Perillyl Alcohol: A Comprehensive Pharmacological and Clinical Review of a Monoterpene's Journey from Oral Disappointment to Intranasal Hope for CNS Malignancies

Introduction: Perillyl Alcohol as an Investigational Oncologic Agent

Perillyl alcohol (POH) is a naturally occurring monoterpene, a C10 isoprenoid synthesized via the mevalonate pathway in a diverse array of plants.[1] It is a key constituent of the essential oils isolated from botanicals such as lavender, peppermint, spearmint, cherries, and celery seeds.[4] For the past three decades, this small molecule has been the subject of intense investigation for its potential anticancer activity, charting a remarkable and instructive course through the landscape of oncologic drug development.[1]

The scientific narrative of perillyl alcohol is one of profound contrasts—a story of initial promise, significant clinical failure, and subsequent rebirth through therapeutic innovation. Based on a wealth of preclinical evidence from animal studies, POH demonstrated compelling antitumor activity, showing an ability to regress pancreatic, mammary, and liver tumors and exhibiting potential as a chemopreventive or chemotherapeutic agent against colon, skin, lung, and prostate cancers.[4] This promising foundation led to a series of clinical trials in the late 1990s and early 2000s. However, these trials, which utilized oral formulations of POH, failed to translate preclinical efficacy into human benefit. The oral route was plagued by poor bioavailability due to extensive first-pass metabolism and dose-limiting gastrointestinal toxicities that proved intolerable for patients, leading to the abandonment of this development pathway.[1]