Bremelanotide (PT-141)

Bremelanotide is a synthetic cyclic heptapeptide derived from α-melanocyte-stimulating hormone (α-MSH) [1] that acts on the brain's melanocortin receptors [5]. It is approved by the US FDA for acquired, generalised hypoactive sexual desire disorder (HSDD) in premenopausal women [4].

Animal work. In female rats, it selectively increased solicitation, the behaviour by which a female initiates mating, without changing lordosis, pacing, general activity or the rewarding value of sex. This was the first drug shown to act on sexual appetite rather than sexual reflexes [5].

Women. In a phase 2b trial of 327 premenopausal women with sexual dysfunction, 1.25–1.75 mg injected as desired for 12 weeks increased satisfying sexual events by 0.7 a month against 0.2 on placebo, and improved sexual function and distress scores [2]. At 1.75 mg, responder rates beat placebo on all seven endpoints [6]. The two phase 3 RECONNECT trials randomised 1,267 women with HSDD to 1.75 mg or placebo as needed for 24 weeks. Desire scores rose by 0.30 and 0.42 points more than placebo, and distress about low desire fell by 0.37 and 0.29 points more [3]. Results held across age, weight, testosterone level and contraceptive use [7]. Of 684 women who entered a 52-week open-label extension, 272 completed it; desire and distress kept improving [8]. Reviews describe the benefit as statistically clear but clinically modest [9][10].

Men. Bremelanotide was first developed for erectile dysfunction. Subcutaneous doses above 1 mg produced erections in healthy men without sexual stimulation, and 4–6 mg worked in men who did not respond well to 100 mg sildenafil [1]. A nasal spray produced erections at doses above 7 mg, starting about 30 minutes after dosing [11], and a low nasal dose added to 25 mg sildenafil gave a stronger response than sildenafil alone [12]. A 2008 trial in 342 sildenafil non-responders reported positive results in 33.5% vs 8.5% on placebo with 10 mg intranasally, but the journal issued an expression of concern about it in 2023 [13]. It was never approved for men.

Bremelanotide activates melanocortin receptors, chiefly MC4R [2], on neurons in the brain rather than acting on blood vessels, which is why it affects desire in women and can produce erections without sexual stimulation in men [1][5]. In rats the effect was specific to appetitive (motivational) sexual behaviour [5].

MC4R agonists can raise blood pressure. In 397 women, 1.25–1.75 mg raised ambulatory systolic pressure by about 2–3 mmHg in the 4 hours after dosing, with peaks lasting under 15 minutes, and lowered heart rate by about 5 beats a minute [14]. Repeated daily dosing can darken patches of skin [4].

Across 3,500 people in 43 studies, the most common adverse events in the phase 3 trials were nausea (40% vs 1.3% on placebo), flushing (20% vs 1.3%), headache (11% vs 1.9%) and injection-site reactions (5.4% vs 0.5%). Nausea was the main reason people stopped. There were no deaths and few serious adverse events [4]; one woman was hospitalised overnight with vomiting and headache [3]. In the phase 2b trial, 4% vomited [2]. No new safety signals appeared over 52 weeks of open-label use [8].

Focal hyperpigmentation was rare with as-needed use but occurred in more than a third of people given up to 16 consecutive daily doses. The blood pressure rise is small and transient, but the authors of the safety review advise caution in people at cardiovascular risk and keeping blood pressure controlled [4]. It did not interact with alcohol [16], but it lowered blood levels of indomethacin and naltrexone [4].