PT-141 (Bremelanotide) and Cannabis: Full Interaction Profile

What bremelanotide is and how it is used

Bremelanotide is FDA-approved as Vyleesi for premenopausal women with acquired, generalized hypoactive sexual desire disorder [1]. It is a 1.75 mg subcutaneous injection from a prefilled autoinjector, given into the abdomen or thigh as needed at least 45 minutes before anticipated sexual activity [1]. The label does not recommend more than one dose in 24 hours or more than 8 doses per month, and the drug is not indicated for men or for postmenopausal women [1].

Products sold as PT-141 that are compounded or labeled for research use are not Vyleesi and are not FDA-approved drugs. Compounded drugs are not reviewed by FDA for safety, effectiveness or quality before marketing [1][2]. The label facts on this page describe Vyleesi.

Bremelanotide is a melanocortin receptor agonist that activates several receptor subtypes in this order of potency: MC1R, MC4R, MC3R, MC5R, MC2R. At therapeutic doses, binding to MC1R and MC4R matters most, and how the drug improves sexual desire is not known [1]. After a 1.75 mg subcutaneous dose the median time to peak blood level is about 1 hour and the mean terminal half-life is about 2.7 hours. The drug is metabolized by hydrolysis of amide bonds [1].

What the Vyleesi label lists as interactions

The label's interactions section covers two things. First, Vyleesi may slow gastric emptying and reduce absorption of oral medicines. The label says to avoid it with oral drugs that depend on threshold blood concentrations (antibiotics, for example) and to consider skipping it when a fast effect from an oral drug such as indomethacin is wanted [1]. Second, Vyleesi may significantly decrease the systemic exposure of oral naltrexone. The label says to avoid that combination with naltrexone products intended to treat alcohol or opioid addiction, because treatment failure would be serious [1].

The label also reports an alcohol study in 24 healthy volunteers. In that crossover study, alcohol at 0.6 g/kg did not change bremelanotide blood levels, and flushing and headache rates with the combination were similar to the higher of the two single-agent rates. That study used a 20 mg intranasal dose, about 2.5-fold the Cmax of Vyleesi [1].

The shared concern: blood pressure and heart rate

The label describes a transient rise in blood pressure and a fall in heart rate after each dose. In clinical studies the maximal increases were 6 mmHg systolic and 3 mmHg diastolic, peaking between 2 and 4 hours after the injection, with a heart rate reduction of up to 5 beats per minute. Blood pressure and heart rate usually returned to baseline within 12 hours, and no additive effect was seen with repeat daily dosing 24 hours apart for up to 16 days [1]. Those 6 and 3 mmHg figures are maximal, not average.

In a separate open-label ambulatory monitoring study of 127 premenopausal women dosed once daily for 8 days, the mean daytime increase was 1.9 mmHg systolic (95% CI 1.0 to 2.7) and 1.7 mmHg diastolic (95% CI 0.9 to 2.4), with a mean heart rate decrease of 0.5 beats per minute [1].

Vyleesi is contraindicated in patients with uncontrolled hypertension or known cardiovascular disease, and it is not recommended for patients at high risk of cardiovascular disease [1]. The label says to consider the patient's cardiovascular risk before starting and periodically during treatment, and to ensure blood pressure is well controlled [1]. It also notes that more frequent dosing lengthens the time each month during which blood pressure is raised [1].

Cannabis and the cardiovascular system

The American Heart Association's scientific statement on medical marijuana, recreational cannabis and cardiovascular health concluded that cannabis may have therapeutic benefits but few are cardiovascular in nature. It also said that many of the concerning health implications of cannabis include cardiovascular diseases, although these may be mediated by mechanisms of delivery [3]. Cannabinoid effects are mediated by CB1 and CB2 receptors, with CB1 the prominent subtype in the central nervous system [4].

The label does not report a study of Vyleesi together with cannabis, so how the two combine in the cardiovascular system is not described.

Nausea and dizziness

Nausea is the most common side effect of bremelanotide. In the pooled phase 3 trials of 1,247 premenopausal women (627 on Vyleesi, 620 on placebo), nausea occurred in 40.0% versus 1.3%, flushing in 20.3% versus 0.3%, headache in 11.3% versus 1.9%, dizziness in 2.2% versus 0.5% and fatigue in 3.2% versus 0.5% [1]. The median onset of nausea was within one hour of the dose and it lasted about two hours. It was highest after the first dose (21% of patients) and fell to about 3% with later doses [1]. Thirteen percent of patients took an anti-nausea medicine and 8% stopped the trials because of nausea [1]. Pretreating with 8 mg oral ondansetron 30 minutes before the injection did not reduce nausea in a phase 4 study of 228 healthy women, and the label does not recommend that pretreatment [1].

Cannabinoids also act on nausea and vomiting. In animal studies, CB1 agonists suppress vomiting and CBD suppresses nausea and vomiting within a limited dose range [5]. Cannabinoid hyperemesis syndrome is a cyclic vomiting syndrome preceded by daily to weekly cannabis use. It is usually relieved by hot bathing and resolves when cannabis stops, and its pathophysiology is unclear [6].

For persistent or severe nausea, the label says to consider discontinuing Vyleesi or starting anti-nausea therapy, and it offers the anti-nausea option for patients bothered by nausea who want to continue [1].