PT-141 (Bremelanotide) for Sexual Desire, and What the Trials Found

Patients rarely open a visit with their sex life, so the question tends to arrive in the last two minutes. The men have usually tried sildenafil or tadalafil and found that a pill can restore blood flow without restoring any wish to use it, and the women have discovered that almost nothing in the pharmacy was designed for them. Both have read about PT-141, and they ask me whether a peptide can bring desire back.

A tanning drug with an unexpected side effect

PT-141 descends from a sunless tanning experiment. In the 1990s, researchers at the University of Arizona were developing Melanotan II, a synthetic analog of alpha-melanocyte-stimulating hormone (alpha-MSH, the hormone that tells skin cells to make pigment), as a way to tan without sun. Dorr and colleagues, in their 1996 pilot phase 1 study, injected three male volunteers and recorded darker skin in two of them, mild nausea, and a bout of stretching and yawning that preceded spontaneous erections lasting one to five hours [1]. The same group then tested the effect on purpose in a double-blind, placebo-controlled crossover study of 10 men with psychogenic erectile dysfunction, meaning no physical cause could be found. Eight developed erections on Melanotan II, and rigid erections lasted an average of 38 minutes against 3 minutes on placebo [2]. Bremelanotide, which its developer labeled PT-141, is a variation of Melanotan II designed for the sexual effect instead of the tan [3].

It works in the brain, not the blood vessels

Sildenafil and tadalafil relax the smooth muscle in penile arteries, so they improve blood flow once arousal has started and do nothing for arousal itself. Bremelanotide binds melanocortin receptors, with high affinity for the type 4 receptor, which researchers think modulates the brain pathways behind sexual response [4]. The clearest demonstration comes from a 2004 rat study in the Proceedings of the National Academy of Sciences, in which Pfaus and colleagues found that PT-141 selectively increased solicitation, the behaviors a female rat uses to initiate mating, without changing the reflexive parts of sex or her general activity. They concluded that central melanocortin systems help regulate female desire [5]. This means PT-141 targets wanting, which no erectile dysfunction pill does.

The trials in men

The erectile dysfunction studies are early-phase and two decades old. Diamond and colleagues gave intranasal PT-141 to healthy men and to men with mild-to-moderate erectile dysfunction, and doses above 7 mg produced a statistically significant erectile response, with the first erection arriving in about 30 minutes [6]. Rosen and colleagues then tested subcutaneous injections in men who reported an inadequate response to 100 mg of sildenafil, and both 4 mg and 6 mg produced significant erectile responses against placebo in a crossover design [7]. Both studies measured penile rigidity with a monitor in a laboratory, which tells us nothing about months of use at home. Bremelanotide has never been approved for men, so any use in men is off-label. Melanocortin-4 agonists can also raise blood pressure, a concern that shaped how the later trials were run [8].

The trials in women, and FDA approval

The best evidence comes from RECONNECT, two identical phase 3 trials that randomized 1,267 premenopausal women with hypoactive sexual desire disorder, persistently low desire that causes distress, to 1.75 mg of subcutaneous bremelanotide or placebo, used as needed for 24 weeks. Desire scores rose 0.35 points more on the drug than on placebo and distress scores fell 0.33 points more, both statistically significant [9]. On that evidence the FDA approved bremelanotide in 2019 as Vyleesi, a self-administered, on-demand injection for premenopausal women with the acquired, generalized form of the disorder [4].

Is a statistically significant effect a large one? Spielmans, reanalyzing the trials from the FDA application in 2021, confirmed the efficacy numbers and added two findings the original paper omitted. Women on bremelanotide had roughly 12 times the odds of quitting because of adverse events, and fewer of them finished the trial and chose to continue into the open-label extension [10]. A safety review coauthored by the developer's own scientists reports that 70 percent of the bremelanotide group moved on to the open-label phase, against 87 percent of the placebo group [11]. My read is that the drug helps some women noticeably and helps many others too little to justify the nausea.

Side effects, and who shouldn't use it

Nausea is the main cost, and across the phase 3 program 40 percent of women on bremelanotide reported it against 1.3 percent on placebo, followed by flushing in 20 percent and headache in 11 percent [11]. The tanning ancestry shows up as focal hyperpigmentation, patches of darkened skin, which was rare when women dosed as the label directs yet appeared in more than a third of subjects who dosed daily for up to 16 days [11].

White and colleagues monitored 397 premenopausal women with ambulatory blood pressure cuffs and found that the 1.75 mg dose raised systolic pressure by about 3 mmHg in the first four hours, with peaks that typically lasted less than 15 minutes, alongside a slower heart rate [8]. The rise is small and brief, but the safety reviewers still advised caution in anyone at risk of cardiovascular disease and good blood pressure control during treatment [11]. We won't prescribe it to patients with uncontrolled hypertension or known cardiovascular disease, or during pregnancy. Bremelanotide also lowered blood levels of naltrexone in interaction studies, which matters if you take it [11].

You should never buy melanocortin peptides online. Nelson and colleagues described a 39-year-old man who injected 6 mg of internet-purchased Melanotan II and arrived in the emergency department sweating and tremulous with a heart rate that peaked at 146, then spent three days in intensive care with kidney injury and rhabdomyolysis, the breakdown of muscle tissue [3]. If you compete in a drug-tested sport, check any peptide with your anti-doping authority before you use it.

What the B6 adds

The product on our formulary pairs bremelanotide with pyridoxine, vitamin B6, at 10 mg of each per mL. It's a compounded preparation, which means it isn't FDA-approved, unlike Vyleesi. Compounders presumably add pyridoxine to blunt the nausea, and the evidence for that idea comes from pregnancy. Vutyavanich and colleagues randomized 342 women in early pregnancy to 30 mg of oral pyridoxine a day or placebo, and nausea scores fell significantly more on pyridoxine, while the reduction in vomiting didn't reach significance [12]. No trial has tested pyridoxine against bremelanotide-induced nausea, so I consider the B6 a low-risk guess and not a proven remedy.

What to do

Low desire and erectile trouble are often the first symptoms of a metabolic problem, so the workup matters more than the peptide. Thompson and colleagues followed the 9,457 men in the placebo arm of the Prostate Cancer Prevention Trial and found that new erectile dysfunction carried a hazard ratio of 1.25 for later cardiovascular events, a risk the authors placed in the range of current smoking or a family history of heart attack [13]. Esposito and colleagues supplied the encouraging half of that story when they randomized 110 obese men with erectile dysfunction to intensive advice on weight loss and exercise or to general health information, and after two years 17 of 55 men in the intervention group had regained normal erectile scores, against 3 of 55 controls [14].

• Get the labs first, including fasting insulin, the core metabolic panel, and in men a morning testosterone (we cover treatment in our post on enclomiphene and low testosterone).
• Check your blood pressure, and if it isn't controlled, fix that before you consider bremelanotide.
• Review your medications with your physician, since SSRI antidepressants commonly blunt desire and orgasm, and don't stop one on your own.
• Protect your sleep, lift weights, walk, lose visceral fat, and cut back on alcohol, because each one improves the vascular and hormonal footing that desire depends on.
• If you try PT-141, expect nausea with the first doses, follow the limits on how often you dose, and judge it honestly after a handful of uses.

Bremelanotide has a real, modest effect on desire, with the best data in premenopausal women and only early laboratory studies in men. We use it as an adjunct once the workup is done, never as a substitute for it.

Ask a provider about PT-141

References

1. Dorr RT, Lines R, Levine N, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996. PMID: 8637402
2. Wessells H, Fuciarelli K, Hansen J, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol. 1998. PMID: 9679884
3. Nelson ME, Bryant SM, Aks SE. Melanotan II injection resulting in systemic toxicity and rhabdomyolysis. Clin Toxicol (Phila). 2012. PMID: 23121206
4. Dhillon S, Keam SJ. Bremelanotide: First Approval. Drugs. 2019. PMID: 31429064
5. Pfaus JG, Shadiack A, Van Soest T, et al. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc Natl Acad Sci U S A. 2004. PMID: 15226502
6. Diamond LE, Earle DC, Rosen RC, et al. Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res. 2004. PMID: 14963471
7. Rosen RC, Diamond LE, Earle DC, et al. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res. 2004. PMID: 14999221
8. White WB, Myers MG, Jordan R, et al. Usefulness of ambulatory blood pressure monitoring to assess the melanocortin receptor agonist bremelanotide. J Hypertens. 2017. PMID: 27977473
9. Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol. 2019. PMID: 31599840
10. Spielmans GI. Re-Analyzing Phase III Bremelanotide Trials for "Hypoactive Sexual Desire Disorder" in Women. J Sex Res. 2021. PMID: 33678061
11. Clayton AH, Kingsberg SA, Portman D, et al. Safety Profile of Bremelanotide Across the Clinical Development Program. J Womens Health (Larchmt). 2022. PMID: 35147466
12. Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 1995. PMID: 7573262
13. Thompson IM, Tangen CM, Goodman PJ, et al. Erectile dysfunction and subsequent cardiovascular disease. JAMA. 2005. PMID: 16414947
14. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA. 2004. PMID: 15213209