor-δ agonist GW501516, and the Rev-ErbA agonist SR9009. None of the 5 products purchased from 1 supplier contained the compounds listed on the label (Table). In 2 of 5 products obtained from this supplier, the analyses detected banned substances not listed on the label.

Of the 44 products, 20 (45%) were sold as dietary supplements and contained Supplement Fact panels on their labels. No product label included a Drug Fact panel. There were 24 products (55%) labeled as being for research use only, not for human consumption, or both (Table). The retail cost, product form (capsules or solution), and contents (quantity or solution volume) appear in the Table.

Quiz Ref IDThis limited investigation found that products containing investigational selective androgen receptor modulators and other performance-enhancing drugs not approved by the FDA can be purchased from internet sites without a prescription. Although the tested products were advertised as selective androgen receptor modulators, some products contained growth hormone secretagogues,¹⁰ PPAR-δ agonists,¹¹ and Rev-ErbA agonists,¹² all of which are recognized by WADA as banned substances.¹³ Neither the efficacy nor the safety of these investigational drugs has been demonstrated. For many products, the ingredients and their amounts found in these analyses did not match the label information. These findings suggest the need for greater regulatory oversight of products sold on the internet.

Most tested products were investigational drugs that have not received FDA approval. The FDA requires all drugs to have an approved application for continued marketing.^14,15 Such approval from the FDA requires demonstration of safety and efficacy.¹⁵ Some compounds such as Ostarine,¹⁶ Andarine, LGD4033,⁶ and ibutamoren¹⁰ have undergone some human studies, but have not received FDA approval. The development of GW501516¹⁷ was halted because of safety concerns. Preclinical studies have occurred for SR9009, but no human trials. Quiz Ref IDInternet sales of drugs that are not approved by the FDA and whose benefits and safety have not been demonstrated raise public safety concerns. Individuals who use these products generally do not disclose the use of these products to their physicians; furthermore, clinicians do not have ready access to information about the contents and safety of such unapproved products, further increasing the health risk to the user.

The Fair Packaging and Labeling Act¹⁴ requires consumer products to be labeled to disclose the contents and the product identity.⁸ For drugs, a listing of drug facts with potential adverse effects and guidelines for safe use are required.¹⁸ Of the products tested, some did not contain the compound listed on the label and others contained amounts that differed substantially from the label. Nearly one-quarter of tested products contained compounds not included on the label, and some included a mixture of 2 or more compounds.

Quiz Ref IDNearly half the products were marketed as dietary supplements. The FDA defines dietary supplements as products taken by mouth that contain a “dietary ingredient” such as vitamins, minerals, amino acids, and herbs or botanicals that can be used to supplement the diet.¹⁹ None of the tested compounds meets the definition of a dietary supplement.

Antidoping agencies have identified cases of doping with selective androgen receptor modulators by athletes.²⁰ Contamination of dietary supplements by anabolic steroids also has been reported.²¹ This investigation demonstrates the ease with which unapproved appearance- and performance-enhancing drugs can be purchased over the internet, which could increase abuse by adolescents, military personnel, and recreational weightlifters.

Quiz Ref IDIn addition, the ability of small laboratories located inside and outside the United States to synthesize and package pharmaceutical agents has contributed to the ease of global purchasing of these compounds. Vendors easily disseminate information about the products to potential users via the internet. The ease of website creation makes it possible for suppliers to create and remove websites as often as needed to stay ahead of law enforcement, regulators, and posted reviews from users who experienced adverse effects.

This investigation has several strengths. Rigorous testing procedures, which are similar to those used to detect banned substances in the WADA-certified testing program, were used for the analyses of these compounds. The chain of custody was recorded and products were stored in secure locations. The sensitivity of these procedures enabled detection of even small quantities of compounds.

This study has several limitations. Because all possible internet sites were not searched, this search should not be viewed as exhaustive. It is possible that additional appearance- and performance-enhancing substances are being sold on the internet as selective androgen receptor modulators. The results apply only to the products purchased. Therefore, these findings should not be viewed as representative of all products sold through internet sites because the sample is limited to a single point in purchase time. Because of the rapidly changing nature of such internet sites, the results of similar searches will vary.

In this limited investigation involving chemical analyses of 44 products marketed as selective androgen receptor modulators and sold via the internet, most products contained unapproved drugs and substances. Only 52% contained selective androgen receptor modulators and many were inaccurately labeled.

Corresponding Author: Shalender Bhasin, MB, BS, Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital, 221 Longwood Ave, Boston, MA 02115 (sbhasin@bwh.harvard.edu).

Accepted for Publication: October 20, 2017.

Correction: This article was corrected on February 20, 2018, to add conflict of interest disclosures to the existing disclosures for Dr Bhasin.

Author Contributions: Drs Van Wagoner and D. Eichner had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Van Wagoner, A. Eichner, Bhasin, D. Eichner.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Van Wagoner, A. Eichner, Bhasin, D. Eichner.

Statistical analysis: D. Eichner.

Obtained funding: D. Eichner.

Administrative, technical, or material support: Bhasin, D. Eichner.

Supervision: A. Eichner, Bhasin, Deuster, D. Eichner.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bhasin reported receiving investigator-initiated research grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Child Health and Human Development, the National Institute on Aging, the National Institute of Nursing Research, Abbott, Ligand, Transition Therapeutics, Regeneron, Novartis, Althea, Biosensics, Merck, AbbVie, Transition Therapeutics, Metro International Biotechnology, and Takeda Pharmaceuticals (these grants were managed by the Brigham and Women’s Hospital); receiving consulting fees from AbbVie, Novartis, Sanofi, and Regeneron; owning an equity interest in FPT LLC; serving as the chair of the Endocrine Society’s expert panel that developed guideline for testosterone therapy of androgen deficiency in men; and serving on the American Board of Internal Medicine Endocrinology Board’s examination writing committee from 2006 to 2015 and as this committee’s chair from 2011 to 2015. No other disclosures were reported.

Funding/Support: This project was partially funded by Defense Health Program grant HT9404-13-1-0017 (primary investigator: Dr Deuster) through the Henry M. Jackson Foundation for the Advancement of Military Medicine to the US Anti-Doping Agency (primary investigator: Dr A. Eichner).

Role of the Funder/Sponsor: The Henry M. Jackson Foundation for the Advancement of Military Medicine had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The opinions or assertions expressed are the private views of the authors and are not to be construed as official or as reflecting the views of the Uniformed Services University or the US Department of Defense.