SARMs & Weight Loss: MK-2866 + Cardarine
Although the goal of Selective Androgen Receptor Modulator (SARM) research has historically aimed to boost lean body mass, scientists are increasingly curious about a possible role for SARMs in weight loss. Specifically, is it possible for SARMs to efficiently promote fat loss as part of an exercise regimen, rather than promote overall body mass gains? Given that most clinical research has thus far focused on strength and anabolic metrics, we need to consider SARM-adjacent research for insights into how to leverage SARMs for shedding pounds rather than building muscle.
The good news is that there is plenty of evidence that increasing natural androgen levels can effectively promote weight loss, especially for those who are over their target weight by more than 30% –. Read on to discover why a stack containing MK-2866 plus Cardarine may prove to be the optimal SARM-oriented solution for weight loss to be elucidated by emergent clinical trials.
First, it is important to recall that SARMs function by mimicking the action of androgens (ie. testosterone) in selective tissues of the body, and it turns out that androgens actually affect a much broader array of tissues than you might think. For instance, one of the target tissues of testosterone is the brain, where it functions in part to modify behavior. Moreover, it turns out that behavioral adaptation in response to increasing androgens is an exciting area of ongoing research.
Being overweight is largely a consequence of behavior (ie. lack of motivation to exercise, lack of motivation to curb overeating, etc). Intriguingly, research has shown that raising testosterone levels in the brain causes positive behavioral changes that make losing weight easier. So why not just inject testosterone or use testosterone creams? Unfortunately, the negative side effects of testosterone replacement therapy (TRT) (acne, risk of blood clots, testicle shrinkage) in addition to the more serious cardiovascular riskshave made physicians reluctant to prescribe androgens . Fortunately, the improved safety profile of SARMs vs conventional androgens offers a better alternative .
SARMs Reinforce A Neurobehavioral Positive Feedback Cycle
If you are overweight, then losing those unwanted pounds will require behavioral changes that are driven primarily by being accountable to yourself and your goals. Moreover, successful behavioral changes need to be reinforced via neurobehavioral plasticity in order for habits to become second nature. Fortunately, research has shown that androgens promote self-accountability and neurobehavioral reinforcement due to their positive effect on promoting social competition and motivation –.
Accumulating evidence show that androgens modulate the motivation to complete goals via actions on the mesocorticolimbic dopaminergic system in the brain. Work in animals has so far supported this assumption by identifying the neurobiological pathways linking testosterone, and its primary metabolites 5α-dihydrotestosterone (DHT) and estradiol to several brain regions of the dopaminergic system. For instance, fundamental neurobiological studies have demonstrated that dopamine neurons contain androgen receptors (AR) , and thus they can be activated by SARMs such as MK-2866.
In the brains of adolescent male rats, testosterone is also able to change—via direct action at AR—the levels of dopamine receptors, and levels of the dopamine transporter protein, which regulates dopamine availability , . These groundbreaking studies provide solid peer-reviewed evidence to back up the anecdotal evidence of SARMs promoting a key positive feedback loop of weight loss: motivation to lose weight, followed by exercise and dietary changes, reinforced by the dopamine reward system, thus promoting a continuing motivation to lose more weight (Fig. 1).
Clinically, both men and women with suboptimal androgen levels exhibit apathy and lack of motivation for self-improvement (ie. weight loss) . Intriguingly, even single-dose androgen administration in healthy subjects increases motivation to engage in cued behaviors and increases BOLD activation in the ventral striatum (ie. Blood-oxygen-level-dependent imaging in the part of the brain important for reward behavior) which is most pronounced in individuals with low motivation . Thus, if your low motivation to lose weight is hampering your efforts, activating AR via SARMs can potentiate the induction of the dopamine induced positive reinforcement of the necessary behavioral changes to keep shedding pounds.
SARMs To Help You Compete Against Yourself
The most successful athletes (ie. those who are among the fittest people on earth) have learned to continually push themselves by setting progressive goals. This phenomenon can be thought of as self-competition, and it is crucial to main consistent results . An interesting and open question is the role of androgens a self-competition.
Evidence supports a role of androgens in this regard by showing that individuals’ level of self-efficacy, effort, and motivation are positively related to serum androgen levels in both men and women , . Furthermore, successful achievements of effortful challenges (ie. successful weight loss) enhance motivation and increase the value of the achievement as reflected by increased dopamine signaling in the ventral striatum (ie. the midbrain) , which as we’ve discussed can be potentiated with SARMs such as MK-2866.
SARMs & Fat Oxidation (ie. Fat Burning)
In addition to boosting motivation to lose weight, SARMs can also promote fat oxidation by activating Androgen Receptors (AR) in numerous tissues and cell types. It turns out these receptors, which are activated by SARMs, are present not only in muscle tissues but also in adipose tissues (ie. fat cells) that consume and expend energy . Previously it has been reported that blocking androgen hormone production decreases fat oxidation during acute exercise  which can be seen in Fig. 2. Thus, by deduction we know that the action of SARMs can promote fat oxidation in adipose tissues during exercise.
Recent findings from large clinical studies have shown that long-term androgen therapy in men can produces significant and sustained weight loss, substantial reduction in waist circumference and BMI and overall improvement in body composition. Further, androgen therapy ameliorates components of the metabolic syndrome. These improvements induced by Androgen Receptor have been attributed to improved mitochondrial function, increased energy utilization, increased motivation and vigor resulting in improved cardio-metabolic function and enhanced physical activity , , .
According to a recently published review of ARs, androgens bound to the AR stimulate the induction of enzymes required for uptake of fatty acids released by lipolysis (ie. fat burning) from blood circulation and directly from adipocytes . Future investigations will be necessary to elucidate the effects of AR by particular SARMs on resting metabolism and determine a clear mechanism of increased fatty acids transport.
Cardarine: The Ideal SARM Companion to Supercharge Weight Loss?
What if your sincere desire to exercise in order to lose weight is hampered by lack of stamina and endurance necessary to burn calories? In this scenario, no SARM will be able to match the benefits offered by another compound, Cardarine, which is often misclassified as a SARM, but actually does not bind to AR. Instead, Cardarine binds to the PPAR family of gene regulators which promotes endurance capacity via aerobic glycolysis.
In the above study, which is also consistent with preclinical models, a significant decrease in serum insulin was observed at the 2 lower doses of Cardarine, implying an improvement in insulin sensitivity. Moreover, a different study demonstrated that Cardarine can reduce liver fat (Fig. 4). Fatty liver is an extremely common problem that affects roughly 1 in 4 American adults. If you carry excess abdominal weight you probably have a fatty liver.
In the context of trying to achieve exercise-induced fat burning, fatty liver actually prevents overall weight loss, as demonstrated by a recent clinical study . Thus, Cardarine’s effect on reducing fatty liver allows the body to more efficiently lose weight during exercise by enabling the liver to process fatty acids faster.
In order to lose weight, behavioral changes are always necessary. Research into the Androgen Receptor has provided valuable clues as to why SARMs like MK-2866 can supercharge fat burning. SARMs promote neurobiological plasticity and dopamine neuron reinforcement to jumpstart the positive feedback loop of motivation, exercise, and reward-satisfaction.
SARMs can also promote lipolysis/ fat oxidation in muscle and adipose cells. Finally, in order for your body to permit the cardio-metabolic endurance necessary to burn calories, Cardarine adds fuel to the fire by lowering free fatty acids and reducing fatty liver in order to allow your body to oxidize fat optimally. Excitingly, future clinical research will explore the underlying mechanisms responsible for the potent weight-loss combination of MK-2866 plus Cardarine.
*This information is for educational purposes only. These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.
- A. M. Traish, “Testosterone and weight loss: the evidence,” Current opinion in endocrinology, diabetes, and obesity. 2014.
- P. Mårin et al., “Androgen Treatment of Abdominally Obese Men,” Obes. Res., 1993.
- K. Groti, I. Žuran, B. Antonič, L. Foršnarič, and M. Pfeifer, “The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes,” Aging Male, 2018.
- D. Francomano, R. Bruzziches, G. Barbaro, A. Lenzi, and A. Aversa, “Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: A pilot study,” J. Endocrinol. Invest., 2014.
- P. Marin et al., “The effects of testosterone treatment on body composition and metabolism in middle-aged obese men,” Int. J. Obes., 1992.
- H. M. Behre et al., “A randomized, double-blind, placebo-controlled trial of testosterone gel on body composition and health-related quality-of-life in men with hypogonadal to low-normal levels of serum testosterone and symptoms of androgen deficiency over 6 months with 12 months open-label follow-up,” Aging Male, 2012.
- Y. A.A., Y. D.-J., E. D. Y., S. R., and S. F., “Early weight loss predicts the reduction of obesity in long-term testosterone replacement therapy regardless of age,” Endocrine Reviews. 2013.
- D. Francomano, A. Lenzi, and A. Aversa, “Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome,” Int. J. Endocrinol., 2014.
- G. Hackett et al., “The response to testosterone undecanoate in men with type 2 diabetes is dependent on achieving threshold serum levels (the BLAST study),” Int. J. Clin. Pract., 2014.
- D. J. Yassin, G. Doros, P. G. Hammerer, and A. A. Yassin, “Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life,” J. Sex. Med., 2014.
- S. Y. Kalinchenko, Y. A. Tishova, G. J. Mskhalaya, L. J. G. Gooren, E. J. Giltay, and F. Saad, “Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: The double-blinded placebo-controlled Moscow study,” Clin. Endocrinol. (Oxf)., 2010.
- O. Canguven, R. A. Talib, W. El Ansari, D. J. Yassin, M. Salman, and A. Al-Ansari, “Testosterone therapy has positive effects on anthropometric measures, metabolic syndrome components (obesity, lipid profile, Diabetes Mellitus control), blood indices, liver enzymes, and prostate health indicators in elderly hypogonadal men,” Andrologia, 2017.
- A. Grech, J. Breck, and J. Heidelbaugh, “Adverse effects of testosterone replacement therapy: An update on the evidence and controversy,” Therapeutic Advances in Drug Safety. 2014.
- S. Bhasin and R. Jasuja, “Selective androgen receptor modulators as function promoting therapies,” Current Opinion in Clinical Nutrition and Metabolic Care. 2009.
- A. B. Losecaat Vermeer, I. Riečanský, and C. Eisenegger, “Competition, testosterone, and adult neurobehavioral plasticity,” in Progress in Brain Research, 2016.
- P. B. Gray, T. S. McHale, and J. M. Carré, “A review of human male field studies of hormones and behavioral reproductive effort,” Hormones and Behavior. 2017.
- B. Studer and S. Knecht, Motivation: Theory, Neurobiology and Applications. 2016.
- L. M. Creutz and M. F. Kritzer, “Mesostriatal and mesolimbic projections of midbrain neurons immunoreactive for estrogen receptor beta or androgen receptors in rats,” J. Comp. Neurol., 2004.
- T. D. Purves-Tyson, S. J. Owens, K. L. Double, R. Desai, D. J. Handelsman, and C. S. Weickert, “Testosterone induces molecular changes in dopamine signaling pathway molecules in the adolescent male rat nigrostriatal pathway,” PLoS One, 2014.
- T. D. Purves-Tyson, D. J. Handelsman, K. L. Double, S. J. Owens, S. Bustamante, and C. S. Weickert, “Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra,” BMC Neurosci., 2012.
- S. Bhasin et al., “Testosterone therapy in men with androgen deficiency syndromes: An endocrine society clinical practice guideline,” Journal of Clinical Endocrinology and Metabolism. 2010.
- E. J. Hermans, P. A. Bos, L. Ossewaarde, N. F. Ramsey, G. Fernández, and J. van Honk, “Effects of exogenous testosterone on the ventral striatal BOLD response during reward anticipation in healthy women,” Neuroimage, 2010.
- T. McGarry, D. I. Anderson, S. A. Wallace, M. D. Hughes, and I. M. Franks, “Sport competition as a dynamical self-organizing system,” Journal of Sports Sciences. 2002.
- R. Costa, M. A. Serrano, and A. Salvador, “Importance of self-efficacy in psychoendocrine responses to competition and performance in women,” Psicothema, 2016.
- L. van der Meij, A. P. Buunk, M. Almela, and A. Salvador, “Testosterone responses to competition: The opponent’s psychological state makes it challenging,” Biol. Psychol., 2010.
- K. Lutz, A. Pedroni, K. Nadig, R. Luechinger, and L. Jäncke, “The rewarding value of good motor performance in the context of monetary incentives,” Neuropsychologia, 2012.
- S. Rodriguez-Cuenca, M. Monjo, M. Frontera, M. Gianotti, A. M. Proenza, and P. Roca, “Sex steroid receptor expression profile in brown adipose tissue. Effects of hormonal status,” Cell. Physiol. Biochem., 2007.
- N. Kim, J. Kim, K. Lim, and J. Park, “Role of dihydrotestosterone in whole-body energy utilization during acute running exercise in mice,” J. Exerc. Nutr. Biochem., 2018.
- D. M. Kelly and T. H. Jones, “Testosterone and obesity,” Obes. Rev., 2015.
- F. Saad, A. Aversa, A. M. Isidori, and L. J. Gooren, “Testosterone as Potential Effective Therapy in Treatment of Obesity in Men with Testosterone Deficiency: A Review,” Curr. Diabetes Rev., 2012.
- L. M. Butler, M. M. Centenera, and J. V. Swinnen, “Androgen control of lipid metabolism in prostate cancer: Novel insights and future applications,” Endocrine-Related Cancer. 2016.
- U. Risérus et al., “Activation of peroxisome proliferator-activated receptor (PPAR)δ promotes reversal of multiple metabolic abnormalities, Reduces oxidative stress, and increases fatty acid oxidation in moderately obese men,” Diabetes, 2008.
- A. Dudekula, V. Rachakonda, B. Shaik, and J. Behari, “Weight loss in nonalcoholic fatty liver disease patients in an ambulatory care setting is largely unsuccessful but correlates with frequency of clinic visits,” PLoS One, 2014.