LGD-4033 (Ligandrol)

Overview

LGD-4033, also known as Ligandrol or VK5211, is a non-steroidal selective androgen receptor modulator developed by Ligand Pharmaceuticals and subsequently licensed to Viking Therapeutics for clinical development. Among the second wave of SARMs to enter clinical testing, LGD-4033 is notable for its potency: it produces measurable increases in lean body mass at doses as low as 1 mg daily, making it one of the most potent SARMs characterized to date on a milligram-for-milligram basis.

The compound completed a first-in-human phase I study published in the Journal of Gerontology in 2013 by Basaria et al., establishing its safety and pharmacokinetic profile in healthy young men. Viking Therapeutics subsequently advanced the compound into a phase II trial for hip fracture recovery under the designation VK5211. The hip fracture indication targets a population with acute, severe muscle loss and functional decline, where an anabolic agent that avoids the complications of testosterone could address a significant unmet need.

Mechanism of Action

LGD-4033 binds to the androgen receptor with high affinity (Ki of approximately 1 nM) and acts as a full agonist in muscle and bone tissue. Its non-steroidal structure prevents it from being metabolized by 5-alpha reductase or aromatase, meaning it cannot be converted to DHT or estradiol. This metabolic stability contributes to its tissue-selective profile, as many of the unwanted effects of testosterone in skin and prostate are mediated by its conversion to the more potent androgen DHT.

In skeletal muscle, LGD-4033 activates the AR and drives anabolic gene transcription through mechanisms shared with other SARMs: promotion of protein synthesis, inhibition of protein degradation, and stimulation of satellite cell proliferation. The potency of LGD-4033 in the muscle compartment is evidenced by the clinical trial data showing lean mass gains at doses approximately 10-fold lower than those typically required with Ostarine.

In bone tissue, preclinical studies demonstrated that LGD-4033 increased periosteal bone formation, trabecular bone volume, and bone strength in orchidectomized rat models. These osteoanabolic effects are mediated through AR activation in osteoblasts and osteocytes and suggest potential utility in osteoporosis and fracture healing.

Like other SARMs, LGD-4033 suppresses the HPG axis in a dose-dependent manner. The phase I trial documented significant, dose-dependent reductions in total testosterone, free testosterone, LH, FSH, and SHBG. These suppressions were reversible, with hormone levels returning to baseline within five to eight weeks of discontinuation at the doses tested. The mechanism of suppression is negative feedback at the hypothalamus and pituitary mediated by the exogenous AR agonism.

Research Summary

The phase I study by Basaria et al. was a randomized, double-blind, placebo-controlled trial in 76 healthy men aged 21 to 50. Subjects received placebo or LGD-4033 at 0.1, 0.3, or 1.0 mg daily for 21 days. The 1.0 mg group showed a statistically significant increase in lean body mass of approximately 1.21 kg, a notable finding given the low dose and short treatment duration. This increase exceeded the lean mass changes observed in Ostarine trials at higher doses and longer durations, confirming LGD-4033’s superior potency.

Fat mass showed a trend toward reduction in the LGD-4033 groups, though the changes did not reach statistical significance in this short-duration trial. Strength measures (leg press and stair climbing) showed trends favoring LGD-4033, consistent with the anabolic effects on muscle tissue. No significant changes in PSA, hemoglobin, or liver function tests were observed at any dose level.

Viking Therapeutics completed a phase II trial (NCT02578095) in patients recovering from hip fracture surgery. The trial tested VK5211 at 0.5, 1.0, and 2.0 mg daily for 12 weeks. Results announced in 2018 showed dose-dependent increases in lean body mass, with the 2.0 mg group gaining approximately 1.6 kg more lean mass than placebo. Functional measures including the Short Physical Performance Battery showed improvements in the active treatment groups. These results were considered promising and provided the basis for further clinical development planning.

Pharmacokinetic analysis revealed a half-life of 24 to 36 hours, supporting once-daily dosing. The compound showed linear pharmacokinetics across the tested dose range, with steady-state reached within approximately 10 days of once-daily administration. No significant food effect on absorption was identified.

Dosing in Published Research

LGD-4033 (ligandrol) is a selective androgen receptor modulator. It is not an approved medicine and has no labeled dose. Its most-cited human study is a Phase 1, placebo-controlled, ascending-dose trial in 76 healthy men (Basaria et al., Journal of Gerontology, 2013), in which participants received placebo or LGD-4033 at 0.1, 0.3 or 1.0 mg daily for 21 days. Hormone suppression was most evident at the 1.0 mg dose. These figures describe what was administered in that specific short trial.

Safety and Side Effects

In the phase I trial, LGD-4033 was well tolerated with no dose-limiting toxicities and no serious adverse events. The adverse event profile was similar between treatment and placebo groups for all symptoms except hormonal changes. The dose-dependent suppression of total testosterone, free testosterone, SHBG, LH, and FSH was the most notable safety signal. At the 1.0 mg dose, total testosterone decreased by approximately 50% from baseline at day 21, with recovery to baseline occurring within 35 days of discontinuation.

HDL cholesterol showed a modest, dose-dependent decline, consistent with the effects of androgens on hepatic lipase. Hemoglobin and hematocrit increased slightly, reflecting the erythropoietic effects of AR activation. No clinically significant changes in liver transaminases, PSA, or ECG parameters were observed.

In the research community, where doses of 5 to 20 mg daily are commonly reported (substantially exceeding the clinical trial range), more pronounced side effects are described. Users report significant HPG axis suppression requiring extended recovery periods, more substantial HDL reductions, and occasional complaints of water retention, headache, and lethargy. Liver enzyme elevations have been reported in isolated cases at these higher doses.

The phase II hip fracture trial showed a similarly favorable safety profile at doses up to 2.0 mg daily for 12 weeks. No virilization was reported in the female subjects enrolled in the trial, and no dose-limiting hepatic or cardiovascular toxicities were identified.

Current Research Status

LGD-4033 is an investigational compound with no approved medical indications. Viking Therapeutics has indicated plans for further clinical development, potentially including a phase IIb or phase III trial in the hip fracture indication. The compound is prohibited by WADA and has been detected in numerous anti-doping violations across multiple sports. LGD-4033 stands out among investigational SARMs for its combination of clinical potency, published human pharmacokinetic and safety data, and active pharmaceutical development. It is available through research chemical suppliers, with the caveat that product quality and purity in the unregulated market cannot be assured.

Further reading: RAD-140 vs LGD-4033: Comparing Two Researched SARMs compares the research on these two selective androgen receptor modulators.

Frequently Asked Questions