Ligandrol (LGD-4033) or Anabolic Steroids: A Comparison of Risks

Ligandrol is often marketed as a «milder» alternative to anabolic steroids: supposedly, selective action means fewer side effects. The editorial team compared what is actually known about the risks of LGD-4033 and classic anabolic-androgenic steroids (AAS), and why the word «selective» is misleading here.

What exactly we are comparing

Anabolic steroids are testosterone and its synthetic derivatives with a steroid backbone. They act through the androgen receptor in all tissues where it is present, and some of them additionally convert into estradiol or dihydrotestosterone. This group includes both registered medicines (testosterone, nandrolone, oxandrolone in some countries) and substances that exist only on the illegal market.

LGD-4033 is a non-steroidal molecule that also binds to the androgen receptor but, according to preclinical data, has higher activity in muscle and bone compared with the prostate. It does not aromatize into estrogens and is not a substrate of 5-alpha-reductase. It is on these properties that the idea of «selectivity» is built.

The comparison is complicated by the fact that «steroids» are a heterogeneous group. Injectable testosterone in a therapeutic dose and an oral 17-alpha-alkylated steroid in a supraphysiological dose have very different risk profiles. Therefore, in the tables below we speak about tendencies, not about specific drugs.

It is also important to distinguish doses. In the clinical study of LGD-4033, the maximum dose was 1 mg per day for 21 days. Data on AAS mostly concern either medical doses or observations of people who used doses many times higher than physiological ones for years. A direct «head to head» comparison under identical conditions has never been conducted.

The volume of evidence: decades versus weeks

A huge amount of data has been accumulated on anabolic steroids: randomized studies of testosterone (in particular the classic works of Bhasin and co-authors), large cohorts, autopsy series, observations of former athletes. This makes it possible to describe fairly precisely both the short-term and the long-term consequences — from changes in lipids to cardiomyopathy and prolonged hypogonadism.

On LGD-4033 in humans there is mainly one published randomized phase 1 study (Basaria et al., 2013) lasting three weeks and separate data from subsequent developments under the name VK5211. The rest are descriptions of clinical cases of complications in people who took a product from the illegal market.

Hence the key conclusion: the absence of reports of long-term complications of LGD-4033 is an absence of data, not proven safety. Cardiomyopathy, for example, is detected in AAS users after years of use; for SARMs there are simply no such years of observation.

In addition, the Basaria study was conducted on healthy young men under medical supervision, with a pharmaceutical substance of known purity. The real conditions of illegal use — different doses, different duration, an unknown composition of the product — make extrapolation even less reliable.

Hormones, lipids, liver: a comparative table

Despite the different chemical structure, many of the risks of LGD-4033 and AAS coincide, because both types of substances work through the same androgen receptor. Below is a generalized comparison by the main systems.

As can be seen, the «advantage» of LGD-4033 concerns mainly estrogenic and DHT-mediated effects. Meanwhile, hormone suppression and a decrease in HDL manifest here too, and at doses that are considered «low» on the illegal market.

As for the liver, the situation is ambiguous. Injectable testosterone rarely affects the liver, whereas oral alkylated steroids are known for cholestasis. LGD-4033 is an oral compound, and clinical cases of cholestatic damage place it closer to the second group than to the first.

Thus, it is more correct to speak not of a «safer» profile but of a different set of risks, part of which coincides and part of which simply has not yet been studied.

Risks that are often underestimated

Suppression of one’s own testosterone is the least noticeable but systemic risk. In the Basaria study, the level of total testosterone decreased in a dose-dependent manner, as did SHBG. After discontinuation the indicators recovered, but the duration of intake was only three weeks. With longer courses and higher doses, characteristic of illegal use, the picture may be different.

The mental effects of AAS — irritability, aggressiveness, depressive states after discontinuation, the development of dependence — are described in sufficient detail (Pope et al., 2014; Kanayama & Pope). For SARMs there are no systematic psychiatric studies, but the mechanism of action through the androgen receptor and the suppression of endogenous testosterone give grounds to expect similar problems, in particular after discontinuation.

• Recovery of the hormonal axis is not guaranteed and has no predictable timeframe.
• A decrease in HDL over months and years increases cardiovascular risk.
• The absence of estrogenic effects does not mean the absence of harm to the heart.
• For women, both classes carry a risk of virilization, partly irreversible.

Another underestimated risk is an unknown composition. Van Wagoner and co-authors (2017) showed that only about half of the products sold as SARMs contained the declared substance. A person who thinks they have chosen a «mild» compound may get an entirely different drug.

The myth of a «safe alternative»

The word «selective» in the name of the class describes the preclinical ratio of activity in muscle and prostate, obtained in animal models. It does not mean that the substance does not affect the liver, lipids, heart, hormonal axis, or psyche. It is precisely these systems that determine the main medical risks.

In 2017, the FDA warned consumers about the danger of products containing SARMs, emphasizing the risk of liver damage, heart attack, and stroke. The regulator does not regard these substances as a safer replacement for steroids.

From the point of view of anti-doping rules, there is no difference at all: both anabolic steroids and LGD-4033 are included in section S1 of the WADA Prohibited List and are banned at all times. Methods for detecting SARMs in urine are well developed, and ligandrol metabolites are detected for a long time after intake (Thevis & Schänzer, 2018).

So the real difference between LGD-4033 and steroids lies not in safety but in uncertainty: about steroids we know a lot of bad things, about SARMs — simply little.

Editorial conclusions

LGD-4033 does not aromatize and does not convert into DHT, so certain side effects of steroids are less characteristic of it. This is the only well-founded «advantage».

Testosterone suppression, a decrease in HDL, and a risk of liver damage are documented for LGD-4033 as well, even at low doses and over a short time.

The long-term risks of SARMs have not been studied, so the comparison will always be incomplete — and this in itself is an argument in favor of caution.

The editorial team also recommends familiarizing yourself with the materials on the interaction of ligandrol with other substances, on the comparison of the risks of testolone (RAD-140) and steroids, and on the recovery of the hormonal system.

References

1. Basaria S, Collins L, Dillon EL, et al. 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;68(1):87–95.
2. Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
3. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996;335(1):1–7.
4. Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol. 2018;465:134–142.
5. Van Wagoner RM, Eichner A, Bhasin S, et al. Chemical composition and labeling of substances marketed as selective androgen receptor modulators and sold via the internet. JAMA. 2017;318(20):2004–2010.
6. Thevis M, Schänzer W. Detection of SARMs in doping control analysis. Mol Cell Endocrinol. 2018;464:34–45.
7. Kanayama G, Pope HG Jr. History and epidemiology of anabolic androgens in athletes and non-athletes. Mol Cell Endocrinol. 2018;464:4–13.
8. U.S. Food and Drug Administration. FDA warns against using SARMs in body-building products. 2017.