What are SARMs?
Discovered in the late 1990s, SARMs are performance-enhancing agents that stimulate anabolism (i.e., increase muscle mass and strength) and facilitate recovery from exercise.
SARMs are not anabolic steroids; rather, they are synthetic ligands that bind to androgen receptors (ARs).
Depending on their chemical structure, they function as full agonists, partial agonists, or antagonists.
Each SARMs complex possesses a different conformation, and various tissues display a unique pattern of AR expression (e.g., skeletal muscle, bone, prostate, brain, skin, liver).
It is, thus, in a tissue-selective manner that SARMs mediate coregulators and transcription factors or signaling cascade proteins to promote anabolic activity.
Nonsteroidal SARMs serve as an attractive alternative to anabolic-androgenic steroids because they have fewer limitations.
In contrast to steroidal androgen preparations, SARMs display high oral bioavailability.
SARMs also exhibit diminished androgenic activity because they are not metabolized to dihydrotestosterone (DHT) by 5 alpha-reductase, an enzyme that is highly expressed in androgenic tissues.
They are also not metabolized to estrogen by aromatase.
For these features combined, nonsteroidal SARMs have been deemed to be advantageous over their steroidal counterparts.
Indeed, SARMs have shown substantial therapeutic promise for:
- Male contraception
- Treatment of osteoporosis
- Prostate cancer
- sexual dysfunction
- benign prostatic hyperplasia
- Alzheimer’s disease
- muscular dystrophy
- breast cancer
- muscle wasting associated with cachexia and sarcopenia.
Fueled, at least in part, by the perception that SARMs are safer than anabolic steroids, recreational users are now leveraging the various anabolic profiles of different SARMs to selectively achieve results in terms of “bulking” and “cutting".
Bulking refers to a muscle-gaining phase that combines a weight-gain diet with intense weight training.
Cutting refers to a fat-losing phase that combines adherence to a strict weight-loss diet with aerobic exercise and lighter training.
Anecdotal evidence claims that different SARMs yield different results in terms of bulking versus cutting, which is why bodybuilders and other fitness enthusiasts commonly use them in combination (or stacked) with each other.
SARMs Ostarine (Enobosarm, GTx-024, MK-2866, S-22)
Ostarine is an orally bioavailable, nonsteroidal SARM that was developed by Gtx, Inc. in the late 1990s primarily for the treatment of muscle wasting and osteoporosis.
Ostarine MK-2866 is the best clinically characterized SARM.
The few published clinical trials have examined its potential for treating skeletal muscle deficits seen with stress urinary incontinence, breast cancer, non–small-cell lung cancer, and cancer-related cachexia.
In clinical trials conducted thus far a significant increase in total lean body mass was consistently observed, including in cancer patients.
In some studies, there was also an accompanying decrease in total fat mass with no difference in total body weight.
Common low-grade side effects included headache, nausea, fatigue, and back pain.
Other observed effects were transient elevation in the alanine transaminase (ALT), reductions in high density lipoprotein (HDL), blood glucose, insulin, and insulin resistance.
These altered parameters all returned to normal upon cessation of treatment. Information provided on personal blogs and commercial websites advises fitness and bodybuilding enthusiasts to supplement with Ostarine at dose ranges from 10 mg to 30 mg for at least 12 weeks.
These doses are 10 times those studied clinically.
Anecdotal evidence suggests that SARMs Ostarine at these high doses over this extended time period can adversely lead to lowered testosterone levels.
The side effects of decreased testosterone include reduced sex drive, erectile dysfunction, infertility, muscle weakness, loss of bone density, weight gain accompanied by increased body fat, insomnia, and depression.
Potential drug-drug interactions between Ostarine (and its major metabolite) and itraconazole, probenecid, celecoxib, and rosuvastatin have been examined with little evidence of clinically relevant drug interactions.
According to one website promoting SARMs, it is recommended that SARMs be “stacked” for enhanced and differential benefits.
Whether taking higher doses of multiple SARMs chronically poses a risk for adverse drug-drug interactions remains unknown.
SARMS LGD-4033 (Ligandrol, VK5211)
Developed by Ligand Pharmaceuticals, there has been only one clinical trial involving the drug.20 In the placebo-controlled study, 76 healthy men were randomized to placebo or 0.1 mg, 0.3 mg, or 1.0 mg LGD-4033 daily for 3 weeks.
LGD-4033 was well tolerated, with no serious adverse events.
Hemoglobin, prostate-specific antigen, aspartate aminotransferase (AST), ALT, and QT intervals were not altered at any dose.
At the 1.0 mg dose, follicle-stimulating hormone and free testosterone were significantly suppressed; there was no change in luteinizing hormone.
Hormone levels returned to normal when the treatment was discontinued.
Lean body mass increased dose-dependently, but there were no statistically significant changes in fat or appendicular skeletal muscle mass.
Strength and stair-climbing speed and power trended toward a dose-dependent improvement but were not statistically significant.
Total and low density lipoprotein (LDL) cholesterol did not change significantly from baseline at any dose.
Although HDL increased at the 0.3 and 1.0 mg doses, it returned to normal upon discontinuation. Triglyceride levels decreased from baseline at all doses.
Headache and dry mouth were the most common side effects.
In a recent case report, a healthy 24-year-old man displayed signs of hepatocellular liver injury.
These symptoms developed a week after drug cessation.
The man had a history of binge drinking, was not on regular medications, and had no previous history of liver disease.
Of concern, this hepatotoxicity lies within the spectrum of liver injury associated with androgenic anabolic steroids.
Many online blogs tout Ligandrol as being extremely effective for enhancing performance, bulking (vs. cutting), muscle hardening, increasing vascularity, gaining size, and enhancing recovery.
Fitness enthusiasts are advised to take between 5 mg and 10 mg daily for 6 to 10 weeks, along with the disclosure that there is a risk of testosterone suppression at doses greater than 10 mg.
Similar to Ostarine, Ligandrol is often combined in SARMs stack for additional benefits.
Anecdotal side effects described in the fitness and bodybuilding arenas include nausea, fatigue, headaches, and low libido, which may all be attributable to reduced testosterone.
Testolone RAD-140 SARM
Testolone is a SARM used primarily for the treatment of muscle wasting and breast cancer. Developed by Radius Health, Inc.,
Testolone is reportedly still in first-stage clinical trials, with results expected later this year.
Thus, little is currently known about its safety.
One recent case report, however, describes significant liver injury in a 49-year-old man who had taken the drug (dose not reported).
Elevations in bilirubin, AST, ALT, and creatinine indicated mixed hepatocellular-cholestatic liver injury.
Liver histology also revealed inflammation.
However, all liver tests had completely normalized at 12 months following his initial presentation.
For gaining lean muscle mass and strength in the gym, SARMs users anecdotally recommended that RAD-140 SARM be taken at 5 mg to 30 mg daily for 8 to 16 weeks.
There is additional anecdotal evidence of side effects including sleeplessness and lethargy.
Andarine S4 (GTx-007)
To date, there are no human clinical studies with Andarine.
In the fitness community and on various online forums, it is touted as a muscle-boosting supplement that elicits weight loss and promotes muscle building and repair.
However, it is regarded as being comparatively weaker than other popular SARMs, so it is commonly stacked with other SARMs.
Using Andarine by itself at 25 mg per day purportedly improves mood and general wellness, whereas increasing the dose to 50 mg per day only modestly boosts strength, lean mass, and fat burning.
For bulking, it is recommended that Andarine S4 (50 mg) be stacked with Testolone (10 mg) daily for 8 to 12 weeks.
For strength, it is suggested that Andarine (50 mg) be stacked with Ligandrol (10 mg) daily for 2 to 3 weeks.
For cutting, it is advised that it (25 mg) be stacked with Cardarine (20 mg, a non-SARM, paroxisome proliferator-activated receptor-delta agonist) daily for 12 weeks.
For body recomposition (i.e., simultaneously losing fat and gaining muscle), it is recommended that Andarine (50 mg) be stacked with both Ostarine (25 mg) and Cardarine (20 mg) daily for 9 to 12 weeks.
The primary side effects reported with Andarine are altered vision (i.e., yellow-tinged) and suppression of testosterone.
SARMs PCT (Post Cycle Therapy)
In the fitness and bodybuilding communities, it is generally recognized that a weeks-long SARM regimen likely lowers testosterone levels.
In order to maintain gains in muscle mass and strength, facilitate the body’s recovery from any potential hormonal imbalance, and expedite the elevation of testosterone levels to normal.
It is recommended on numerous nonmedical, online forums that periods of post cycle therapy (PCT) be incorporated in between each cycle of SARMs use.
Many different PCT formulations that claim to naturally increase testosterone, reduce estrogen, stabilize cortisol, and enhance liver health are available commercially.
These formulations may include, but are not limited to, ingredients such as the aromatase inhibitor arimistane (an antiestrogen supplement) and D-aspartic acid (DAA).
Other common PCT supplements are Clomid (clomiphene citrate) and Nolvadex (tamoxifen).
These are prescription drugs in the United States but may be acquired online through foreign sources.
Clomid is a selective estrogen receptor modulator (SERM) that increases testosterone production, thereby preventing gynecomastia.
Clomiphene is advised when the SARM cycle is heavy, as it acts as a strong PCT.
However, it also carries the most reported side effects—mood swings, headaches, and altered vision at high dosages.
Nolvadex is a less potent SERM that works similarly.
Although formulations including natural extracts and non-SERM ingredients are theoretically safer than Clomid and Nolvadex, their effectiveness has not been scientifically proven.
Recreational or Bodybuilding SARMs users recommend that the PCT dosage be front-loaded when testosterone levels are lowest, thereby lowering the dose required when testosterone levels are closer to or returned to normal.
Users also advise that PCT therapy be started immediately the day after a SARM cycle is done, typically lasting 4 weeks.
To complicate matters, the length and even necessity of a PCT cycle are influenced by the strength and dose of the SARM used.
Until there are concrete clinical data, the potential adverse effects of cycling SARMs with PCT supplements will remain unknown.
Selective androgen receptor modulators SARMs are intended to have the same kind of effects as androgens however they are more selective in their action allowing them to be medically for more uses than traditional steroids.
SARMs signify a new era of tissue-selective androgens with an unknown potential to treat (and possibly cure) several diseases.
SARMs Comparison to testosterone
Currently used androgens for male hormone replacement therapy are typically injectable or skin delivery formulations of testosterone or testosterone esters.
Injectable forms of testosterone esters (such as testosterone enanthate, propionate, or cypionate) produce undesirable fluctuations in testosterone blood levels, with overly high levels shortly after injection and overly low afterward.
Skin patches do provide a better blood level profile of testosterone, but skin irritation and daily application still limit their usefulness.
SARMs provide the ability to design molecules that can be delivered orally, but that selectively target the androgen receptors in different tissues differently.
The goal of research in this area is to allow a customized response:
Tissues that are the target of the therapy will respond as they would to testosterone; other tissues where undesirable side-effects are produced will not.
None of the SARMs yet developed are truly selective for anabolic effects in muscle or bone tissues without producing any androgenic effects in tissues such as the prostate gland.
However, several nonsteroidal androgens show a ratio of anabolic to androgenic effects of greater than 3:1 and up to as much as 90:1 (RAD-140), compared to testosterone, which has a ratio of 1:1.
Research is continuing into more potent and selective SARMs, as well as optimizing characteristics such as oral bioavailability and increased half-life in vivo, and seeing as the first tissue-selective SARMs were only demonstrated in 2003, the compounds tested so far represent only the first generation of SARMs and future development may produce more selective agents compared to those available at present.
SARMs For Men
For example, if the target is bone growth in elderly men with osteopenia or osteoporosis, but with no overt signs of hypogonadism, a SARM targeting bone and muscle tissue but with lesser activity on the prostate or testes would be more desirable.
SARMs for Women
A SARM for women would ideally stimulate bone retention, or libido and other function that androgens can influence, without negative side-effects such as development of male gender characteristics (virilization), increased LDL/HDL ratios, liver dysfunction, and so forth.
MK-2866 also known as Ostarine or Enobosarm
- Enobosarm (Ostarine MK-2866, GTx-024, S-22) – One of the most popular SARMs, affects both muscle and bone, intended mainly for osteoporosis but also general treatment for andropause and reversing muscle sarcopenia in the elderly and for cachexia in cancer patients.
- BMS-564,929 – Mainly affects muscle growth, intended as general treatment for symptoms of andropause
- LGD-4033 (Ligandrol) – pharmacological profile similar to that of enobosarm.
In 2013, some supplement companies began selling various SARMs as supplements, in purported violation of both the Food and Drug Administration's Dietary Supplement Health and Education Act of 1994 (DSHEA) and the intellectual rights of the patent holders of the compounds.
In 2017 it was found that many of the supplements being sold claiming to be SARMs do not actually contain the chemical in question.
In reality, only 52% of the products contained any traces of SARMs at all.
In October 2017, the Food and Drug Administration issued warning letters to three supplement companies notifying them that SARMS are classed as unapproved drugs and can cause potential adverse side effects associated including cardiovascular and liver damage.
Are SARMs Legal?
In 2015, quarterback of the Florida Gators, Will Grier, allegedly tested positive for Ligandrol (LGD-4033), a claim that the University of Florida denies.
In 2017, Joakim Noah was banned for twenty games by the NBA for testing positive for Ligandrol.
Sean O'Malley, the American mixed martial artist who competes in the Bantamweight division of Ultimate Fighting Championship, was temporarily suspended by the Nevada State Athletic Commission.
In June 2019 after his sample tested positive for Ostarine MK-2866 ahead of this fight against Marlon Vera at UFC 239 on July 6 in Las Vegas.
In July 2019, tennis player Beatriz Haddad Maia from Brazil received a provisional suspension after she tested positive for selective androgen receptor modulators.
Shayna Jack, the Australian swimmer, was forced to withdraw in July 2019 from the national squad before the world championships in Gwangju, South Korea after she tested positive for LGD-4033.