While the exact half-life of RAD-140 in humans is not yet known, preclinical studies suggest that it may be around 60 hours. Ostarine and LGD-4033, while still effective in promoting muscle growth, may not be as potent as RAD-140 in this regard. A typical PCT protocol may last for 4-6 weeks and include the use of aromatase inhibitor like 6-Oxo, testosterone boster like Alchemy and complete products like Fusion Supplements’ Post Cycle Matrix. These effects are typically mild and transient, but they can be more pronounced in some individuals. SARMs are more selective, affecting androgen receptors in muscle and bone, and their structure is nonsteroidal. Similarly, two phase III trials with anamorelin, a non-peptide, orally-active, centrally-penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor, in subjects with lung cancer and cachexia showed that it increased muscle mass but failed to improve hand grip strength (104). The dissociation of anabolic from androgenic effects is proposed to result from tissue-selective actions. In this paper we critically evaluate the evidence for the purported enhanced tissue selectivity of SARMs compared with traditional steroidal androgens, and assess their results in clinical research. In 1999, the term "selective androgen receptor modulator" or "SARM" was introduced, as the mixed agonist–antagonist and tissue-selective activity of these nonsteroidal androgen receptor agonists had similarities with selective estrogen receptor modulators (SERMs). Phase II trials of enobosarm for stress urinary incontinence—considered promising, given that the levator ani muscle in the pelvic floor has a high androgen receptor density—did not meet their endpoint and were abandoned. Those that have advanced to human trials show stronger effects in bone and muscle tissue and weaker effects in the prostate. The pharmaceutical industry invested billions in their development precisely because they represent a more targeted approach to treating muscle wasting, osteoporosis, and age-related sarcopenia with fewer side effects than testosterone. Selective androgen receptor modulators have been almost universally condemned in the fitness and health space. Our cross-sectional data imply that these compounds might alter intramuscular androgenic hormone and receptor concentrations along with promoting muscular strength, when compared with previously published data from trained males. MK-677 increases growth hormone and IGF-1 through ghrelin receptor agonism, complementing the AR-mediated anabolic effects of RAD-140. Preclinical data suggest RAD-140 is anabolically potent per milligram, comparable to moderate testosterone doses ( mg/week). The combination of anabolic activity without estrogenic water retention makes RAD-140 a compound of interest for simultaneous fat loss and lean mass gain. The theory is that at these lower doses, you get tissue-selective anabolic signaling without triggering meaningful HPTA suppression. For most medical applications, an AAS with potent anabolic and minimal androgenic and cardiovascular effects would be an advantage. Anabolic androgenic steroids (AAS) are used to treat a variety of medical conditions, but their side effects have fueled a search for a new class of drugs, with a better separation between desirable anabolic and undesirable androgenic effects. Cardarine (GW ) is a PPAR-delta agonist that enhances fatty acid oxidation and endurance without interacting with the androgen receptor. This effect is consistent with its selective AR agonism in bone tissue and may benefit populations at risk for osteoporosis. Clinical trials at lower doses (1-3 mg) still showed statistically significant lean mass increases, suggesting a dose-dependent anabolic response. In skeletal muscle, MK-2866 robustly activates anabolic signaling pathways including PI3K/Akt/mTOR, increasing muscle protein synthesis and reducing protein degradation via suppression of ubiquitin-proteasome and myostatin pathways. The tissue selectivity of MK-2866 arises from its non-steroidal structure, which produces a distinct AR conformational change compared to testosterone or DHT. The DNA Binding Domain (DBD) is highly conserved between receptors, has two zinc finger motifs that are responsible for DNA recognition and dimerization, and plays a role in AR binding to Androgen Responsive Elements (ARE) within the regulatory regions of androgen responsive genes. Decades after the discovery of SERMs, Selective Androgen Receptor Modulators (SARMs) (20) were first described and subsequently developed to facilitate tissue-selective activation of the AR. Tamoxifen and raloxifene are classical examples of SERMs that function as antagonists in the breast, but as agonists in the uterus or bone, respectively, either directly or through metabolic conversion (16–19). To circumvent the limitations resulting from global receptor activation, researchers sought ligands, referred to as Selective Receptor Modulators (SRMs) that activate receptors in a tissue-specific manner. As it is ideal to have targeted therapeutic effects, the ubiquitous expression of receptors presents a therapeutic challenge and precludes wider use of exogenous hormone administration. Although both the beneficial and the growth-promoting effects arise from agonistic activities of estrogens, the tissue of action determines whether the effect is beneficial or detrimental. Nevertheless, because negative feedback on the hypothalamo-pituitary gonadal axis (HPGA) largely relies on estrogenic feedback, gonadotropin suppression may be mild in therapeutic dosages, as also is the case for nonaromatizable steroidal androgens (51–54). When SARMs suppress gonadotropin release, testosterone and estradiol levels fall, potentially causing a relative or absolute estrogen deficiency. Finally, an overarching issue in SARM development for many clinical applications is their lack of estrogenic effects. DHN has lower AR binding affinity than nandrolone and thus may result in reduced rather than amplified activity in tissues expressing 5α-reductase (47). "More research needs to be done to know more about SARMs’ effects and their long-term effects, but the preliminary research has raised a number of concerns," Dr. Sanyal shares. In truth, though, SARMs may be more harmful than we initially thought because they could cause widespread complications for your body. Examples of SARMs include ostarine (Enobosarm, MK 2866), andarine (S4), ligandrol (LGD-4033), LGD-3033, TT-701, RAD140 (Testolone) RAD150, and S23. Teens are targeted on social media with marketing promoting use of SARMs to increase muscle and athletic performance. The "overdose" risk is more about taking high doses for an extended time period for body building or performance enhancement. Long-term effects may include risk of heart attack or stroke, permanent liver damage, and increased risk of tendon rupture. Short-term effects include acute liver injury, increased blood pressure and heart rate, chest pain, psychological effects (such as mood swings, psychosis, irritability, anxiety), sleep disturbance, fatigue, acne, and hair loss). "SARMs are still in the investigational stages by the FDA, so their safety profile and long-term effects haven’t been well studied," says Dr. Sanyal. Furthermore, the risks of misusing anabolic steroids have been well-studied and understood for years. "SARMs have yet to be subjected to the high-quality clinical studies that need to happen to fully understand their risks and any benefits," continues Dr. Sanyal.
