Are SARMs side effect free?
Also known as the Selective Androgen Receptor Modulators, SARMs are tissue selective anabolic agents designed with the intention of replicating the anabolic effects of steroids in muscle tissue and bone without the androgenicity in other affected tissues.
On paper, SARMs have a distinct advantage in terms of tissue selectivity, androgen-receptor specificity, and apparent lack of side effects that are otherwise commonly experienced with anabolic steroid use.
Anabolic steroids can cause various adverse effects in the human body, most notably deriving from their androgenicity.
Side effects like hair loss on the scalp, acne flare ups, hair growth on the body, infertility, among several others can all occur with steroid use.
These side effects are even more pronounced in females because of their Estrogen dominant hormone profile.
Even a mild increase in the androgen index in women can result in male-like manifestations like hirsutism and deepening of the voice.
Obviously, the therapeutic potential of SARMs is incredibly promising.
They are designed to provide the same muscle growth as Testosterone, but without any of the negative androgenic side effects that would occur with exogenous androgen use.
However, SARMs aren't without their own issues, despite what many advocates will repeatedly state.
Two Sides of the SARMs Side Effect Argument
There is a lot of hype around SARMs.
Typically, individuals will fall into either one of two categories.
One group will tell you that SARMs are side effect free steroid alternatives, and the other group will tell you that SARMs suck and are useless.
Now, to be clear, SARMs DO bind with a high affinity to the androgen receptor, they DO transcribe tissue-selective anabolic effects via androgen receptor activation, and they DO work.
They are not side effect free though.
The Misinterpretation Of SARMs Studies
When you actually get into the data of what a SARM is to begin with, you will quickly realize that this “tissue selective” category of anabolic agents is fairly general, and compounds of varying levels of efficacy will be lumped into the same category as one another.
Basically, effective SARMs are lumped into the same category as poor SARMs, simply because they all have a better anabolic to androgenic activity ratio than Testosterone.
The reference androgen used to evaluate the efficacy of a SARM is Testosterone.
The problem with that is that Testosterone is not tissue selective at all.
It's 5 alpha-reduced into a far more androgenic metabolite, DHT.
In the medical community, Testosterone is seen as a subpar treatment for musculoskeletal degenerative diseases because of its androgenic activity in the body.
Anabolic steroids were designed for this very purpose, and the pursuit of synthesizing anabolic steroids with greater levels of efficacy than Testosterone was fueled by the therapeutic limitations of Testosterone in a clinical setting.
If an old frail woman comes in with a muscle wasting disease, while slamming her with Testosterone will probably help prevent further muscle loss, it will inevitably lead to horrible masculinizing side effects.
Clearly you can see where the limitations of steroids lie in this capacity.
Clinical studies use the anabolic to androgenic tissue selectivity of Testosterone as the benchmark for SARMs, which frankly, is not very good.
If you have an anabolic agent with superior tissue selectivity to Testosterone, that doesn't mean it is free of some level of androgenic activity itself.
For example, if SARM #1 has a 500:1 level of tissue selectivity, but SARM #2 has a 4:1 level of tissue selectivity, they will both be categorized as “SARMs” in the clinical data.
You can imagine how misleading this ends up being when this information is poorly interpreted and regurgitated.
Both are SARMs and are tissue selective relative to Testosterone, but are they equal to one another in efficacy?
Not even close.
MENT And Trenbolone Have SARM-Like Actions
Looking at the clinical data, you'll see things like MENT (Trestolone) and Trenbolone, being referred to for their SARM-like characteristics.
Trenbolone, despite being a very potent anabolic androgenic steroid, is described as “SARM-like” because of its level of tissue selectivity relative to Testosterone [R].
Just because an anabolic compound milligram per milligram may be more efficacious than testosterone, it's still going to induce androgenic effects at some level, and this is dependent on the chemical makeup of the compound in question and how it interacts with the androgen receptor.
All things considered, there are tons of different factors to take into account here, but the point is that SARMs are not free of androgenic activity as they are often implied to.
As the efficacy of SARMs is nuanced—meaning, some are better or worse than others—one common issue with this particular class of compounds is many of them negatively affect many of the same health markers as traditional anabolic steroids.
The Two Polar Opposite Arguments For And Against SARMs
The main problem with SARMs comes from the lack of accurate information coming from both camps of individuals.
Both the advocates and the critics of SARMs disseminate incorrect information constantly, and it leaves the general public who have interest in this niche completely clueless as to who to believe.
When the “gurus” and “experts” in the industry don't even know what the hell they're talking about, how can you possibly make an informed decision?
You can't, unless you delve into the data yourself and make an educated conclusion, because the “gurus” sure as hell aren't interpreting the data correctly before they hop on social media and parrot to the masses about how great (or how horrible) SARMs are and why.
Side Effects Of SARMs Currently In Clinical Trials
Here's the deal, there are only a handful of SARMs being pushed through pharmaceutical pipelines in clinical development right now.
As of now, the following compounds are the only SARMs that have been studied on humans:
Ostarine Side Effects
Ostarine also known also known as Enobosarm, GTx-024 and MK-2866 is the most well known and extensively studied selective androgen receptor modulator (SARM) right now.
It is categorized as a SARM because of its unique selectivity at the androgen receptor where it exhibits a significant amount of anabolic activity in the body relative to androgenic activity.
It is being researched to determine if it is a potential treatment for the management of muscle and bone wasting diseases.
Increased Hemoglobin And Hematocrit
Small, statistically significant increases in hemoglobin and hematocrit were observed with Ostarine 3 mg compared to placebo [R].
Effect On Lipids
Reductions in serum lipids (namely HDL and LDL) occurred in a dose dependent manner with Ostarine usage, while another study only showed reductions of HDL levels (otherwise known as “good cholesterol”) [R, R].
We at least know for sure that Ostarine has a negative effect on HDL levels, which is notable as this is a common side effect of all traditional anabolic steroids, and other SARMs.
Natural Testosterone Suppression
Ostarine has also shown to significantly lower Sex Hormone-Binding Globulin (SHBG) and serum total testosterone levels in clinical trials in subjects treated with 1 mg of Ostarine or higher [R].
While SHBG was always significantly impacted at notable dosages, suppression of LH and FSH wasn't consistently proven throughout Ostarine's clinical trials.
However, after referencing anecdotal logs of baseline pre-Ostarine blood work compared to mid-Ostarine blood work with dosages several times higher than the 0.1 mg, 0.3 mg, 1 mg, 3 mg dosages used in trials (users commonly use Ostarine at upwards of 25 mg per day for several months), I believe it's safe to say that Ostarine does also show blatant reductions in all of these hormones markers in a dose dependent manner, the dosages in the studies just weren't high enough to yield this data.
The degree to which even high dosages of Ostarine suppress LH and FSH is far less than that of traditional anabolic steroids though, which should be noted.
The process of recovering to baseline healthy endocrine function would be hindered to a far greater extent in steroid users.
Short-lived increases in ALT to above the upper limit of normal were observed in eight subjects in one of Ostarine's clinical trials.
The ALT observations in seven of eight subjects had resolved while still continuing their daily dosage, and no subject had clinically significant abnormal levels of ALT or AST at the end of study.
One subject was discontinued due to an elevation in ALT 4.2 times the upper limit of normal.
The ALT level in that subject returned to normal levels after discontinuation of the Ostarine [R].
This was with dosages of no higher than 3 mg per day, so it is only logical to assume that common recreational dosages of Osatarine (upwards of 25 mg) may exhibit some level of liver enzyme elevation.
This is contradictory to common broscience theories that assert that there is zero chance of liver toxicity from SARMs at any dosage amount, or that an increase in ALT in their blood work must mean that they received methylated prohormones instead of SARMs.
At therapeutic dosages, there appears to be a low risk profile, but it should be noted that there may be some notable degree of liver toxicity at dosages commonly used for performance enhancement, which would likely resolve itself after cycling off.
LGD-4033 Side Effects
LGD-4033, also known as Ligandrol, was originally developed by Ligand Pharmaceuticals, Inc. and was licensed afterwards to Viking Therapeutics.
It is now officially named VK5211 under Viking Therapeutics.
LGD-4033 is a selective androgen receptor modulator (SARM) developed to be a potential treatment for a variety of musculoskeletal degenerative diseases.
LGD-4033 is purported to be the most potent SARM currently in clinical trials, with its data exhibiting the most favorable ratio of anabolic activity relative to androgenic activity.
While LGD-4033 was generally regarded as safe in human trials using dosages as high as 22 mg per day, that doesn't mean it had no negative side effects.
These were some of the negative side effects reported in the clinical data.
Effect On Lipids
The clinical data shows dose-dependent suppression of HDL cholesterol and triglyceride levels with LGD-4033 usage [R].
A negative effect on HDL levels is consistently noted as a common side effect of all traditional anabolic steroids, and other SARMs.
Despite SARMs ability to be selective about how they exert anabolic activity in the body, they evidently do not differ much from anabolic steroids in regards to their effects on lipid profiles.
Natural Testosterone Suppression
SARMs have shown to suppress luteinizing hormone (LH) and follicle stimulating hormone (FSH) through the hypothalamus-pituitary-testis axis, thus decreasing testosterone in a dose-dependent manner [R].
Ligandrol suppressed Sex Hormone-Binding Globulin (SHBG) and total testosterone levels in clinical trials in a dose-dependent manner.
Serum free testosterone and FSH levels were only suppressed in the subjects treated with 1 mg of Ligandrol [R].
There was no LH suppression in subjects treated with Ligandrol during the 21 day clinical trial conducted on healthy young men.
However, the treated groups were only administered either 0.1 mg, 0.3 mg, or 1.0 mg for three weeks, which are relatively low dosages and is also a short time frame.
Based on the overwhelming supporting data on anabolic agents collected over the past 50 years, I believe it's safe to say that LGD-4033 will show blatant reductions in all of these hormone markers in a dose dependent manner, and the dosages in the studies just weren't high enough to consistently yield this data.
At higher dosages (above 1 mg), I am sure serum free testosterone levels would drop considerably as the dose was titrated up, and other markers would decrease in parallel.
LGD-4033 did not result in any significant changes in AST or ALT levels in human trials [R].
However, it should be noted that in a relevant clinical trial conducted on Ostarine (a SARM with an identical mechanism of action), short-lived increases in ALT to above the upper limit of normal were observed in eight subjects [R].
Taking this into consideration, it's entirely possible that LGD-4033 could potentially also exhibit some degree of liver toxicity at dosages higher than the 1 mg trialed where they assessed those health markers.
At therapeutic dosages, there appears to be a strong safety profile and the data suggests a complete absence of liver toxicity.
GSK2881078 Side Effects
GSK2881078, a SARM being investigated by GlaxoSmithKline for the treatment of musculoskeletal degenerative diseases, was tested in a 2-part, randomized, double-blind, placebo-controlled dose-escalation Phase 1 study [R].
This trial was conducted on 108 participants broken up into cohorts of young men and postmenopausal women.
GSK2881078 was found to be well tolerated.
Expectedly, GSK2881078 caused reductions in HDL levels.
A few individuals noted constipation, dyspepsia, and nausea.
1 woman developed a maculopapular rash with biopsy consistent with a drug reactions.
2 women experienced elevated ALT values 2-2.5 times the upper limit of normal during treatment.
2 men experienced muscle soreness and elevated creatine kinase levels weeks into the follow-up period.
PF-06260414 Side Effects
PF-06260414, a novel SARM, was involved in a Phase 1 combination, randomized, double-blind, placebo-controlled, single- and multiple-dose escalation, parallel-group study in 72 healthy adult men of mixed ethnicity [R].
PF-06260414 was found to be well tolerated.
Decreases in HDL levels and increases in serum ALT levels were noted and consistent with other findings we have on SARMs.
Headaches, decreased appetite, dizziness, and upper respiratory infection were also noted in some of the participants.
1 man discontinued the drug due to fatigue, and another discontinued due to anxiety.
Elevated Estrogen Or Decreased Estrogen
This side effect applies to all SARMs and is not reported in the clinical data, as the therapeutic dosages used, or durations of exposure, were likely insufficient to produce this outcome.
SARMs do not aromatize into Estrogen, however, by suppressing natural Testosterone levels it can create an unfavorable balance between Testosterone and Estrogen in the body.
By occupying the androgen receptor with such a high affinity, SARMs can divert a significant amount of Testosterone to aromatize into Estrogen that wouldn't have otherwise.
The consequence of this is a systemic elevation of Estrogen levels in the body, which is commonly misinterpreted as prohormone laced SARMs.
Common symptoms of high estrogen include:
- Acne, oily skin
- Erectile dysfunction
- Low libido
- Gynecomastia (man boobs)
- Water retention
- High blood pressure
- Enlarged prostate
- Shrunken testicles
- Sugar cravings
While SARMs can cause Estrogen levels to rise via the increased aromatization of circulating Testosterone, long-term use, or high dosages of SARMs can cause an opposite effect, where the body has such a low level of circulating Testosterone via endocrine suppression that the body no longer has enough aromatization occurring to satisfy Estrogen fulfilled physiological functions.
Low Estrogen levels can lead to a variety of health problems.
Common symptoms of low estrogen include:
- Dull weak orgasms
- Dry skin and lips
- Erectile dysfunction
- Low libido
- Mood swings
- Loss of appetite
- Decreased bone mass and strength
Interpreting The Data – SARMs Vs Anabolic Steroids
There is a common misconception that all of the human trials on SARMs have been conducted using minuscule dosages, and would lead to catastrophic outcomes if used at the same dosages of traditional steroids.
While I agree that the data on “high dosages” of SARMs is too limited right now, there were ascending dose studies to evaluate the tolerability of these compounds, they are often just overlooked.
Highest Dosage Of Ostarine Well Tolerated In Humans
Ostarine has been evaluated in 27 completed or ongoing clinical trials.
About 1500 subjects in total have been treated with Ostarine in some capacity, with dosages ranging from as low as 0.1 mg all the way up to 100 mg.
Ostarine was observed to be generally safe and well tolerated in all of those trials.
One notable Phase 2 clinical trial that evaluated Ostarine as a form of hormonal therapy for women with estrogen receptor positive (ER+) and androgen receptor positive (AR+) breast cancer was broken down into two dose cohorts (9 mg and 18 mg daily).
The Phase 2 trial pre-specified threshold for success, clinical benefit response (CBR), was attained meeting the trial’s primary efficacy endpoint.
The trial enrolled the predefined number of evaluable patients in both dosage arms with at least 44 patients in each of two cohorts receiving 9 mg or 18 mg daily doses of Ostarine (Enobosarm) respectively [R, R].
This study in particular presented the first opportunity for us to gather clinical data representing what results would occur from what would generally be considered “high dosages” of Ostarine.
Highest Dosage Of LGD-4033 Well Tolerated In Humans
The first Phase 1 trial involving LGD-4033 was a randomized, double blind, placebo controlled trial conducted in 2009 on 48 healthy male volunteers.
The volunteers were divided into six cohorts and received an escalating daily dosage of LGD-4033 ranging from 0.1 mg per day to 22 mg per day.
All doses of LGD-4033 tested in humans (even the 22 mg per day dosage) were shown to be safe and well-tolerated, with predictable pharmacokinetics.
Are SARMs Safer Than Steroids?
In a therapeutic context, when compared with steroidal androgens, SARMs appear to be much better tolerated with fewer incidences of severe adverse events.
They are also orally bioavailable, which lowers the risk of accidental exposure, which is a limitation of topical Testosterone.
Obviously when it comes to adoption and use, oral therapies are going to be favored over injections as well.
The most consistent hindrance of health markers shared between most SARMs are decreases in HDL levels and transient increases in ALT.
However, this is in a therapeutic context, not a supraphysiological muscle bulding context for bodybuilding purposes.
When it comes to using massive dosages for bodybuilding purposes, are SARMs still safer than steroids?
From an androgenicity context, I think the answer is undoubtedly yes.
However, when it comes to hepatotoxicity, suppressed lipids and HPTA, is the risk to reward that much different?
That remains to be seen.
Frankly, I believe certain SARMs are safer at all dosages, but the issue is that their muscle building potential is lower than that of many anabolic steroids.
Significantly lower when it comes to certain SARMs (some are formidable to many traditionally used steroids).
Some are much more effective than others, but the question arises, if you are going to smash your lipids and shut down your natural Testosterone levels anyways with megadoses of SARMs, would it not be worth it to just take the plunge into a steroid cycle instead if muscle growth is the goal?
This is where the real debate is.
The debate is not whether or not SARMs work.
We already know they work and will continue to improve as more powerful SARMs are developed, the debate lies in the anabolic ceiling of the current SARMs in development, and their risk to reward profile in a supraphysiological context.
The SARMs Side Effect Bottom Line
I think SARMs are the future of performance enhancement as well as musculoskeletal degenerative disease treatment.
They will continue to improve and become more and more efficacious as time goes on, and slowly phase out traditional less tissue selective anabolic steroids.
However, this does not mean that SARMs are side effect free, and they certainly are not all equal to one another simply because they are categorized as a SARM.
Take S23 for example.
S23 is a selective androgen receptor modulator (SARM) currently under development for potential use as a male hormonal contraceptive.
While it has a superior level of anabolic to androgenic tissue selectivity when compared to Testosterone, this does not mean it is an ideal SARM at all.
Something overlooked is that S23 is also being evaluated as a potential treatment for androgen deficiency in postmenopausal women.
Basically, something better than Testosterone to increase the libido of androgen deficient women in menopause.
That in itself should tell you everything you need to know about its inherent androgenicity.
It's literally being developed as a contraceptive for men which would replace the androgen dependent functions typically mediated by Testosterone and DHT in the body, as well as a means to increase the androgen index in postmenopausal women.
Just because its more tissue selective than Testosterone, this doesn't mean its as tissue selective as another more efficacious SARM like LGD-4033.
At the end of the day, SARMs are not side effect free, but they aren't as bad as they are made out to be by the critics.
There isn't enough data to make any conclusive statements on their long-term safety or overall efficacy, but from what we do know, we can see that their development is definitely on the right track and is paving the way for superior anabolic agents.