Since its first use as a treatment for strabismus in the early 1980s, the potential roles for botulinum toxin in clinical medicine have rapidly expanded. In addition to the well-known cosmetic applications, botulinum toxin has received U.S. Food and Drug Administration approval for 7 indications to date, and it is being investigated for dozens of other conditions, with over 10,000 scientific articles published within the past 10 years alone. It is, therefore, no surprise (particularly to urologists) that someone, at some point, was going to inject it into their penis. The real question is, is there a potential rationale for its use to treat erectile dysfunction (ED), or, more importantly, is it safe to do so?

Physiology of ED and the Role for Botulinum Toxin

Before discussing a potential mechanism for the use of botulinum toxin in men with ED, it is worthwhile to review its pharmacological profile in the context of erectile function physiology. Although botulinum toxin likely exhibits several physiological effects, its primary mechanism of action is to inhibit the presynaptic release of neurochemicals. In addition to the well-known suppression of acetylcholine at the neuromuscular junction (which results in targeted muscle paralysis), it has also been shown to prevent the release of norepinephrine, substance P and others. Interestingly, and although the data remain premature, botulinum toxin does not appear to impact nonadrenergic, noncholinergic (NANC) nerve fibers.¹

This latter point is particularly important, since the primary event leading to an erection is the release of nitric oxide from NANC nerve terminals. A cascade is then initiated whereby cyclic guanosine monophosphate (GMP) is generated, which then activates protein kinase G and ultimately reduces intracellular smooth muscle calcium. The loss of calcium relaxes the cavernosal and vascular smooth muscles and results in penile tumescence. The erection is then maintained based on a balance of relaxing and contracting factors. Detumescence may then occur through several mechanisms, including cyclic GMP deactivation by phosphodiesterase-5 (PDE5), direct contraction from norepinephrine via alpha-1 receptors (such as following ejaculation) or other causes.

Botulinum toxin is therefore relatively unique pharmacologically, given that it is able to inhibit norepinephrine (contracting factor) without impacting NANC nerves (relaxing factor).¹ Additionally, botulinum toxin has been shown to directly stimulate production of cyclic adenosine monophosphate, which plays a role similar to (albeit lesser than) cyclic GMP in achieving/maintaining tumescence.² It may also impact other chemicals relevant to erectile physiology, including vasoactive intestinal peptide, neuropeptide Y and others. These findings are notable, in that botulinum toxin may potentially improve erectile function while maintaining the body’s ability to physiologically regulate erections. In this manner, the therapy would be more like PDE5 inhibitors and less like intracavernosal injection therapies, and may therefore be a preferred and longer lasting treatment for many men. But the key question remains: does it actually work?

Are There Any Data?

One of the earliest published reports on the intentional use of botulinum toxin to treat erectile pathology was published in 2018.³ In this case report of a single patient with refractory, recurrent ischemic priapism, intracavernosal botulinum toxin resulted in complete resolution of symptoms for a period of at least 6 months (until the time of publication). In addition to the surprising and counterintuitive efficacy reported, this case is notable in that it suggests that the effects of botulinum toxin in the penis are likely complex and that it may indeed have a potential role in regulating penile physiology.

Three subsequent publications, including a randomized, placebo-controlled trial, evaluated the safety and efficacy of botulinum toxin in men with ED refractory to PDE5 inhibitors and/or intracavernosal injections with TriMix.^4–6 The studies reported on a combined 346 men, who received doses ranging from 50–500 units of botulinum toxin. Results demonstrated clinically significant improvements in erectile function out to 3 months, with higher dosages leading to persistent benefits to at least 6 months. In general, approximately 50% of men responded to therapy, which is notable given the refractory nature of the cohorts. Most importantly, no significant adverse effects were reported.

Word of Caution and Take-Home Message

Although the recent data on the use of botulinum toxin in men with ED are encouraging, more research is needed prior to its routine implementation. It is notable that all 4 manuscripts described above included men with essentially end-stage penile conditions. Although no significant adverse effects occurred, it is unclear if similar safety profiles would be observed in younger and less refractory cohorts. More to the point, given the long duration of action of botulinum toxin, if unopposed relaxation of the penis developed, this could hypothetically lead to a prolonged high-flow priapism or, worse yet, ischemic priapism. However, despite these cautions, the potential for a new class of therapy to treat ED (and possibly priapism) is exciting and, at a minimum, will lead to an improved understanding of erectile function physiology. And it is very likely that within the next 2–3 years, sufficient data will be available to either support or refute the prior findings. At that point, the only issue will be whether there will be any advertising space left between the bathtubs, bent vegetables and latest Men’s Health clinic spots!