Does Ligandrol (LGD 4033) Work? Full Review Of The Evidence

After finishing reviewing Beta Alanine, D Aspartic Acid, and Cissus, I decided to turn my attention to something a little more controversial. Ligandrol was a natural choice.

Ligandrol or LGD-4033, is a selective androgen receptor modulator (SARM) discovered by Ligand Pharmaceuticals and currently under development by Viking Therapeutics [1], [2].

That sounds very technical and it is! I will elaborate more on what this means in the next section.

LGD was developed for the treatment of muscle wasting conditions, such as aging, osteoporosis, muscular dystrophy and cancer.

Why is this important? Well, in the case of cancer alone, for example, the prevalence of muscle loss has been reported as between 20% and 70%, depending on the type of tumor and the criteria used for assessment [3]. Muscle wasting, including a loss of skeletal muscle, is a cancer-related symptom that begins early in the progression of cancer and affects a patient’s quality of life, ability to tolerate chemotherapy, and survival [8].

In addition to legitimate medical uses, it is also being used as a performance enhancing drug. In the body-building world, LGD is being promoted as a side-effect free alterative to steroids, such as testosterone, to increase muscle mass and athletic performance.

The drug is popular with a wide range of athletes and professionals who are conscious of their muscle size and body composition, including weight lifters, bodybuilders, models, crossfitters, athletes and strongmen.

Recently, there has been a lot of hype around LGD. Although it is not a steroid, Ligandrol has been making headlines lately for getting athletes in trouble for taking illegal performance enhancing supplements. Florida Gators quarterback Will Grier was found to have Ligandrol in his system during a routine test [4], [5].

Substances like LGD, which are developed for therapeutic use, are often misused by athletes as doping agents and or for image-enhancement. This has generated a market for counterfeit doping substances, which may be of poor pharmaceutical quality and therefore constitute health risks to consumers [6].

Since LGD is getting a lot of publicity, it’s worthwhile taking a look at the research.

What Actually Is Ligandrol?

LGD-4033 is a non-steroidal selective androgen receptor modulator (SARM).

An androgen (from Greek ‘andro’ meaning male human being) is a compound (natural or synthetic) that regulates the development and maintenance of male characteristics in vertebrates (including humans) by binding to androgen receptors (special receptors on cells). Androgens are often steroid hormones.

A selective androgen receptor modulator (SARM) is selective in its target tissues in the body. That means it has a high a
ffinity to bond with androgen receptors. Being “selective”, SARMS can be taken by mouth but only binds to specific target areas- in this case – to androgen receptors in your muscles.

There are many conditions that result in muscle loss. As we age, we lose muscle mass and muscle strength, which is called “Sarcopenia”. Sarcopenia is known to increase the risk of falls, fractures, physical disability, and result in poor quality of life with significant health and economic effects.

LGD 4033

Similarly, many illnesses, such as chronic obstructive lung disease, muscular dystrophy, end-stage renal disease, and some types of cancer, is punctuated by the loss of muscle mass and physical function, which contributes to mobility limitation and disability [2], [3].

Thus, there is a need for anabolic therapies that combat muscle loss and physical function and reduce the burden of disability in persons experiencing muscle loss due to aging or illness [7]. Among the various candidate anabolic therapies that are in development, androgens are the farthest along in development [2].

It is widely recognized that testosterone administration increases muscle mass and strength but concerns regarding its potential adverse effects have motivated efforts to develop SARMs, a new class of androgen receptor ligands that are tissue selective [7]. SARMs modulate the same anabolic pathways targeted with classical steroidal androgens8.

The last decade has witnessed substantial pharmaceutical efforts to develop nonsteroidal SARMs to treat muscle wasting and functional limitations associated with acute and chronic illness and aging.

The class of SARMs has been the subject of much clinical research over the past two decades8. LGD-4033 binds androgen receptors with high affinity and selectivity, ie it binds in a strong and targeted manner [2]. It is expected to produce the therapeutic benefits of testosterone with improved safety, tolerability and patient acceptance.

How Much Research Is There?

There has been a lot of research into the efficacy of SARMs but very little published research to date on LGD.

LGD-4033 has exhibited desirable in vivo efficacy on skeletal muscle and bone measurements in animal models of disease. There is only one published study on the effects of LGD in humans as well as Phase I Clinical Trial results.

A 2010 Phase I clinical trial was the first study in humans of LGD-4033, and evaluated the safety, tolerability and pharmacokinetic profiles (how it acts in the body) of the molecule in a single escalating dose, double blind, placebo-controlled study in 48 healthy volunteers.

In 2013, Basaria conducted a rigorous 3-week placebo-controlled study of 76 healthy men (21–50 years) that looked at the safety and tolerability of LGD-4033. It hopefully paves the way for longer term efficacy trials in one or more populations of older individuals for which SARMs may be indicated [2].

During this study, participants were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. The study evaluated the safety, tolerability, pharmacokinetics (how it works in the body), and effects of ascending doses of LGD-4033 administered daily for 21 days on lean body mass, muscle strength, stair-climbing power, and sex hormones [2].

Despite being a well designed, thorough study, the sample size, although substantially larger than in most phase I ascending-dose studies, was still fairly small, was not based on considerations of effect sizes [2], as the study’s primary aim was to establish safety and tolerability rather than efficacy. Similarly, the 3-week study duration was not designed to demonstrate maximal effects on muscle mass and strength [2]. Therefore larger and longer studies are needed to assess the efficacy of LGD.

One further thing to note is that the study was supported by Ligand Pharmaceuticals, who developed LGD, so it’s impossible to say that the research was completely impartial.

Does Ligandrol Increase Testosterone?

No. Research by Basiria showed a dose-dependent suppression of total testosterone and from baseline to day 21 [2], rather than an increase.

Does Ligandrol Promote Fat Loss?

No. The research does not show that LGD promotes fat loss [2].

Does Ligandrol Promote Muscle Growth?

Yes…. But it’s very early, weak evidence at this stage. The research by Basiria showed an increase in lean body mass that was dose related, so as the dose of LGD taken increased, so did the effect of increased muscle mass [2].

The mechanisms by which androgens increase muscle mass remain incompletely understood [2]. It would be plausible that increased muscle mass would translate into increased muscle strength.

Research has shown that SARMs increase muscle mass and improve physical function in healthy and diseased individuals, and potentially may provide a new therapy for muscle wasting, especially in the case of cancer8.

However, the increase in strength measured by stair climbing speed and power also showed improvement, but not enough to be statistically significant. With a larger sample size and or a longer study, it is possible that this effect may be demonstrated.

If You’re Using It Anyway…

You probably shouldn’t be, as there is not enough research yet. But no adverse effects have been noted at this stage.

How Long Does It Take To “Kick In”?

LGD-4033 displayed an immediate effect on hormones in the body from the time it was taken. In terms of functionality, the research showed gains in lean muscle mass within the 21 day study, which is a pretty amazing result for a short space of time [2].

How Long Does It Stay In Your System?

LGD-4033 displayed a prolonged elimination half-life, which means the time it takes for half of the dose to leave your system, of 24–36 hours. That is, every 24-36 hours, the level of LGD in your system drops by half [2]. The following day, the level drops by half again, and so forth.

Upon discontinuation of LGD-4033, the hormone levels returned to baseline by day 56 [2].

Is Ligandrol Safe? Are There Side Effects?

Both the Phase I Trial and study by Basiria showed that LGD-4033 was safe and well tolerated at all doses administered (0.1mg, 0.3mg and 1.0mg). The frequency of adverse events was similar between the placebo and any dose group. Headache, pain related to muscle biopsy, and dry mouth were the most common events and did not show dose relationship.

One of the clinically useful features of LGD is its half life. Its prolonged elimination half-life means that is can be given once daily or even a less frequent dosing regimen. Research showed that there was a robust relationship between the dose and the blood plasma concentrations.

Conclusion: What Should We Think About Ligandrol?

The past decade has witnessed the emergence of a number of non-steroidal SARMs from several pharmaceutical companies as a new class of function-promoting therapies to treat the loss of muscle mass.

Recent clinical efficacy data for LGD-4033 is very promising, showing it to be safe and able to increase lean body mass even during a three week period, which is a fantastic result in a short time. But it must be remembered that this was recorded in a single study with a small sample size (76 people), and the Phase I Clinical trial also had a small sample size (48 people).

There just is not enough research to show its efficacy at this stage, despite it looking super promising!

Although future research may show LGD to be safe and efficacious, the evidence is just not strong enough to support it right now. Given the global burden of diseases that involve muscle wastage, including aging, cancer and osteoporosis, it is very likely that further research and trials will come out with stronger evidence for its clinical usage.

References

  1. www.ligand.com
  2. Basaria S1, Collins L, Dillon EL, Orwoll K, Storer TW, Miciek R, Ulloor J, Zhang A, Eder R, Zientek H, Gordon G, Kazmi S, Sheffield-Moore M, Bhasin S. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J Gerontol A Biol Sci Med Sci. 2013 Jan;68(1):87-95. doi: 10.1093/gerona/gls078. Epub 2012 Mar 28.
  3. Ryan AM, Power DG, Daly L, et al. Cancer- associated malnutrition, cachexia and sarcopenia: the skeleton in the hospital closet 40 years later. Proc Nutr Soc 2016; 75: 199–211.
  4. http://www.charlotteobserver.com/sports/college/football/article108042467.html
  5. http://www.orlandosentinel.com/sports/highschool/84686793-132.html
  6. Christina Weber, Oliver Krug, Matthias Kamber & Mario Thevis. Qualitative and Semiquantitative Analysis of Doping Products Seized at the Swiss Border, Pages 1-12 | Published online: 03 Feb 2017
  7. Bhasin S, Calof OM, Storer TW, et al. Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Clin Practice Endocrinol Metab. 2006;2:146–159.
  8. Dalton JT, Taylor RP, Mohler ML, Steiner MS. Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer. Curr Opin Support Palliat Care. 2013 Dec;7(4):345-51. doi: 10.1097/SPC.0000000000000015. Review.
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