Table of contents 

Personal Note

Compound description and mechanism of action

LGD-4033 Desired Effects and Uses

LGD-4033 Side Effects

Miscellaneous 

Safety Profile Discussion

Personal note

I have never used LGD-4033 and I’m not affiliated with any SARM manufacturers/suppliers, and do not encourage its use. All information used is based on research, of which is cited. If information is missing a citation email intelligentpersonaltraining0@gmail.com and the citation will be provided to further your own personal research.

Compound description and mechanism of action

LDG-4033 is a non-steroidal selective androgen receptor modulator (SARM). SARMS are a class of drugs developed to activate the androgen receptors in specific tissues and transcribe anabolic effects. They were developed as an alternative treatment to AAS in treatment of muscle wasting conditions, in order to minimize potential impact on reproductive tissues commonly associated with AAS. 

There are a few mechanisms associated with their tissue-specific activities; 5 alpha reductase non activation, and androgen receptor coregulators. It should be noted that these are still debated and are all largely theoretical. Other theories such as non-genomic signaling and tissue distribution theories have mostly conflicting evidence.

5 alpha reductase non activation: 5 alpha reductase is only expressed in certain tissues, and that’s why DHT is found in high levels in the scalp and prostate but not in muscle tissues. It has been argued that since SARMS cannot be metabolized by 5 alpha reductase, they can’t be converted into a more potent molecule in the scalp and prostate, and their effects on these 5AR dense areas are limited to their effects only. 

Androgen receptor coregulators: Androgen receptors are found in the cytosol of the cell. When a hormone binds to the AR, this complex moves to the nucleus where it regulates gene expression. For example Testosterone is an agonist of the AR and leads to the upregulation of gene expression which increases the synthesis of contractile proteins (muscle growth). However there are also antagonists of the AR which down regulate gene expression. However SARMS are mixed agonist/antagonists, meaning they agonize AR receptors in bone and muscle, but are antagonists of the AR in tissues such as the prostate. The reason they are agonists in muscle and bone tissue, and antagonists in prostate tissue is because in bone and muscle tissue coactivators of AR are in excess whereas in prostate tissues corepressors are in excess. 

LGD-4033 has been shown to be a full and partial agonist, exerting full agonistic/anabolic effects on AR in muscles and bones, and partial agonistic effects in the prostate gland and sebaceous glands. Its half life is shown to be greater than 24 hours.

LGD-4033 is also referred to as VK5211 in studies, and as Ligandrol in bodybuilding circles. LGD-4033 was first developed by Ligand Pharmaceuticals, but was sold and is now being developed by Viking Therapeutics. 

LGD-4033 DESIRED EFFECTS AND USES

EFFECT ON MUSCLE MASS 

In a phase 1 randomized, placebo-controlled clinical trial, titled ‘The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men’, demonstrated LGD-4033’s beneficial effects on muscle mass. The study had 71 healthy younger men (21-50), and researchers found a dose-dependent increase in lean body mass with LGD-4033 administration, with an average increase of 1.21kg at a 1mg dose, which was statistically significant compared to placebo. The study length was 21 days, making the average increase in fat free mass quite notable.

 

The next study to look into effects on building muscle come from a  phase 2 clinical trial titled ‘VK5211, a Novel Selective Androgen Receptor Modulator (SARM), Significantly Improves Lean Body Mass in Hip Fracture Patients: Results of a 12 Week Phase 2 Trial’. 

In this 12 week trial, patients who received LGD-4033 (VK5211) showed significant increases in lean body mass compared to those who received a placebo. The placebo-adjusted increases were 4.8% at 0.5mg, 7.2% at 1.0mg, and 9.1% at 2.0mg. 81% of patients who took 2.0mg saw at least a 2.0 kg increase in lean body mass, and 65% at 1.0mg. 

Clearly the increase in muscle mass is dose-dependent, but it should be noted that at 1mg (the max dose) from the phase 1 trial, the average increase in LBM was 1.21kg after 3 weeks, whereas in the phase 2 trial most (65%) patients saw an increase of more than 2.0kg after 12 weeks, which indicates the muscle mass increase is sustained over time. It’s quite commonplace for initial spikes in lean body mass to be interpreted as an increase in muscle mass, whereas they are likely largely an initial increase in water retention from the compound tested. However for LGD-4033, seeing that this increase in muscle mass was sustained over two tested durations, it’s likely that most of the lean body mass increase was in fact muscle mass. 

There was also an initial phase 1 study that is not easily publicly available that I was able to find. This paper was titled ‘P8-2-7 Phase I clinical trial of LGD-4033, a novel selective androgen receptor modulator(SARM)’. Not much of the data is publicly available either, but according to this poster presentation from the 14^th International Congress of Endocrinology in Kyoto, Japan, LGD-4033 was administered in this trial from 0.1mg all the way up to 22mg in 48 young male volunteers. There was no direct data for muscle growth but according to a press release statement it demonstrated the potential to treat muscle wasting disorders, indicating it had positive effects on muscle mass.

There are also some relevant insights that we can gain from this abstract. Many of the sketchy ‘SARM suppliers’ online sell LGD-4033 at a dosage of 10mg or higher but in my opinion this makes no sense. LGD-4033 was studied up to an extremely high dose of 22mg, and although it was said to be well tolerated, the fact that the highest dose it was studied at in subsequent trials suggests that researchers believed its benefits tapered off at around 2.0mg. Yes the benefits are ‘dose-dependent’ but the entire point SARMS were studied was to build muscle mass without affecting the rest of your bodily functions and logically this would entail using the lowest dose possible with the most benefits. The researchers have seen it studied up to 22mg, and chose to later study it at 2mg, where in subsequent trials this dosage began to show diminishing returns, suggesting ~2mg to be the optimal dosage. 

It’s no wonder that there are negative case reports about LGD-4033, for example this one titled ‘Ligandrol (LGD-4033)-Induced Liver Injury’, because the user in this was taking 10mg per day, 5x the ‘loosely established’ dosage in the clinical trials. LGD-4033 shows significant benefits on muscle mass at extremely low doses (2mg) that are comparable to some AAS taken at hundreds of milligrams. 

Anecdotally, LGD-4033 is considered to be one of the best SARM’s for building muscle, and most users claim to have gained in between 5-15 pounds for cycles lasting 6-10 weeks. Water retention is not commonly reported.

My concluding thoughts on LGD-4033’s effects on muscle growth; LGD-4033 has demonstrated promising improvements on muscle mass across multiple studies, dose-dependently, with the most optimal dosage being at 2.0mg. A 2.0mg dosage leading to an increase of over 2.0kg in 81% of patients is extremely potent. At said doses it leads to significantly more muscle mass than anabolic-androgenic steroids, however its effects likely become diminished after 2.0mg. 

EFFECT ON STRENGTH

The phase 2 clinical trial, mentioned previously, does report an increase in functional performance metrics, however the researchers do mention the endpoints weren’t powered for significance.

In one of the phase 1 clinical trials titled, ‘The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men’, strength was shown to improve but not to a statistically significant extent.

Based on this it is likely most of the strength improvements are attributable to the increase in muscle mass from LGD-4033.

Most of the evidence that LGD-4033 is a potent strength builder comes anecdotally. Whilst anecdotes rank at the bottom of the scientific hierarchy of evidence and are far from an objective source of information, they shouldn’t be ignored either. Anecdotes provide valuable lines of inquiry and insight, and may help shape future studies. In clinical trials, researchers may not realize a side effect of a compound simply because they weren’t looking for (measuring).

User anecdotes report significant strength improvements when taking LGD-4033 during a bulking phase. The amount of weight improvements on compound exercises varies widely amongst users and strength itself is affected by a variety of factors.

Recreational users can expect a modest improvement in strength from LGD-4033, although this isn’t directly supported by lots of research data, it is supported indirectly due to the significant gains in muscle mass. 

EFFECT ON BONE DENSITY

There is a wide body of literature about androgens positive effect on bone development at the onset of puberty, and the role they play after maturation to maintain bone density. For this reason researchers measured LGD-4033’s effects on bone density during the phase 2 clinical trial, using serum procollagen type 1 propeptide (s-P1NP) as a marker for anabolism within the bone. According to a website statement by Viking Pharmaceuticals LGD-4033 administration resulted in statistically significant improvements in s-P1NP at the 12 week end point.

REDUCED EFFECT ON ACNE 

According to an article titled ‘Deciphering the selective androgen receptor modulators paradigm’, Ligand Pharmaceuticals had a website statement claiming that preclinical data showed a reduced strength of sebaceous glands, however the website has been retracted and the reference material is no longer accessible. Notably, the SARM TFM-4AS-1, has been shown to have reduced effects on acne. TFM-4AS-1 is quite interesting as it is classified as both a SARM and 5 alpha reductase inhibitor, meaning it has properties of both SARMS and drugs like Finasteride and Dutasteride.

LACK OF ANDROGENICITY 

To be clear, all SARMS including LGD-4033 do not completely lack androgenicity. Androgenic side effects have been documented in clinical trials. However compared to androgenic steroids, milligram for milligram, they have less androgenicity due to their tissue specific qualities. Unfortunately at the high doses they are sold at by SARM suppliers, they are sure to cause noticeable androgenic effects, and the extent of androgenicity at lower doses isnt clear.

One measure of androgenicity is prostate-specific antigen (PSA) levels. PSA is a molecule produced by the prostate gland, and is directly regulated by androgens, with elevated levels having adverse health outcomes.

The phase 1 trial on 76 men measured PSA levels during LGD-4033 administration and found there to be no statistically significant changes at any doses. 

At the dosages commonly taken you are likely to experience androgenic side effects such as hair loss.

LGD-4033 SIDE EFFECTS

EFFECT ON TESTOSTERONE 

Contrary to how they are marketed by SARMS providers, SARMS do suppress testosterone levels. SARMs suppress luteinizing hormone (LH) and follicle-stimulating hormone (FSH) via the hypothalamus-pituitary-testis axis (HPTA), leading to a dose-dependent drop in testosterone levels. LGD-4033 is no exception to this, with a dose-dependent effect on testosterone suppression seen in clinical trials. 

In the phase 1 trial titled ‘The Safety, Pharmacokinetics, and Effects of LGD-4033, a Novel Nonsteroidal Oral, Selective Androgen Receptor Modulator, in Healthy Young Men’, researchers measured the effects of 0.1, 0.3, and 1.0mg of LGD-4033, on total and free testosterone, and FSH, LH and SHBG.

There was a does-dependent suppression of total testosterone among the patients, however only 1.0mg was shown to  suppress free testosterone to a statistically significant extent. 

This correlates with the suppression of FSH which was only seen at the 1.0mg dosage. Interestingly, serum LH did not display a dose-dependent suppression and did not reveal any meaningful changes. 

Although the free testosterone levels were only suppressed at the 1.0mg dosage, it is clear the suppression on both free and total testosterone is dose-depend, and when taken at 10mg (the common dosage found by SARM suppliers) the level of suppression is likely to be comparable to those seen by anabolic-androgenic steroids.

All hormone levels returned to baseline by day 56, roughly a month after administration ceased. 

LGD-4033 also suppressed SHBG.

EFFECT ON LIVER HEALTH

The evidence that LGD-4033 affects liver health is conflicting. 

The most compelling piece of evidence comes from the phase 1 trial mentioned above, but shows there to be no effect on liver health biomarkers. The researchers mention no statistically significant changes in the two main liver health biomarkers aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
All other clinical trials did not test, or report any data pertaining to liver health, however doses up to 22mg were taken without significant adverse events.

The main piece of evidence that LGD-4033 harms liver health comes from two case reports. 

Before presenting them it should be mentioned that anecdotes and case reports rank right at the bottom of the scientific hierarchy of evidence. Although they still should be mentioned they lack a control group, have biases, and have literally the smallest sample size possible, 1. Another big issue is that case reports are retrospective. The patients say they took LGD-4033, but there’s no regulation ensuring the quality of SARMs products. So, while the bottle might be labeled LGD-4033, there’s no way to confirm that’s actually what they took.

The first from 2020, titled ‘Ligandrol (LGD-4033)-Induced Liver Injury’ discusses liver damage that occurred a few weeks after a 32 year old man claimed to have taken LGD-4033.

The other case report titled ‘LGD-4033 and a Case of Drug-Induced Liver Injury: Exploring the Clinical Implications of Off-Label Selective Androgen Receptor Modulator Use in Healthy Adults’, examined a 52 year old man who had liver injury after claiming to have taken LGD-4033. 

In both cases, the dosages taken far exceed the 0.1-2mg dosages administered the later 3 clinical trials.

Most anecdotes online agree that slight changes in liver biomarkers are too be expected, but the change is not reflective of what is seen in the two case reports. 

The liver toxicity of LGD-4033 based on the clinical trials does not compare to those seen in oral anabolic-androgenic steroids, such Halotestin or Anadrol. 

EFFECT ON LIPID LEVELS

In the phase 1 trial on 76 men, researchers measured total and low density lipoprotein (LDL) cholesterol. LDL levels did not change, however HDL levels did decrease to a statistically significant extent. Although there is definitely some nuance, higher HDL levels are generally considered better for cardiovascular health. This change in HDL levels was seen at 0.3mg and above.

This is commonplace for other SARMS, and is a probable side effect from LGD-4033 administration. 

HEADACHES AND DRY MOUTH

Aside from the side effects discussed above, headaches, and dry mouth were reported as a common side effect amongst patients. 

However researchers mention it did not show a dose-dependent relationship, so it is likely due to differences in individuals genetics. 

These side effects reflect Grade 1 severity in the adverse events grading system, and are not considered a serious case of concern.

EFFECT ON ESTROGEN + GYNECOMASTIA

LGD-4033 does not aromatise into Estrogen, or 5 alpha reduce. The growth of glandular tissue in men is due to an imbalance in male and female sex hormones in breast tissue. As a result of LGD-4033 administration, less androgens can bind to AR and thus more is available to be aromatised into estrogen, and the suppression of testosterone can cause there to a hormonal imbalance (androgens relative to endogenous) which leads to gynecomastia formation. 

This is an issue commonly reported in anecdotes.

LGD-4033 also has no affinity for progesterone receptors so gynecomastia formation is likely estrogen mediated. 

Depending on an individual’s hormonal profile earlier, and other factors, an individual might experience low estrogen or high estrogen. Each state carries its own side effects which can be viewed in a separate article.

MISCELLANEOUS

What are the potential clinical applications of LGD-4033?  LGD-4033 holds potential in addressing conditions like sarcopenia and cachexia and muscle wasting diseases. LGD-4033 has potential for improving muscle mass and physical function, thus therapeutic value in combating muscle wasting.

How does the tissue selectivity of LGD-4033 affect its potential side effect profile compared to traditional anabolic-androgenic steroids (AAS)? LGD-4033’s tissue selectivity may lead to fewer androgenic side effects, particularly on the prostate, compared to AAS, however at the doses LGD-4033 is sold at it will likely contribute to significant androgenic side effects such as hair loss.

How does LGD-4033’s mechanism of action lead to tissue selective muscular growth?

As described in the compound description section, LGD-4033 acts as a mixed agonist/antagonist of the androgen receptor, due to some specific molecular qualities but further research is definitely required.

How do the dosages of LGD-4033 used in clinical trials compare to the dosages typically marketed by online SARM suppliers, and what are the safety implications? 

There is a discrepancy between the dosages used in research 0.1-2mg (aside from the first phase 1 trial which is mainly used to establish a safety profile) and those commonly found in supplements (10mg or higher). The safety implications of this are currently not well known, but many anecdotes report similar androgenic side effects at these higher doses similar to those from AAS.

What is LGD-4033 (Ligandrol)?

In my opinion the best classification of LGD-4033 is as a nonsteroid SARM and a mixed-partial agonist of the androgen receptor, displaying greater tissue selectivity milligram for milligram than AAS.

Is LGD-4033 legal to buy and use?

This depends on which country you are in, but for most countries it is technically legal when bought and sold for research purposes, and as a result many SARM suppliers (despite often hyping up its abilities) market them as a product only intended for ‘research purposes’. It is essentially a legal exploit.

Do you need post-cycle therapy (PCT) after using LGD-4033?

LGD-4033 suppresses natural testosterone levels dose-dependently. It is common for users of AAS to use a PCT after discontinuation because of their suppressive qualities, and anecdotally many users of LGD-4033 and other SARMs use a PCT too because of these same suppressive qualities. Ultimately it is up to the user’s discretion. 

How does LGD-4033 affect body fat percentage or fat mass?

By increasing muscle mass, users have a higher metabolism making an eventual fat loss phase easier and more efficient, but this is an indirect effect.

What is LGD-4033’s affinity to the AR receptor?

It binds to the AR receptor with an affinity of 0.9nM

Does LGD-4033 bind to progesterone receptors?

Not meaningfully.

Does LGD-4033 bind to glucocorticoid receptors?

Not meaningfully.

Does LGD-4033 bind to mineralocorticoid receptors?

Not meaningfully.

What is the anabolic:androgenic ratio of LGD-4033?

It has been reported as 10:1 but this is not present in the literature.