Systematic Review of Safety of Selective Androgen Receptor Modulators in Healthy Adults: Implications for Recreational Users

Abstract

Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI.

Full text

Citation: Vignali, J.D.; Pak, K.C.;
Beverley, H.R.; DeLuca, J.P.; Downs,
J.W.; Kress, A.T.; Sadowski, B.W.;
Selig, D.J. Systematic Review of
Safety of Selective Androgen
Receptor Modulators in Healthy
Adults: Implications for Recreational
Users. J. Xenobiot. 2023,13, 218–236.
https://doi.org/10.3390/jox13020017
Academic Editor: Francisco Esteves
Received: 24 March 2023
Revised: 5 May 2023
Accepted: 8 May 2023
Published: 10 May 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Systematic Review
Systematic Review of Safety of Selective Androgen Receptor
Modulators in Healthy Adults: Implications for
Recreational Users
Jonathan D. Vignali 1, Kevin C. Pak 2, Holly R. Beverley 3, Jesse P. DeLuca 4, John W. Downs 5, Adrian T. Kress 4,
Brett W. Sadowski 2and Daniel J. Selig 4,*
1Behavioral Biology Branch, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
2Department of Gastroenterology, Naval Medical Center San Diego, San Diego, CA 92134, USA
3Gorgas Memorial Library, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
4Clinical Pharmacology Fellowship, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA
5Department of Toxicology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
*Correspondence: daniel.j.selig.mil@health.mil; Tel.: +1-301-319-9000
Abstract:
Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining
SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recre-
ational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise
serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus,
Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs.
A multi-tiered screening approach was utilized, and any study or case report of generally healthy
individuals exposed to any SARM was included. Thirty-three studies were included in the review
with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed
to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles
tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (
N=1
).
Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed
to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were
reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and
the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite
warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may
improve early detection and prevention of DILI.
Keywords:
athlete; drug-induced liver injury; drug safety; recreation; selective androgen receptor
modulator; tendon rupture
1. Introduction
Selective Androgen Receptor Modulators (SARMs) are non-steroidal compounds
with favorable oral bioavailability that were developed in the early 2000s in an attempt
to overcome the pharmacologic and pharmacokinetic limitations of steroidal androgen
receptor agonists (i.e., testosterone and DHT), which have known associations with liver
and heart disease [
1
]. SARMs have been trialed as a pharmacologic intervention to improve
a wide variety of conditions such as cancer-associated morbidity, deconditioning after hip
fracture, stress incontinence, and benign prostatic hyperplasia [
2
]. Solomon et al. provided
a comprehensive review of current clinical applications [
3
]. Despite a strong warning from
the Food and Drug Administration (FDA) [
4
], SARM abuse is increasingly popular amongst
recreational and professional athletes as a perceived means to improve performance [
5
].
The prevalence of SARM abuse is uncertain; however, estimates of the global lifetime
prevalence rate for use of anabolic-androgenic steroids are 3.3%, with a prevalence rate of
6.4% in males and 1.6% in females [
6
]. According to a British Army survey of 3168 soldiers
J. Xenobiot. 2023,13, 218–236. https://doi.org/10.3390/jox13020017 https://www.mdpi.com/journal/jox

J. Xenobiot. 2023,13 219
in training, 1.1% reported use of anabolic steroids, 2.0% reported use of growth hormone,
and 4.2% reported use of other anabolic-androgenic agents, with a strong association in
young soldiers [
7
]. According to a Department of Defense (DoD) Health-Related Behaviors
Survey in 2015, 4.1% of respondents reported use of anabolic steroids at least one or more
times in their life, with over 20% of steroid users reporting obtaining a prescription outside
of the military health system [
8
]. In the professional athletic setting, the World Anti-Doping
Agency (WADA) banned SARMs. However, despite the ban there was a rise in positive
tests for SARMs between 2015 and 2019 [
9
]. More recent social media trends have observed
a notable increase in searches and views regarding topics related to SARMs, particularly on
platforms such as TikTok, Reddit, and YouTube that include a relatively large portion of
adolescent and young adult populations [10].
In the years 2020–2022, there has been a rapid increase in the number of published
case reports of drug-induced liver injury (DILI) associated with SARM abuse [
11
–
13
]. There
have also been case reports of rhabdomyolysis and tendon rupture associated with SARM
abuse [
14
,
15
]. The mechanisms for these injuries remain unknown. However, Koller et al.
postulated that systemic accumulation of a multitude of metabolites with repeat SARM
dosing likely contribute to the development of a secondary immune response targeting the
liver [
16
]. Machek et al. provided a more comprehensive review on the possible mecha-
nisms of harmful effects of SARMs [
17
]. The growing popularity of SARMs, possibly due
to social media influence, rapid increase in reported serious adverse events associated with
SARM abuse, and general interest in performance-enhancing drugs amongst recreational
and professional athletes represents an emerging public health concern. Several of the DILI
case reports provide important insight into possible risk factors and mechanisms of DILI,
such as significantly increased doses taken compared with those taken in clinical trials and a
large number of SARM metabolites which may have deleterious effects [
11
,
16
,
18
]. However,
to our knowledge, there is currently no systematic review of the safety of SARMs in healthy
populations that reasonably extrapolate to the population of SARM abusers. Therefore,
we performed this systematic review of the safety of SARMs in healthy populations to
better describe the characteristics of SARM-associated DILI and compare safety data from
case reports with the clinical trials. This assists in generating safety signals and clinical
strategies to improve safety of SARM abusers and individuals considering SARM abuse.
2. Materials and Methods
2.1. Inclusion Criteria
The focus of this review is the implications of using SARMs for performance enhance-
ment in highly active and military populations. Therefore, any case report or study was
included if it provided sufficient clinical safety data and the patient population was gener-
ally healthy. Of note Padappayil et al. reported a case of myocarditis associated with SARM
use [
19
]. However, this case report was excluded due to confounding comorbidities in the
patient such as type 1 diabetes mellitus and substance use disorder requiring maintenance
buprenorphine therapy. The rationale for exclusion is further elaborated in the discussion.
Patient populations with cancer or chronic diseases were excluded as the risk-to-benefit of
SARM therapy changes greatly in those populations compared with healthy individuals.
Some chronic diseases present a wide spectrum of illness that studies may have included
or excluded depending on the disease severity of the population. For example, Mohan
et al. was excluded because the patient population studied had baseline severe chronic
obstructive lung disease (COPD) [
20
]. Papanicolaou et al. was included because sarcopenia
is an age-related loss of muscle mass, and the authors were careful to exclude patients with
any chronic disease or cancer [
21
,
22
]. Nash et al. performed a retrospective study finding
22 cases of DILI associated with androgenic-anabolic steroid (AAS), SARMs, and other body
building supplements [
23
]. The dataset in this study included 10 cases of SARM-associated
DILI. This study provided significant insight into AAS and SARM-related DILI; however,
it was not clear if the patients were exclusively taking SARMs or were taking multiple
compounds of different drug classes. Therefore, this study was excluded. No age limit

J. Xenobiot. 2023,13 220
was applied to the inclusion criteria as individuals of all ages may enjoy being active and
improving muscle strength and physical appearance.
2.2. Search Strategy
On 10 November 2022, PubMed, Scopus, Web of Science, and ClinicalTrials.gov were
searched for studies that reported safety data of SARMs in healthy individuals. This review
was registered in PROSPERO (CRD42022380525) and the PRISMA 2020 checklist was used
as a guide to perform, complete, and report the review. The search string utilized was
“(SARMs[Title/Abstract] OR Selective Androgen Receptor Modulators[Title/Abstract]
OR Ostarine OR Enobosarm OR GTX-024 OR MK2866 OR Andarine OR Ligandrol OR
LGD-4033 OR VK5211 OR LY2452473 OR TT-701 OR TT701 OR Testolone OR RAD140)”.
A total of 1225 titles were found across the databases (715 after duplicates removed)
and an additional 33 titles were found in ClinicalTrials.gov. Two investigators (DJS and
JWD) independently screened the titles and/or abstracts. Following this stage of review,
100 articles were identified that may have met inclusion criteria, of which 74 were retrieved.
Two investigators (JPD and ATK) independently screened the 74 full articles for inclusion
and disagreements were resolved by a single author (DJS) resulting in 29 studies included
from the databases. Clinicaltrials.gov was screened sequentially after the screening and
inclusion of studies from PubMed, Scopus, and Web of Science was complete. From
Clinicaltrials.gov, 13 studies in cancer populations, 4 studies with no SARM, 2 studies
terminated with no results (extension studies stopped after lack of efficacy found for Gx-
024 as a therapy for stress incontinence), 7 duplicate studies found in the other databases,
and 3 studies that met the inclusion criteria but had no results (NCT01538420, NCT01275157,
NCT03264651) were excluded. The PRISMA 2020 flow diagram summarizing the search
results is presented in the Supplementary Materials.
2.3. Data Collection, Analysis, and Safety Outcomes of Interest
All data were plotted and analyzed using R (version 4.2, R Foundation for Statistical
Computing, Vienna, Austria) and R Studio (version 2022.07.2 + 576, RStudio Team, Boston,
MA, USA). Data were collected by a single author (DJS) and reviewed by KCP. Studies were
categorized into case reports and clinical studies and are summarized in
Tables 1and 2
.
Data extracted from all studies, when available, were author, publication year, study design,
study population, number of subjects/patients, number of subjects/patients exposed
to SARM, the specific SARM, dose and schedule of SARM, gender age, weight, and
alcohol use.
Table 1. Summary of case reports.
Study Year Age
(Years) SARM Dose
(mg)
Duration
(Weeks)
Time from
Stopping to
Symptoms
(days)
Presenting
Symptoms Imaging Biopsy R Factor Treatmentand
Outcome
Baliss et al. [24] 2020 31 RAD-140 12
3 days of epigastric
pain, jaundice and
pruritis, scleral
icterus
MRI abdomen
normal
Labs
down-trended
after 1 month
Barbara et al. [11]2020 32 LGD-4033 10 2 1–7
diffuse itching,
jaundice, acholic
stool, intermittent
abdominal pain,
nausea, 40 lbs.
weight loss, scleral
icterus
US and
CT-hepatomegaly
MRCP,small
hepatic cyst and
splenomegaly,
otherwise normal
Cholestatic
hepatitis with
mild portal,
periportal,
perisinusoidal
fibrosis
Barbara et al. [18] 2020 52 RAD-140,
LGD-4033 17.86, 10 7 1–7
Right upper
quadrant pain,
pruritus, and greasy
diarrhea, scleral
icterus, jaundice
MRI abdomen
normal
Diffuse
centrilobular
canalicular
cholestasis,
mild portal
and periportal
fibrosis
0.2
Stop alcohol
consumption,
improvement
in labs at
3 months
Bittner et al. [25] 2020 34 LGD-4033 7.5 4 7
Decreased appetite,
worsening pruritus,
dark amber urine,
and cognitive
‘clouding’, jaundice,
scleral icterus
US normal. CT
abdomen–mild
splenomegaly
Inflammation
and diffuse
cholestasis

J. Xenobiot. 2023,13 221
Table 1. Cont.
Study Year Age
(Years) SARM Dose
(mg)
Duration
(Weeks)
Time from
Stopping to
Symptoms
(days)
Presenting
Symptoms Imaging Biopsy R Factor Treatmentand
Outcome
Flores et al. [26] 2020 24 LGD-4033 9 7
jaundice, anorexia,
nausea,
lethargy,5 kg weight
loss
US normal 8.22
Labs
normalized
after 4 months
Flores et al. [26] 2020 49 RAD-140 4 20–30 Jaundice and
itching
Moderate
cholestasis
with
ductopenia
and minimal
fibrosis
and
inflammation,
5
Ursodiol and
cholestyramine,
labs normalized
after 12 months
Bedi et al. [12]2021 40 Enobosarm 8
Jaundice, anorexia,
weight loss, lethargy,
and diarrhea, scleral
icterus
US, CT abdomen,
and MRCP normal
centrilobular
cholestasis
with
yellow-green
bile in
hepatocytes
and canaliculi
0.8
Improvement
in labs over
several months
of follow up
Gould et al. [14] 2021 36 Ostarine and
Carderine 8 35
Asynchronous
bilateral Achilles
tendon rupture after
two 4-week cycles of
SARM compounds
Kintz et al. [9] 2021 43 MK-2866,
Carderine 20, 20 0.7 10
Patient presented
with severe
rhabdomyolysis
after cycling
74.6 miles with
extreme elevations
of ALT,AST, and CK
Koller et al. [16] 2021 19 LGD-4033 7 0
Patient cycled
4 weeks on, 4 weeks
off. Restarted the
cycle for 3 weeks
and stopped after
noticing dark urine,
yellow
sclera, and thinner
light-colored stools
US
abdomen-normal
Mild septal
fibrosis,
canalicular
cholestasis in
the
hepatocytes
with
numerous
biliary plugs
3.9
1000 mg ur-
sodeoxycholic
acid (UDCA)
daily for 2 mo.
Labs
normalized
after 3 months
Koller et al. [16] 2021 28 LGD-4033,
Ostarine 0
For 3 months took
unknown amount of
SARM. After 3-week
break, a formulation
of SARM bought on
internet was taken
for 4 doses, reasons
for seeking medical
care unclear
MRI abdomen
hepatomegaly
without biliary
pathology
Mild bridging
fibrosis,
destruction of
bile ducts,
centrilobular
canalicular
cholestasis
with
numerous bile
plugs
3.3
300 mg
intravenous
N-acetyl
cysteine 4 times
daily,1000 mg
oral UDCA
daily,and
450 mg
silymarin daily.
Labs
significantly
improved at
3 months
Cardaci et al. [27] 2022 25 LGD-4033,
MK-677 10, 15 5
This was an efficacy
case report, no
SAE’s reported,
however, ALT
increased from
20 IU/L to 61 IU/L
after 5 weeks. The
ALT returned to
baseline after
4 weeks off SARM
Khan et al. [28] 2022 29 4
Jaundice, pruritus,
fatigue, scleral
icterus, light-colored
stools, dark urine
CT
abdomen-normal
Centrilobular
bile stasis
with
lipofuscin
pigment
along
with
collection of
neutrophils
within lobular
parenchyma
Labs
normalized by
6 months
Lee et al. [29] 2022 23
LGD-4033,
RAD-140,
YK11
12 7
Jaundice, scleral
icterus,
decrease in appetite,
and worsening
pruritis
MRI and MRCP
normal 0.8
Ursodeoxycholic
acid and
hydroxyzine,
labs normalized
within a year
Peranathan
et al. [30]2022 30 RAD-140 Jaundice and fatigue Unspecified image
normal
Acute
cholestasis
with
canalicular
bile
plugs,
without
evidence of
ductopenia
1.8
ursodeoxycholic
acid and
cholestyramine
down-trending
within
60–80 days

J. Xenobiot. 2023,13 222
Table 1. Cont.
Study Year Age
(Years) SARM Dose
(mg)
Duration
(Weeks)
Time from
Stopping to
Symptoms
(days)
Presenting
Symptoms Imaging Biopsy R Factor Treatmentand
Outcome
Peranathan
et al. [30]2022 43 RAD-140 Jaundice and fatigue Unspecified image
normal
Acute
cholestasis
with
canalicular
bile
plugs,
without
evidence of
ductopenia
2.3
ursodeoxycholic
acid and
cholestyramine
down-trending
within
60–80 days
Weinblatt
et al. [13]2022 31 Enobosarm 2 0 Itch and
dark-colored urine
US abdomen, fatty
liver, otherwise
normal
7.5
Cyproheptadine,
labs
significantly
improved after
7 days and
normalized at
10 month
follow up
Wallstab
et al. [31]2022 37 Ligandrol
(LGD-4033) 4 mg 8 60
Jaundice, pruritus,
anorexia, fatigue,
12 kg weight loss,
dark urine
U/S abdomen
ruled out
extrahepatic
cholestasis and
cholecystolithiasis
Fibroscan
showed fibrosis
10.7 ±2.3 kPa
Canalicular
cholestasis,
ductopenia,
Acute portal
hepatitis with
early
periportal
fibrosis
2.7
Ursodeoxycholic
acid and
cholestyramine,
Linimentum
Aquosum
ointment
Table 2. Summary of clinical trials.
Author Year Study Design SARM Study Population Study Arms and Total
Subjects Summary of Adverse Events
Marcantonio
et al. [32]2010
Randomized,
double-blind,
placebo-controlled,
parallel group
MK-3984 and
MK-2866
Healthy
postmenopausal
women
Placebo (N = 22)
MK-2866 3 mg daily
(N = 22)
MK-3984 50 mg daily
(N = 22)
MK-3984 125 mg daily
(N = 22)
Total exposed = 66
Total N = 88
7/44 subjects receiving the 50 mg
or 125 mg dose of MK-3984 had
ALT elevation > 3 ×ULN and
were discontinued from the study,
but no significant ALT elevation
was reported for the 3 mg dose of
MK-2866.
Meglasson
et al. [33]2010
Double-blind,
placebo-controlled
ascending single
dose
LGD-4033 Healthy adult males 0.1–22 mg No SAE’s reported.
Dalton
et al. [34]2011
Double-blind,
placebo-controlled
phase II trial
Enobosarm
Elderly men and
postmenopausal
women
Daily doses of placebo,
0.1, 0.3, 1, or 3 mg of
Enobosarm for 86 days.
(N = 24 per group, 50%
male and female)
Total Exposed = 96
Total N = 120
No SAE’s reported. ALT increased
in dose-dependent fashion (8 total
patients with 6 of 8 in highest
dose 3 mg group). In these
7 patients, ALT elevations
resolved while on drug. One
subject discontinued (3 mg dose)
due to ALT elevation of 4.2 X ULN
and returned to normal after drug
discontinuation. Dose-dependent
reduction in HDL.
Yi et al. [35] 2012
Pharmacokinetic
and Metabolism
Study
LY2452473 Healthy males
15 mg (N = 6)
Total Exposed N = 6
Total N = 6
No safety events reported.
Basaria
et al. [36]2013
Placebo-controlled
ascending single
and multiple dose
PK
LGD-4033 Healthy adult males
Placebo (N = 33)
0.1 mg (N = 18)
0.3 mg (N = 11)
1 mg (N = 14)
Total Exposed = 43
Total N = 76
No SAE’s, no study
discontinuation due to adverse
events, no clinically significant
changes in liver enzymes.
Dose-dependent reduction in
HDL but returned to baseline
25 days post-last dose.

J. Xenobiot. 2023,13 223
Table 2. Cont.
Author Year Study Design SARM Study Population Study Arms and Total
Subjects Summary of Adverse Events
Papanicolaou
et al. [21]2013
Randomized
placebo-controlled
efficacy and safety
MK-0773 Females with
sarcopenia
Placebo (N = 89)
MK-0773 50 mg BID
(N = 81)
Total Exposed N = 81
Total N = 170
13.5% (N = 23) of participants had
an AE possibly, probably or
definitely related to study therapy.
The most common AE leading to
discontinuation was an increase in
ALT (N = 5, 6.2%). This occurred
within 6–8 weeks and all ALT
returned to baseline with no
clinical sequelae after stopping
therapy. Hematocrit increases
>3% were significantly more
frequent in the MK-0773 group
compared with placebo. Trend
towards increased blood pressure
in MK-0773 compared with
placebo (5 mmgHg difference
from baseline at 6 months in
treatment vs. placebo group).
Bhattacharya
et al. [37]2016
Placebo-controlled
ascending single
and multiple dose
PK
PF-06260414 Healthy adult males
Western:
Placebo N = 17
SAD: 1–400 mg single
dose (N = 6 per group)
MAD: 3–100 mg BID
(N = 6 per group)
Japanese:
Placebo (N = 2)
30 mg BID (N = 5)
Total Exposed = 53
Total N = 72
No severe AE’s. A total of 42 of
67 treatment-emergent AE’s were
considered treatment-related.
Three subjects receiving SARM
discontinued the study (anxiety,
hypertension and ALT increase).
ALT increase occurred in
10 subjects (9 SARM subjects and
1 placebo subject). Five subjects
receiving 100 mg BID had ALT
increases and 3 Japanese subjects
receiving 30 mg BID had ALT
increases. One subject in 100 mg
BID cohort had ALT increases as
early as day 6 with peak of
343 IU/L on day 14, which
normalized by day 42 leading to
discontinuation. Dose-dependent
decreases in HDL
Coss et al. [38] 2016
Drug–drug
interaction study,
crossover design
with 6 to 10-day
washout period
Enobosarm Healthy adult males
All subjects dosed with
Enobosarm 3 mg. The
following studies had
two occasions of
Enobosarm and one
occasion of the
additional drug:
Itraconazole 200 mg
(N = 12)
Rifampin 600 mg
(N = 12)
Probenecid 500 mg
(N = 15)
The following two
studies had one occasion
of Enobosarm and two
occasions of the
following drugs:
Celecoxib 200 mg
(N = 42)
Rosuvastatin 10 mg
(N = 49)
Total Exposed N = 132
Total N = 132
No SAE’s, 21% reported AE’s
while taking Enobosarm, however
only 8 subject’s AE’s were
determined to be related to
Enobosarm. The most common
AE was headache.

J. Xenobiot. 2023,13 224
Table 2. Cont.
Author Year Study Design SARM Study Population Study Arms and Total
Subjects Summary of Adverse Events
Clark et al. [39] 2017
Placebo-controlled
ascending single
and multiple dose
PK
GSK2881078
Healthy adult males
and
postmenopausal
women
SAD: 0–0.2 mg, N = 10
all males)
MAD:
Placebo (N = 22)
0.05–0.75 mg (N = 67,
24 female subjects)
Total Exposed N = 77
Total N = 99
Dose-dependent reductions in
HDL. Female subject on active
treatment developed a
maculopapular rash and ALT
increase to 2.9 X the ULN and
discontinued the study. Another
female developed and ALT
elevation to 2.3 X the ULN. Two
men on active treatment
developed muscle soreness after
demanding activity in the
follow-up period 14 and 28 days,
respectively, with elevation in
CPK (17,841 and 4590 IU,
respectively and mild elevations
in ALT, both resolved over
3 weeks). No other subjects
showed ALT ≥2 X ULN during
treatment.
Neil et al. [40] 2018
Randomized
double-blinded,
placeb0-controlled
dose-escalation
PKPD
GSK2881078 Healthy elderly
men and women
Cohort 1:
Males: 0.75 mg or 1.5 mg
Females: 0.5 mg or
0.75 mg
Dosed twice daily for
3 days followed by daily
for 28 days. (N = 10 each
dosing group,
2:1 placebo)
Cohort 2:
Males: 4 mg daily for
56 days
Females: 0.35 mg daily
for 28 days followed by
1.5 mg daily for 28 days
(N = 10 in each dosing
group, 2:1 placebo)
Total exposed N = 62
Total N = 93
62.9% receiving SARM compared
with 13.3% placebo had ALT
elevations. All elevations in ALT
were transient occurring from
approximately day 14 beginning
to resolve and returning to
baseline by day 28 of dosing. ALT
incidence was most frequent in
highest dose group 4 mg, with
2 individuals having a 5–10 X
ULN elevation in ALT.
Peters et al.
[41]2018
Single arm,
non-randomized
efficacy study
GTX-024
(Enobosarm)
Postmenopausal
females with stress
incontinence
3 mg daily
Total Exposed N = 19
Total N = 19
Minimal adverse events with
none above Grade I. Elevated ALT
in 1 of 19 subjects.
Ristic et al. [42] 2018
Randomized
placebo-controlled
study
VK5211
(ligandrol)
Patients >65
recovering from hip
fracture 3–7 weeks
prior
Placebo
0.5 mg daily
1 mg daily
2 mg daily
Total N = 108, number in
each arm not specified.
No SAE’s reported.
NCT01401543
[43]2019
Bioavailability
study crossover
design
LY2452473 Healthy male
5 mg LY2452473 + 5 mg
tadalafil standard and at
three different particle
sizes (10, 40 and
90 microns) single dose
Total Exposed = 24
Total N = 24
No SAE’s, most common AE was
headache, no report of liver
enzymes.
NCT01160289
[44]2019 Randomized
placebo-control trial LY2452473 Males with erectile
dysfunction
5 mg tadalafil + placebo
(N = 87)
10 mg tadalafil + placebo
(N = 89)
1 mg LY2452473 +
tadalafil daily (N = 85)
5 mg LY2452473 +
tadalafil daily (N = 97)
5 mg LY2452473 +
placebo (N = 52)
Total Exposed N = 234
Total N = 410
SAE’s occurred slightly more
commonly in patients
randomized to LY2452473 (4 of
234 subjects) compared with 0 of
176 subjects randomized to a
placebo group. SAE’s included
humerus fracture, pulmonary
embolus, tubular interstitial
nephritis, arrythmia, lobar
pneumonia and cardiac arrest.
Association with SARM not noted.
Other AE’s occurred at similar
rates between SARM and placebo
groups (20–30% of patients). No
patient in the SARM groups had
AST elevation.

J. Xenobiot. 2023,13 225
Table 2. Cont.
Author Year Study Design SARM Study Population Study Arms and Total
Subjects Summary of Adverse Events
NCT03241342
[45]2020
Randomized
placebo-controlled
study
GTX-024
Females 18–80 years
old with stress
incontinence
Placebo (N = 165)
GTX-024 1 mg daily
(N = 163)
GTX-024 3 mg daily
(N = 163)
Total Exposed N = 326
Total N = 491
5 total SAE’s in GTX-024 groups
vs. 4 in placebo. SAE’s included
hip fracture, dysesthesia,
myocardial infarction, cerebral
vascular accident and goiter.
Non-SAE’s were also similar in
GTX-024 vs. placebo group. Only
2 of 326 subjects experienced
increased ALT.
Efimenko
et al. [46]2021
Cross-sectional
survey study in
SARM users
LGD-4033
RAD-140
MK-2866
Most commonly
healthy adult men
(98.5%) that were
18–29 (72.3%) years
old
Total survey responders
N = 343
54.5% of users reported adverse
effects related to SARM use. The
most common were mood swings
(22.4%), decreased testes size
(20.7%) and acne (15.2%). The
proportion of responders
reporting a side effect increased
significantly with longer reported
exposure times to SARM.
Pencina
et al. [47]2021
Randomized
placebo-controlled,
double blind
OPK-88004 Prostate cancer
survivors
Placebo N = 36
1 mg daily N = 28
5 mg daily N = 14
15 mg daily N = 14
Total Exposed N = 78
Total N = 114
3 SAE’s not considered
treatment-related were coronary
artery bypass grafting, renal
cancer and lung and liver cancer.
Dose-dependent increases in AST
and ALT with only one
participant in the 15-mg group
having AST and ALT elevations
above the ULN. Dose-dependent
decreases in HDL.
NCT03297398
[48]2021 Randomized
placebo control trial OPK-88004
Males with
symptoms of
benign prostatic
hyperplasia
Placebo (N = 38)
OPK-88004 15 mg
(N = 40)
OPK-88004 25 mg
(N = 38)
Total Exposed N = 78
Total N = 114
2 subjects had SAE’s in 25 mg
group (coronary artery disease,
biliary obstruction and
cholangitis)—association not
noted. Other AE’s occurred at
much higher rates in SARM
groups (60–70%) compared with
placebo (10–15%). This appeared
to be heavily driven from lab
abnormalities such as decreased
testosterone, decreased LDL and
decreased HDL. ALT increased in
4 subjects randomized to SARM
(3/40 and 1/38 in the 15 mg and
25 mg groups, respectively).
Many case reports described the change in liver enzymes over time, which was
either manually tabulated or digitized using WebPlotDigitizer (Version 4.6, Ankit Rohatgi,
Pacifica, CA, USA) depending on the presentation of data in the case report. Additionally,
for case reports, the R-factor (or R-ratio or R-value) was extracted as reported in the case
(Table 1) [49]. The R-factor is mathematically defined as:
ALT
ULNALT 
ALP
ULNALP (1)
where ALT is the alanine aminotransferase, ULN
ALT
is the upper limit of normal for alanine
aminotransferase, ALP is the alkaline phosphatase, and ULN
ALP
= is the upper limit of
normal for alkaline phosphatase [
50
]. The R-factor additionally was calculated at each
available time point using Equation (1) above to evaluate trends in the R-factor over time.
As most case reports did not disclose the upper limit of normal (ULN), when calculating
R-factors the ULN were assumed to be 40 I/U and 147 IU/L for alanine aminotransferase
(ALT) and alkaline phosphatase (ALP), respectively [51,52].
For the clinical trials, the proportion of patients with ALT elevation greater than 2 times
the ULN was extracted. To explore the possibility of a dose–response relationship between
SARM use and ALT elevation, doses were categorized as low, medium, or high. For each
respective SARM, doses were considered low if they were in the 1st quartile, medium if in

J. Xenobiot. 2023,13 226
the 2–3rd quartile, and high if in the 4th quartile of doses across all included trials of the
respective SARM. Otherwise, safety was described qualitatively. Given all safety outcomes
were of interest, adverse events may be rare and not discovered in registration trials, and
there was no attempt to estimate a measure of effect, a formal risk of bias assessment was
not performed. Limitations of specific studies are considered in the discussion section.
Missing data were excluded from the analysis. In cases where a demographic variable
was reported in a clinical trial as a range, the mean of the range was assumed to be the
observed mean of the demographic variable of interest. Some SARMs have multiple names.
For pooled analysis, all formulations of Enobosarm (Ostarine, MK-2866) were labeled
as Enobosarm.
3. Results
3.1. Summary of Case Reports
There were 15 unique case report manuscripts with a total of 18 cases (Flores et al., Koller
et al. and Perananthan et al. each reported two cases in a single
manuscript) [16,26,30]
. The
large majority (88%, N = 15) reported DILI associated with SARM use. Other significant
adverse events included one case of severe rhabdomyolysis (Kintz et al.) and one case
of bilateral asynchronous Achilles tendon ruptures (Gould et al.) [
14
,
15
]. The case of
rhabdomyolysis occurred in a 43-year-old male after cycling approximately 75 miles. Ten
days prior to hospital presentation, the patient had taken a single dose of 20 mg MK-2866
and a 4-day course of 20 mg GW-1516 daily. The case of Achilles tendon rupture occurred
in a 36-year-old male competitive powerlifter. The initial tendon rupture occurred in the
right Achilles while playing dodgeball. He underwent surgical correction and 4-days
post-operatively experienced a left Achilles tendon rupture while hopping on his left leg.
Approximately 5 weeks prior to initial injury the patient completed two 4-week cycles of
SARM compounds (cycle 1: ostarine alone, cycle 2: ostarine and cardarine). There was
also a report of an experimental efficacy trial in a single 25-year-old male taking 10 mg
LGD-4033 daily and 15 mg MK-677 daily (Cardaci et al.) [
27
]. There were no significant
adverse events in this report; however, there was a reversible increase in ALT from 20 to
61 IU/L and reversible decrease in high-density lipoprotein (HDL) from 55 to 35 mg/dL
after 5 weeks of SARM use.
In the remaining 15 DILI cases, patients were 100% male with a mean age of
33.5 ±9.3
years.
Weight and race were not consistently reported. Alcohol use was also inconsistently quanti-
fied and reported. Two cases reported a significant history of alcohol use without quantify-
ing [
18
,
26
], one study reported that the patient denied alcohol use [
12
], two studies reported
and quantified less than weekly alcohol use [
13
,
31
], one study reported insignificant alcohol
use without quantifying [
16
], and the remaining seven cases did not report alcohol use,
but implied alcohol use was not significant [
11
,
16
,
24
–
26
,
28
,
30
,
31
]. Use of concomitant
medications including acetaminophen were rarely reported and only Lee et al. reported
acetaminophen levels, which were within normal limits [29].
Patients were reported to commonly use SARMs for muscle building and described
as having interest in being athletic and/or a bodybuilder. Two patients were noted to be
active-duty military [25,29].
The specific SARM was identified in all but one case (Khan et al.) [
30
]. Of cases
reporting a specific SARM, the most common SARM used overall was LGD-4033 (57.1%,
N = 8), followed by RAD-140 (42.9%, N = 6), Enobosarm (21.4%, N =3), and a single case
of YK11 use (Lee et al.) [
29
]. The majority of cases reported single SARM use (78.6% of
cases, N = 11). Khan et al. reported use of a SARM supplement and it is unclear if this
was one or multiple SARMs [
28
]. Of the case reports with single SARM use, the most
common SARM was LGD-4033 (45.5%, N = 5), followed by RAD-140 (36.4%, N = 4) and
Enobosarm (18.2%, N = 2). Two cases reported the use of two SARMs (Barbara et al., Koller
et al.) [
16
,
18
] and one report involved three different SARMs (Lee et al.) [
29
]. The total
daily dose was reported in only four cases with mean 12.6
±
11.1 mg. The frequency was
reported in five cases and SARMs were most commonly taken daily (80% N = 4), while

J. Xenobiot. 2023,13 227
one case reported dosing twice daily. The time course of initiation of SARM to symptom
onset was unclear; however, most cases reported the total duration of SARM consumption
prior to presentation (mean 6.7
±
3.3 weeks) and reported the time from discontinuation to
initial symptoms ranged from 0 to 60 days. Of the eight studies that reported time from
discontinuation to initial symptoms the mean was 14.1 ±20 days.
The majority of the patients described in the case reports presented with symptoms of
hyperbilirubinemia after exposure to SARMs. The most commonly reported symptoms
were jaundice and/or dark-colored urine (93.3%, N = 14). Weight loss and fatigue were
also noted in some cases, with one case reporting a 40-pound weight loss [
11
]. The marked
elevations in bilirubin levels relatively early on can be observed (Figure 1a). Initially, the
pattern of liver injury appeared to favor a hepatocellular pattern. However, the R Factor
decreased over time, suggesting a prevailing cholestatic pattern of injury (Figure 1b). Liver
biopsies were obtained in 66.6% (N = 10) case reports. The biopsy results were universally
supportive of cholestatic injury. Predominant findings on liver biopsy were cholestasis
which is typically seen in cholestatic DILI from anabolic drugs and oral contraceptives [
53
].
There were thirteen cases with reported imaging findings. Eight of these patients had
some form of cross-sectional imaging with either a CT or MRI/MRCP. The majority of
the imaging findings were normal with one patient having hepatic steatosis detected by
ultrasound, and two patients with either hepatomegaly or splenomegaly [11,13,25].
J. Xenobiot. 2023, 13, FOR PEER REVIEW 14
(a) Total bilirubin over time (b) R factor over time
(c) ALT and ALP over time
Figure 1. Trend of alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin,
and R-factor over time from case reports. Thick lines are locally estimated scaerplot smoothing
(LOESS) trend lines and thin lines represent individual patient data.
Generally, patients recovered completely by 3–6 months. Some patients took 10
months to 1 year for labs to normalize [13,26]. Total bilirubin and ALP peaked around
days 25–50, with median time to peak at 18 and 12 days from presenting to receiving care,
respectively. In contrast, ALT peaked early and generally down-trended thereafter (Figure
1c). After 50 days from presentation to receipt of care, almost all patients had downtrends
in all liver-associated enzyme tests. (Figures 1a,c) Mean peak values for total bilirubin,
ALP, and ALT were 28.5 ± 13.4 mg/dL, 283.1 ± 160.9 IU/L, and 226.3 ± 142 IU/L, respec-
tively. All therapy was supportive, and the most commonly prescribed treatment was ur-
sodeoxycholic acid (46.7%, N = 7). Cholestyramine was co-prescribed in four of those
cases. One case reported a trial of 300 mg N-acetyl cysteine intravenously four times daily
while hospitalized [16].
3.2. Summary of Clinical Studies
3.2.1. General Characteristics of Studies
Table 2 summarized the study characteristics. There were 18 clinical studies describ-
ing safety, efficacy, or pharmacokinetics in subjects taking SARMs. One study was a cross-
Figure 1.
Trend of alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and
R-factor over time from case reports. Thick lines are locally estimated scatterplot smoothing (LOESS)
trend lines and thin lines represent individual patient data.

J. Xenobiot. 2023,13 228
Generally, patients recovered completely by 3–6 months. Some patients took 10 months
to 1 year for labs to normalize [
13
,
26
]. Total bilirubin and ALP peaked around days 25–50,
with median time to peak at 18 and 12 days from presenting to receiving care, respectively.
In contrast, ALT peaked early and generally down-trended thereafter (Figure 1c). After
50 days from presentation to receipt of care, almost all patients had downtrends in all liver-
associated enzyme tests. (Figure 1a,c) Mean peak values for total bilirubin, ALP, and ALT
were 28.5
±
13.4 mg/dL, 283.1
±
160.9 IU/L, and 226.3
±
142 IU/L, respectively. All therapy
was supportive, and the most commonly prescribed treatment was ursodeoxycholic acid
(46.7%, N = 7). Cholestyramine was co-prescribed in four of those cases. One case reported
a trial of 300 mg N-acetyl cysteine intravenously four times daily while hospitalized [16].
3.2. Summary of Clinical Studies
3.2.1. General Characteristics of Studies
Table 2summarized the study characteristics. There were 18 clinical studies de-
scribing safety, efficacy, or pharmacokinetics in subjects taking SARMs. One study was
a cross-sectional survey of SARM users that inquired about self-prescription patterns
and perceived positive and negative effects [
46
]. The remaining 17 were clinical tri-
als. Nine of the trials were early phase tolerability, pharmacokinetic, or dose finding
studies [32,33,35–37,39,40,42,47]
, two trials were bioavailability or drug-interaction stud-
ies [
38
,
43
], one was a small pilot efficacy study [
41
], and the remainder were larger efficacy
trials [
21
,
34
,
44
,
45
,
48
]. The 17 clinical trials tested 13 unique SARM compounds and in-
cluded a total of 2136 patients with 1447 patients exposed to a SARM. The most commonly
trialed SARM was Enobosarm (N = 5 trials), followed by LGD-4033 (
N = 3 trials
), LY2452473
(
N=3
), OPK-88004, and GSK2881078 (N = 2 trials), with the remaining compounds each
being tested in one clinical trial. The patient populations were generally healthy, although
SARMs were investigated for different indications such as gain of muscle mass/function,
stress urinary incontinence, erectile dysfunction, and symptomatic benign prostatic hyper-
plasia. The median and range of mean ages across all trials was
57 (24–77) years
(13 trials re-
ported age) and similarly median weight and range was
81.2 (51.9–88.5) kg
(7 trials reported
weight). Nine studies included only men (N = 948, exposed N =
648) [33,35–38,43,44,47,48]
,
four studies included only females (N = 768, exposed N = 492) [
21
,
32
,
41
,
45
], and the remain-
ing four studies included both males and females. Of these studies, Clark et al. included
24.2% females (N = 24, exposed N = 18) [
39
], Dalton et al. included 50% females (N = 60,
exposed N = 48) [
34
], Neil et al. included 50% females (N = 46, exposed N = 31) [
40
], and
Ristic et al. included 76.9% females (N = 83, exposed N = 62) [
42
]. Efimenko et al. reported
343 survey responders that were most commonly adult healthy men (98.5%) with 72.3% of
survey respondents between the ages of 18–29 years old [46].
3.2.2. Serious Adverse Events
Serious adverse events (SAEs) were reported in six of the clinical trials. Clark et al.
(GSK2881078) reported one subject, who developed chest pain, had an emergent cardiac
catheterization which was negative and was followed but withdrawn from further SARM
therapy [
39
]. Drug association was not made clear in the manuscript for this SAE. Another
patient developed a maculopapular rash and ALT elevation 2.9 times the ULN consistent
with a drug reaction. Two other subjects in the same study developed rhabdomyolysis after
strenuous physical activity but these SAEs were not considered drug-related. Papanicolaou
et al. (MK-0773) reported 27 SAEs occurred in 21 subjects, and eight were drug-related [
21
].
Five of the eight drug-related SAEs were attributed to elevations in ALT and AST and
these five subjects were withdrawn from the study. Reassuringly, all subjects’ ALT and
AST levels normalized after discontinuation of the SARM. The remaining drug-related
SAEs were not clearly reported by Papanicolaou et al. Pencina et al. (OPK-88004) reported
three SAEs, which were not considered to be drug-related [
21
,
47
]. One subject underwent
coronary artery bypass grafting, one subject was diagnosed with lung and liver cancers,
and one subject in the placebo group was diagnosed with renal cancer. In NCT03241342

J. Xenobiot. 2023,13 229
(GTx-024), there were five SAEs reported, including acute myocardial infarction, goiter, hip
fracture, cerebrovascular accident, and dysesthesia, but the association to drug was not
reported [
45
]. In NCT01160289 (LY2452473), SAEs occurred in four subjects randomized to
LY2452473 [
44
]. These SAEs included lobar pneumonia, humerus fracture, tubulointerstitial
nephritis, pulmonary embolism, arrhythmia, and cardiac arrest; however, drug causality
was not reported. In NCT03297398 (OPK-88004), SAEs occurred in two subjects including
coronary artery disease, bile duct obstruction, and cholangitis [48].
3.2.3. Hepatobiliary Adverse Events
Elevations in liver enzymes greater than 1 to 2 times the ULN were reported in
10 clinical trials. Mean and median proportion of subjects experiencing LAE elevation
across all trials were 7.1% (N = 78) and 1.3%, respectively, with a range of (0–62.9%). There
was large variability observed even between two separate trials of the same compound. For
example, Clark et al. and Neil et al. (GSK2881078) reported 4.3% and 62.9% subjects with
ALT elevation, respectively [
39
,
40
]. Similarly, for Enobosarm, Dalton et al. and Peters et al.
reported ALT elevations in 7.3% (N = 39) and 2.6% (N = 2) of subjects, respectively [
34
,
41
].
However, Coss et al. and Marcantonio et al. reported 0% of subjects experiencing ALT
elevation and NCT03241342 reported only 0.6% (N = 2) [
32
,
38
]. Importantly, Coss et al.
was not a repeat dose study and doses of SARMs may have differed between trials, which
may explain some of the variability [
38
]. Figure 2summarizes the proportion of subjects
in each trial with elevated ALT and suggests that the majority of cases were associated
with higher doses of SARM. Overall, GSK2881078 was associated with the highest rates
of ALT elevations; however, this finding was largely driven by Neil et al. (Figure 2) [
40
].
Most patients only had mild ALT elevations and were able to continue the SARM with ALT
returning to baseline by day 28 of therapy.
J. Xenobiot. 2023, 13, FOR PEER REVIEW 16
example, Clark et al. and Neil et al. (GSK2881078) reported 4.3% and 62.9% subjects with
ALT elevation, respectively [39,40]. Similarly, for Enobosarm, Dalton et al. and Peters et
al. reported ALT elevations in 7.3% (N = 39) and 2.6% (N = 2) of subjects, respectively
[34,41]. However, Coss et al. and Marcantonio et al. reported 0% of subjects experiencing
ALT elevation and NCT03241342 reported only 0.6% (N = 2) [32,38]. Importantly, Coss et
al. was not a repeat dose study and doses of SARMs may have differed between trials,
which may explain some of the variability [38]. Figure 2 summarizes the proportion of
subjects in each trial with elevated ALT and suggests that the majority of cases were asso-
ciated with higher doses of SARM. Overall, GSK2881078 was associated with the highest
rates of ALT elevations; however, this finding was largely driven by Neil et al. (Figure 2)
[40]. Most patients only had mild ALT elevations and were able to continue the SARM
with ALT returning to baseline by day 28 of therapy.
Figure 2. Proportion of alanine aminotransferase (ALT) elevation observed in clinical or observa-
tional trials. For each respective SARM, doses were considered low if they were in the 1st quartile,
medium if in the 2–3rd quartile, and high if in the 4th quartile of doses across all included trials of
the respective SARM.
Similar to GSK2881078, most ALT elevations for other compounds were mild. How-
ever, there were several subjects that had greater than four times the ULN elevations in
ALT (2 in Neil et al., 1 in Dalton et al., and 1 in Bhaacharya et al. [34,37,40]) with the
greatest reported ALT at 343 IU/L in a patient receiving PF-06260414 [35]. Other hepato-
biliary enzymes were not as consistently reported. Elevation in alkaline phosphatase
(ALP) was only reported in one patient receiving GTX-024 in the clinical trial
NCT03241342 [45]. Elevation in serum bilirubin levels were not reported in any of the
clinical trials, although bile duct obstruction and cholangitis were two SAEs reported in
NCT03297398 observing OPK-88004 [48]. In addition to the NCT03241342 trial, two other
trials analyzed the ALP levels and bilirubin levels. Both Pencina et al. (OPK-88004) and
Neil et al. (GSK2881078) reported a decrease in ALP and unchanged bilirubin levels
[40,47]. Pencina et al. separately reported bone-specific ALP which also demonstrated a
Figure 2.
Proportion of alanine aminotransferase (ALT) elevation observed in clinical or observational
trials [
21
,
32
–
43
,
45
,
47
,
48
]. For each respective SARM, doses were considered low if they were in the
1st quartile, medium if in the 2–3rd quartile, and high if in the 4th quartile of doses across all included
trials of the respective SARM.

J. Xenobiot. 2023,13 230
Similar to GSK2881078, most ALT elevations for other compounds were mild. How-
ever, there were several subjects that had greater than four times the ULN elevations in
ALT (2 in Neil et al., 1 in Dalton et al., and 1 in Bhattacharya et al. [
34
,
37
,
40
]) with the
greatest reported ALT at 343 IU/L in a patient receiving PF-06260414 [
35
]. Other hepatobil-
iary enzymes were not as consistently reported. Elevation in alkaline phosphatase (ALP)
was only reported in one patient receiving GTX-024 in the clinical trial NCT03241342 [
45
].
Elevation in serum bilirubin levels were not reported in any of the clinical trials, although
bile duct obstruction and cholangitis were two SAEs reported in NCT03297398 observing
OPK-88004 [
48
]. In addition to the NCT03241342 trial, two other trials analyzed the ALP
levels and bilirubin levels. Both Pencina et al. (OPK-88004) and Neil et al. (GSK2881078)
reported a decrease in ALP and unchanged bilirubin levels [
40
,
47
]. Pencina et al. separately
reported bone-specific ALP which also demonstrated a decrease. Based on the overall
findings, the liver injuries observed were mostly mild hepatocellular injuries [
47
]. SARMs
associated with liver injury from the clinical trials were PF-06260414, GSK2881078, GTX-024,
MK-3984, MK-0773, and OPK-88004.
3.2.4. Other Non-Serious Adverse Events
Eight clinical trials reported reductions in HDL. The SARMs in the studies that re-
ported a reduction in HDL were LGD-4033, PF-06260414, GSK2881078, OPK-88004, and
LY2452473 [
36
,
37
,
39
,
40
,
44
,
47
]. A decrease in total testosterone levels in male patients was
also observed in the studies that reported hormonal data. The SARMs that were used by
these patients were LGD-4033, RAD-140, and MK-2866. In four studies that reported hor-
monal levels, in addition to reduced total testosterone levels, there were reduced levels of
sex hormone-binding globulin (SHBG). Commonly reported symptoms and findings for all
SARMs were headaches, dry mouth, and upper respiratory infections (URIs), constipation,
dyspepsia, and nausea. Papanicolaou et al. reported elevated hemoglobin and hematocrit
greater than 3% in approximately 5% of patients [
21
]. There was also a trend towards
an increase in systolic blood pressure with the SARM group having a mean increase of
approximately 3 mmHg from baseline, compared with placebo, which had a decrease
of approximately 2 mmHg from baseline. In contrast, Pencina et al. (OPK-88004) found
inconsistent small elevations of hematocrit (<1%) in only one subgroup (5 mg); however,
hematocrit decreased in the 15 mg subgroup and remained unchanged in the 1 mg sub-
group [
47
]. NCT03241342 (GTX-024) did not specifically report hemoglobin/hematocrit
levels but reported one event of polycythemia and one event of thrombocytosis. Hyper-
tension was reported in nine subjects receiving GTX-024 in NCT03241342; however, drug
causality was not mentioned [
45
]. The clinical trials did not commonly investigate or report
testicular size, development of acne, or mood swings. Of note, these were the most common
adverse effects of survey respondents in the study by Efimenko et al., with reported rates of
22.4% for mood swings, 20.7% for decreased testes size, and 15.2% for acne [
46
]. Elevations
in blood pressure were also noted in Efimenko et al., but not quantified.
4. Discussion
Multiple reports of serious and potentially life or limb threatening adverse events
have been reported in the last 2–3 years. SARM use has become increasingly popular
among younger males in particular, possibly as a result of the growing popularity of a large
number of social media fitness influencers [
54
]. We systematically reviewed the literature
and concisely presented the most important safety findings associated with SARMs. This
study elucidates trends in SARM-associated DILI, raises awareness of other possible lesser-
known significant adverse events associated with SARM use, and allows for comparison of
the adverse events found in clinical trials to those found in case reports.
The clinical trials clearly demonstrated a signal for potential of DILI. Although the
mechanism is not clear, Neil et al. evaluated microRNA-122 levels and found an association
between SARM use and mild hepatocellular liver injury [
40
]. Koller et al. discussed
at length the theoretical mechanisms for DILI and hypothesized SARM-associated DILI

J. Xenobiot. 2023,13 231
is idiosyncratic, with elevated doses playing a significant role [
16
]. This hypothesis is
consistent with the strong suggestion of dose response of SARM use to a proportion
of subjects with ALT elevation in clinical trials. Fortunately, in the closely monitored
clinical trial setting, subjects were either withdrawn from SARM therapy or were closely
followed, and ALT generally quickly returned to baseline. In contrast, patients in case
reports generally reported taking SARMs at 4–10 times the doses in clinical trials and
were commonly using multiple SARMs. Furthermore, they were not observed with serial
ALT monitoring, and only presented for clinical care with significant symptoms of biliary
obstruction. Of note, many patients in the case reports were reported to initially have a
hepatocellular pattern of DILI. Over time, however, the DILI consistently converted to
a cholestatic pattern (Figure 1b). This finding is again consistent with the clinical trials,
where the majority of patients had hepatocellular injury and were able to recover with early
withdrawal of SARM. Consequently, although clinicians should strongly discourage the
use of SARM supplementation, if a patient continues to abuse SARMs despite warnings
from the clinician, serial ALT monitoring and encouraging lower doses are two strategies
that may reduce the risk of DILI and improve patient safety. It is important to inform
the patient that these strategies do not endorse SARM use and are only being used as a
last resort measure to ensure the safety of the patient while maintaining a confidential
patient–provider relationship.
Aside from DILI and elevated ALT, there were concerning safety signals for mus-
culoskeletal side effects. Both Clark et al. (GSK2881078) and Kintz et al. (case report)
reported rhabdomyolysis [
15
,
39
]. In both the case report and Clark et al., the subjects
were reported to have performed significant physical activity, and the association with
the drug is not certain [
39
]. Of note, there have been several case reports relating anabolic
steroid use to the development of rhabdomyolysis [
55
–
58
]. The mechanism underlying
proposed anabolic steroid-induced rhabdomyolysis is unknown, and the causality is not
fully established. However, SARMs have many metabolites and high potential for off-target
effects [
35
,
59
–
62
]. Furthermore, it is rational to hypothesize that individuals starting a
workout supplement may perform more strenuous activity if the individual believes that
the supplement will enhance performance. Therefore, individuals choosing to take SARMs
should be aware of the possibility of rhabdomyolysis, and only gradually increase exercise
activity over time. Furthermore, it would be reasonable to screen for SARM use when
patients present rhabdomyolysis.
A striking case report was reported by Gould et al., asynchronous bilateral tendon
ruptures [
14
]. Of note, androgenic anabolic steroids have been linked to tendon rupture
through case reports and a cross-sectional survey study [
14
,
63
,
64
]. However, the mechanical
and biological effects of anabolic steroids on tendons and causality of tendon rupture
remain unclear [
65
]. Nevertheless, similar to rhabdomyolysis, given the multiple metabolic
pathways of SARMs and potential for off-target effects, in combination with reports of
tendon rupture associated with SARMs and anabolic steroids, there is significant concern
for tendon injury in SARM users. Active SARM users should be made aware of the
association of tendon rupture, and patients presenting with ruptured tendons should be
screened for SARM use.
Regarding cardiovascular health, dose-dependent, reversible reductions in HDL were
observed in many of the clinical trials, regardless of the individual SARM. Papanicolaou
et al. reported mild elevations in hemoglobin/hematocrit and a trend for increase in
systolic blood pressure [
21
]. Furthermore, although unclear if related to SARM therapy,
NCT03297398 reported a subject in the SARM group to have coronary artery disease and
in NCT01160289 one subject on SARM therapy was reported to have a pulmonary embo-
lus [
44
,
48
]. The convergence of decreasing HDL, increasing hemoglobin, and increasing
blood pressure in combination is highly concerning. Especially since there is a likely causal
association of anabolic steroid use and adverse cardiovascular outcomes [
66
]. Therefore,
although patients should be strongly discouraged to initiate or continue SARM supple-
mentation, patients that use SARMs should be screened and monitored for underlying

J. Xenobiot. 2023,13 232
cardiovascular disease throughout the duration of their use. Further, SARM users should
be educated about the possible adverse cardiovascular outcomes.
There was not enough evidence to quantify risk of use of concomitant medications,
in particular acetaminophen, on developing SARM-associated DILI. However, cases were
generally inconsistent with acetaminophen toxicity as peak aminotransferases were gen-
erally less than 1000 I/U and liver biopsy results did not demonstrate zone 3 hepatic
necrosis [
67
,
68
]. Nevertheless, this does not rule out acetaminophen as a risk for SARM-
associated DILI or vice versa. SARMS have been found to have a multitude of metabolites,
including phase II metabolites through sulfation and glucuronidation. Acetaminophen
liver injury occurs when a higher percentage of acetaminophen is metabolized via the
cytochrome P-450 pathway resulting in a build-up of toxic metabolites [
67
]. Therefore, it
is reasonable to hypothesize that concomitant SARM and acetaminophen use may place
an individual at higher risk for acetaminophen-induced liver injury if doses of SARM and
acetaminophen are high enough to overwhelm the phase II metabolism pathway.
Limitations to this review include the inability to determine causality of SARM ther-
apy to the reported adverse event and insufficient data to determine risk in subgroups.
For example, Padappayil et al. reported a case of myocarditis associated with RAD-140
use [
19
]. However, the patient had a history of type 1 diabetes mellitus with poor glycemic
control (HbA1C 10.2 mmol/mol) and a history of substance abuse requiring buprenorphine
maintenance therapy. Diabetes mellitus in general is a risk factor for cardiomyopathy, in
particular type 1 diabetes mellitus with poor glycemic control is a risk for cardiac autoim-
munity [
69
,
70
]. Furthermore, viral infections are the most commonly reported cause of
myocarditis in the United States [
71
]. Although Padappayil et al. reported a negative upper
respiratory viral panel, this does not definitively rule out a viral infection as the cause of
myocarditis [
72
]. This case highlights the importance of using probability scales such as the
Adverse Drug Reaction Scale to better standardize the reporting of causality [
73
]. Neverthe-
less, although causality was not able to be determined definitively in many cases presented
in this review, one main purpose of this review was to highlight all possible significant
adverse effects related to SARMs. This is of particular importance given adverse events
may be underreported in a clinical trial setting, further highlighting the need for continued
pharmacovigilance after trial completion [
74
]. Finding three cases of rhabdomyolysis across
the case reports and clinical trials is one example of how this review may raise awareness
for new safety signals other than DILI. Regarding DILI, the rates of ALT elevation were
not consistently reported by subgroups of age, gender, or weight. Therefore, inference was
not able to be made regarding these subgroups. All patients in case reports were healthy
males. This does not imply females are at lower risk for DILI. Rather, males appear to be far
more likely to use SARM supplementation, as evidenced by Efimenko et al., where nearly
100% of survey respondents using SARMs were male [
46
]. Therefore, females considering
SARM supplementation or actively using SARM supplementation should be counseled
and monitored to the same standard as males. Alcohol use and precise quantification were
not consistently reported in the case reports. Only two cases reported a significant history
of alcohol use and therefore alcohol as a risk factor for SARM-related DILI remains unclear.
5. Conclusions
SARM use may be associated with DILI, rhabdomyolysis, tendon rupture, and adverse
cardiovascular outcomes. Despite clear and repeated warnings by the FDA regarding use
of these unapproved drug products, they continue to be available online and used in the
fitness and athletic communities. Providers and public health officials should strongly
discourage SARM supplementation and strongly counsel patients on the potential risks
of SARM use. SARM-related DILI appears to be dose-related and may initially present
with a hepatocellular injury, later converting to a mixed or cholestatic injury. If a patient
continues to use SARMs despite warnings, ALT monitoring and dose reduction are strongly
recommended in order to detect and reduce the risk of potential DILI as early as possible.
The clinician should make clear to the patient that ALT monitoring and dose negotiations

J. Xenobiot. 2023,13 233
do not endorse SARM use. Rather, these are only last resort methods to ensure safety while
maintaining a confidential and trusted patient–provider relationship.
Supplementary Materials:
The following supporting information can be downloaded at: https://
www.mdpi.com/article/10.3390/jox13020017/s1, PRISMA Flow diagram [75].
Author Contributions:
Conceptualization, J.D.V., D.J.S. and K.C.P.; data curation—search meth-
ods, H.R.B., J.D.V. and D.J.S.; data curation—abstract and title screening, J.W.D. and D.J.S.; data
curation—full
text screening, A.T.K. and J.P.D.; data curation—data extraction, D.J.S.;
writing—original
draft preparation, J.D.V., D.J.S. and K.C.P.; writing—review and editing, J.D.V., K.C.P., H.R.B., J.P.D.,
J.W.D., A.T.K., B.W.S. and D.J.S.; supervision—hepatology subject matter expertise: K.C.P. and B.W.S.;
supervision—sports medicine subject matter expertise, J.P.D. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement:
The data presented in this study are available on reasonable request
from the corresponding author.
Acknowledgments: We would like to thank Zanete Wright for her hard work and dedication to the
clinical pharmacology fellowship.
Conflicts of Interest:
The authors declare no conflict of interest. Material has been reviewed by the
Walter Reed Army Institute of Research, the Uniformed Services University of the Health Sciences
and the Naval Medical Center San Diego. There is no objection to its presentation and/or publication.
The opinions and assertions expressed in this article are those of the authors and do not reflect the
official policy or position of the U.S. Army Medical Department, Department of the Army, DoD, or
the U.S. Government.
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