About Herbs

Bottom Line: This is insufficient data indicating perillyl alcohol is an effective cancer treatment in human.

Perillyl alcohol is a natural substance called a monoterpene, isolated from the essential oils of lavender, peppermint, spearmint, cherries, celery seeds, and several other plants. Scientists are not exactly sure how perillyl alcohol works, but laboratory evidence suggests that it interferes with the replication of dividing cells. Perillyl alcohol has shown promising anti-tumor activity against a range of cancer types (including pancreatic, stomach, colon, skin, and liver cancers) in animals and in the laboratory setting, but these results often do not translate into effects in humans. Clinical trials show no anticancer effect. 

In addition, the research data about perillyl alcohol's ability to prevent cancer in animals is not consistent. In one study that exposed rats to colon cancer-causing substances, rats that were fed a diet supplemented with perillyl alcohol developed fewer colon tumors that rats fed a normal diet. However, another study demonstrated that perillyl alcohol was not effective in preventing the early stages of liver cancer. There is no evidence that perilly alcohol prevents cancer in humans.

Cancer treatment:
A few phase I clinical trials have been performed in the past few years in an attempt to establish the highest tolerable dose of perillyl alcohol. While most patients in these studies did not respond favorably to perillyl alcohol, three patients with ovarian cancer did have tumor shrinkage or stable disease. This prompted a phase II clinical trial to study the effect of this supplement in 20 women with stage III and IV ovarian cancer. All of the women who took part in this study had undergone two or three previous chemotherapy regimens. Perillyl alcohol was given four times a day by mouth at a dose of 1200 mg/m² and the progress of their disease was monitored. In past groups of women with advanced ovarian cancer, the median survival without progression of disease was about 4.5 months; in this group receiving perillyl alcohol, it was 1.7 months. Perillyl alcohol was not able to shrink tumor size in any of the women. In addition, many of the women experienced nausea and fatigue. A similar study with similar results was reported on patients with prostate cancer as well.

Perillyl, POH, p-metha,1,7-diene-6-ol, 4-isopropenyl-cyclohexenecarbinol

Derived from essential oils in various botanicals including lavender, peppermint, cherries, sage, and lemongrass. Patients use this supplement to prevent and treat cancer. Perillyl alcohol is a cyclic monoterpene that causes G1 cell cycle arrest, induces apoptosis, and inhibits posttranslational modification of signal transduction proteins ^{(1) (2)}. Following oral administration, perillyl alcohol is rapidly metabolized to perillic acid and dihydroperillic acid. Both metabolites exhibit a relatively short biologic half-life of approximately 2 hours ⁽⁶⁾. Side effects include nausea, early satiety, and fatigue ⁽³⁾. Dose limiting toxicities, reported at higher levels, included stomatitis, hypokalemia, nausea, and fatigue ^{(2) (8)}. In vitro studies suggest that perillyl alcohol inhibits angiogenesis ⁽⁹⁾. A phase II study in patients with prostate cancer showed no effect of perillyl alcohol on patient survival ⁽¹⁰⁾.

The exact mechanism of action is unknown. Metabolites of perillyl alcohol, perillic acid and dihydroperillic acid may inhibit tumor growth through inhibition of p21 dependent signaling and apoptosis resulting from induction of the transforming growth factor beta-signaling pathway ^{(1) (2)}. Perillyl alcohol metabolites also appear to cause G1 cell cycle arrest, inhibit posttranslational modification of signal transduction proteins, and cause differential expression of cell cycle- and apoptosis-related genes ⁽³⁾. Activity of perillyl alcohol was demonstrated in animal models with pancreatic, stomach, colon ⁽⁴⁾, skin, and liver cancers ⁽⁵⁾. The role of perillyl alcohol for chemoprevention remains unknown, as efficacy data are inconsistent.

Following oral administration, perillyl alcohol is rapidly absorbed and subsequently metabolized to perillic acid (PA) and dihydroperillic acid (DPA). Peak plasma levels of the PA and DPA occur within approximately 2 hours and 4 hours, respectively, with an estimated biologic half-life of 2 hours ⁽⁶⁾. Continuous doses of 1600-2800 mg/m²/day perillyl alcohol results in PA and DPA plasma levels from 390-480 micromolar and 11-57 micromolar, respectively. The maximum tolerated dose (MTD) is 8,400mg/m²  per day ⁽⁸⁾. Administration with food appears to reduce the rate and extent of perillyl alcohol absorption. Approximately 10% of PA and 2% of DPA is eliminated in the urine ⁽¹⁾.

Common: (1600 mg/m²/day) Nausea, unpleasant taste, early satiety, and fatigue ^{(3) (10)}
Toxicity: (1200 mg/m2/day) one instance of hypokalemia has been reported  ⁽¹⁰⁾.
(doses > 2800 mg/m²/day) Nausea, fatigue, diarrhea, hypokalemia, stomatitis, and anorexia ⁽²⁾

No known drug interactions exist.

Bailey HH, et al. A phase II trial of daily perillyl alcohol in patients with advanced ovarian cancer: Eastern Cooperative Oncology Group study E2E96. Gynecol Oncol 2002;85:464-8.
Based on three cases of prolonged (>6 months) stable disease in ovarian cancer patients in phase I trials, this phase II trial was performed to compare the six-month progression-free survival of 20 women given 1200 mg/m² QID perillyl alcohol to an historical control. Six-month disease-free survival was chosen as primary endpoint rather than objective response rate, the authors state, because chronically administered novel static agents may exhibit a beneficial effect without producing objective tumor regression. No patient achieved a complete or partial response, and median progression-free survival was 1.7 months (historical control, approx. 4.5 months). Grade 1-2 GI toxicity and fatigue were common. It should be noted that there is little to no in vitro data regarding ovarian carcinoma and perillyl alcohol, and most patients experiencing clinical benefit from this agent in phase I trials received doses from 1600 to 2400 mg/m².

Liu G, Oettel K, Bailey H, Ummersen LV, Tutsch K, Staab MJ, Horvath D, Alberti D, Arzoomanian R, Rezazadeh H, McGovern J, Robinson E, DeMets D, Wilding G. Phase II trial of perillyl alcohol (NSC 641066) administered daily in patients with metastatic androgen independent prostate cancer. Invest New Drugs. 2003 Aug;21(3):367-72.
Fiften patients with metastatic androgen independent prostate cancer who had failyed to respond to at least one prior chemotherapeutic or experimental regimen participated in a phase II study of perillyl alcohol. Patients received 1200 mg/m²/dose four times daily. Adverse effects including gastrointestinal intolerance and fatigue were found in over half of the patients. Six patients did not even receive one cycle of therapy and only six participated long enough to be evaluable for response. No objective responses were seen.