Ligandrol [LGD-4033]: Benefits, Uses, Side Effects

SARMS or selective androgen receptor modulators are highly selective non-steroidal anabolic compounds. Commonly used by athletes, or bodybuilders studies have shown that SARMS and specifically Lingadrol, have high anabolic activity and can facilitate the growth of muscle

What Is Lingandrol, LGD-4033 

Ligandrol, or more commonly known as LGD-4033, is a non-steroidal selective androgen receptor modulator (SARM) currently under investigation for the treatment of muscle wasting, osteoporosis, and other clinical indications. Ligandrol was discovered and created by Ligland Pharmaceuticals and is currently under development by Viking Therapeutics and is now branded as VK5211.

How Does Ligandrol, LGD-4033 Work

Like other SARMS, Ligandrol binds androgen receptors with high affinity and selectivity.  

SARMS were developed in the early 2000s, in an attempt to overcome the pharmacologic and pharmacokinetic limitations of steroidal androgen receptor agonists (i.e., testosterone and DHT), which have known associations with liver and heart disease [R]. SARMS have been investigated for several indications including muscle wasting (cachexia), sarcopenia, osteoporosis, stress urinary incontinence, erectile dysfunction, symptomatic benign prostatic hyperplasia, Alzheimer’s disease, muscular dystrophy, breast cancer [R].

SARMS are not anabolic steroids; rather, they are synthetic ligands that bind to androgen receptors. Depending on their molecular structure, they act as agonists, partial agonists, and antagonists. It is thus in a selective manner, that SARMS modulate or mediate coregulators and transcription factors or signaling cascade proteins to promote anabolic activity.

Unlike anabolic steroids which bind to androgen receptors in many tissues all over the body, individual SARMs selectively bind to androgen receptors in certain tissues, but not in others. Nonetheless, they are still exhibit androgenic and anabolic effects.

Androgen receptors are ubiquitous in muscle tissue and bone, thus making them highly receptive to activate or be inhibited my anabolic agents, creating undesirable systemic effects.  SARMS have a high binding affinity for muscle tissue and bone, in a dose dependent selective manner, thus limiting growth in undesirable tissue, such as the prostate.

Nonsteroidal SARMS serve as alternative to anabolic-androgenic steroids, with fewer limitations, also exhibiting high-bioavailability.

All SARMS bind to androgen receptors and display tissue-selective activation of androgenic signaling. Non-steroidal SARMS do not serve as substrates CYP19 aromatase or 5-alpha reductase, as full agonists in muscle and bone, and partial agonists in prostate.

Thus, SARMs do not undergo aromatization to estrogen or 5-alpha reduction which may contribute to their prostate-sparing effect. Nonsteroidal SARMs also exhibit diminished androgenic activity because they are not metabolized to dihydrotestosterone (DHT).

Unique interactions of SARM ligands with androgen receptor result in specific conformational change in the androgen receptor protein, recruitment of a unique repertoire of co-regulator proteins thus contributing to their tissue-specific transcriptional regulation of gene expression

Individual SARMS do, however, have different etiologies, to some degree.

Each SARM-AR complex possesses a different conformation, and various tissues (e.g., skeletal muscle, bone, prostate, brain, skin, liver) display a unique pattern of AR expression.

Ligandrol Benefits

Increases Lean Muscle Mass

Of all investigational SARMS, preclinical trials have shown that Lingadrol has the highest anabolic activity, with greater than 500:1 anabolic to androgenic selectivity.

A Phase 1, 21 day study was completed to determine and evaluate the safety, tolerability, pharmacokinetics, and efficacy of ascending doses of LGD-4033,  lean body mass, muscle strength, stair-climbing power, and sex hormones [R].

76 healthy men, ages (21–50 years) were randomized to placebo or 0.1, 0.3, or 1.0 mg LGD-4033 daily for 21 days. Blood counts, chemistries, lipids, prostate-specific antigen, electrocardiogram, hormones, lean and fat mass, and muscle strength were measured during and for 5 weeks after intervention.

Results showed that doses of LGD-4033 were well tolerated with no adverse events. Hemoglobin, prostate-specific antigen, aspartate aminotransferase (AST), alanine aminotransferase (ALT), or QT intervals did not change significantly at any dose LGD-4033 administration was associated with dose-dependent suppression of total testosterone, sex hormone–binding globulin, high density lipoprotein cholesterol, and triglyceride levels. follicle-stimulating hormone and free testosterone showed significant suppression at 1.0-mg dose only. Lean body mass increased dose dependently, but fat mass did not change significantly. Hormone levels and lipids returned to baseline after treatment discontinuation.

Previous Phase 1 studies also established the safety of up to 22 mg LGD-4033. 

LGD-4033 displayed a prolonged elimination half-life (24–36 hours) FSH and free testosterone only showed significant suppression at the 1 mg per day dosage.

What was most impressive, is that LGD-4033 increased lean body mass on average 1.21 kg (2.67 pounds) at the 1 mg dosage [R]. The increase in lean body mass was directly correlated with dose.

In phase 2 trials, scope of treatment is focused on conditions to establish indications of treatment. The study was a randomized, double-blind, placebo-controlled, parallel group study designed to evaluate the efficacy, safety and tolerability of VK5211 in up to 120 patients recovering from hip fracture surgery.

Study design was to evaluate those recovering from hip fracture surgery. These patients are the perfect candidates for selective androgen receptor treatment, as mobility and movement are limited, resulting in muscle atrophy, bone degradation, and muscle wasting.

Within the first year after a hip fracture, body fat levels increase on average up to 7%,, while lean muscle mass decreases by up to 11% and bone mineral density by 4.6% [RR].

Patients recovering from hip fracture are known to lose bone and muscle at accelerated rates, placing them at increased risk of further morbidity, re-fracture and prolonged disability.

LGD-4033 produced significant increases in lean body mass and appendicular lean mass following 12 weeks of daily dosing in all subjects.

Ligandrol, LGD-4033 Side Effects

Although clinical trials have shown that Lingandrol is very well tolerated and safe, SAMRS do exhibit several side effects. Without long-term efficacy and toxicity studies, it is impossible to know the long-term detriment, these compounds can create [R].

Studies show that Lingandrol does suppress high-density lipoproteins, (HDL) otherwise known as good cholesterol [R]. Negative effects are also notorious and associated with therapeutic application of all anabolic steroids and non-steroidal anabolics.

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].

Studies also show a reduction in other hormones such as reduced levels of sex hormone-binding globulin (SHBG). Commonly reported symptoms and findings for all SARMs were headaches, dry mouth, and upper respiratory infections (URIs), constipation, dyspepsia, and nausea. 

Moreover, Lingandrol does not aromatize into Estrogen, yet it can still cause a systemic increase or decrease in Estrogen levels.

LGD-4033, like other SARMS, suppresses natural Testosterone levels, which can result in an disparaging balance between Testosterone and Estrogen levels in the body. 

This can result in symptoms such as

  • Acne
  • Low Libido
  • Lethargy
  • Gynecomastia
  • Depressive Mood State
  • High Blood Pressure
  • Change in testicular size

The average terminal half-life of S-4 in animals is four hours. After oral dosing, S-4 was rapidly absorbed and completely bioavailable.  

Pharmacokinetics studies show that the terminal half-life of SARMs range from 4.1 to 14.7 hours.

Therefore, post cycle therapy is recommended to be started immediately after application has been concluded.  

Any anabolic agent, SARMS or not, increase androgen activity. While ligandrol is selective for muscle and bone relative to androgen modulation there is still potential for androgen related side effects.

Anabolic agents are well known to cause liver damage which may manifest with elevated liver enzymes. Selective androgen receptor modulators (SARMs) have been heavily marketed as alternatives to androgenic anabolic steroids (AASs) for muscle gain and physical performance because of their perceived superior side-effect profile. 

LGD-4033 did not result in any significant changes in AST or ALT levels in human trials [R].

At therapeutic dosages, there appears to be a low risk associated with use and liver damage. However, it should be noted, that any anabolic modulator may have some degree of liver toxicity with ergogenic dosages. 

With doses higher than 1mg per day, it is possible, that ligandrol, will exhibit some some degree of liver toxicity, However, at therapeutic dosages, there appears to be a strong safety profile and the data suggests a complete absence of liver toxicity.

Is Ligandrol Legal 

Ligandrol, LGD-4033 is classified as experimental and used for research purposes.

Ligandrol is classified as an investigational new drug by the FDA, meaning that it is still being studied and has not been approved for human use. As such, it is illegal to sell or distribute ligandrol in the U.S. for any purpose other than FDA-approved clinical trials. 

Thus, it is legal to sell and buy SARMs that are marketed for research purposes, which commonly occurs online. However, it is illegal to sell and buy those that are packaged in capsules for human consumption and/or labeled as dietary supplements. Furthermore, SARMS cannot be marketed to the public as dietary supplements and claims regarding their benefits cannot be made.

SARMs were banned by the World Anti-Doping Agency in January 2008, despite no drugs from this class yet being in clinical use, and blood tests for all known SARMs have been developed.

Ligandrol is still under investigation, however at this point, it seems the drugs progression into Phase 3 clincal trials, has come to a halt. 

Per the FDA requirement for Phase 3, an “approvable endpoint” for a Phase 3 trial would require showing a functional benefit, rather than just an increase in muscle mass. This requirement, makes it more challenging to design a trial with confidence since it becomes nearly impossible to account for the uncontrollable aspects of such things like a patient’s willpower to push forward. Finding investment to take on the possibility or risk of potentially failure to get approval, seems unlikely.

Ligandrol, LGD-4033: Takeaway

Clinical research shows that Ligandrol is a promising new compound, in relation to increasing lean body mass, with minimal side effects as compared to steroidal anabolic agents. Studies show, well tolerated safety and efficacy profile, while meeting primary and secondary endpoints, without increases in liver enzymes, AST, and ASL. 

At therapeutic dosages, there appears to be a low risk associated with use and liver damage. However, it should be noted, that any anabolic modulator may have some degree of liver toxicity with ergogenic dosages.

Results show that Ligandrol, has the highest anabolic capabilities of any known SARM. Pre-clinical trials showed that VK5211 demonstrated greater than 500-fold selectivity for maintaining muscle weight. 

Phase 1 studies showed a 2.67 gain in lean muscle mass. LGD-4033 therefore, is significantly more potent than many very well known testosterone analogs [R].

Swolverine is no way supports or condones the use of illegal or nefarious substances or compounds. This article is for informational purposes only.

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