Perillyl Alcohol

Health Care Professional Information

Common Name

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

Clinical Summary

Derived from essential oils in various botanicals including lavender, peppermint, cherries, sage, and lemongrass, perillyl alcohol is used to prevent and treat cancer. It is a cyclic monoterpene that causes G1 cell cycle arrest, induces apoptosis, and inhibits post-translational modification of signal transduction proteins (1) (2).
In vitro studies show that perillyl alcohol has antiangiogenesis (9) and anticancer (11) (12) (16) (17) effects.

Data from clinical trials are conflicting: Perillyl alcohol did not benefit patients with pancreatic cancer (10), skin cancer (13), or in those with treatment-refractory breast cancer (14), but preliminary results from a study of patients with malignant gliomas reported regression of tumor size (15). Further research is needed.

Dose limiting toxicities, reported at higher levels, included stomatitis, hypokalemia, nausea, and fatigue (2) (8).

Purported Uses
  • Cancer prevention
  • Cancer treatment
Mechanism of Action

The 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 data are inconsistent.

Pharmacokinetics

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).

Adverse Reactions

Common: At (1600 mg/m2/day), nausea, unpleasant taste, early satiety, and fatigue are common. (3) (10)
Toxicity: At (1200 mg/m2/day), one instance of hypokalemia has been reported (10).
At (doses > 2800 mg/m2/day), nausea, fatigue, diarrhea, hypokalemia, stomatitis, and anorexia have been reported. (2)

Literature Summary and Critique

Liu G, Oettel K, Bailey H, et al. 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.
Fifteen patients with metastatic androgen independent prostate cancer who had failed 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.

References
  1. Belanger JT. Perillyl alcohol: applications in oncology. Altern Med Rev 1998;3:448-57.
  2. Hudes GR, et al. Phase I pharmacokinetic trial of perillyl alcohol (NSC 641066) in patients with refractory solid malignancies. Clin Cancer Res 2000;6:3071-80.
  3. Ripple GH. Phase I clinical and pharmacokinetic study of perillyl alcohol administered four times a day. Clin Cancer Res 2000;6:390-6.
  4. Reddy BS, et al. Chemoprevention of colon carcinogenesis by dietary perillyl alcohol. Cancer Res 1997;57:420-5.
  5. Low-Baselli A, et al. Failure to demonstrate chemoprevention by the monoterpene perillyl alcohol during early rat hepatocarcinogenesis: a cautionary note. Carcinogenesis 2000;21:1869-77.
  6. Murren JR, et al. Phase I study of perillyl alcohol in patients with refractory malignancies. Cancer Biol Ther 2002;1:130-5.
  7. 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.
  8. Azzoli C, et al. A phase I trial of perillyl alcohol in patients with advanced solid tumors. Cancer Chemother Pharmacol 2003 Jun;51(6):493-8.
  9. Loutrari H, Hatziapostolou M, Skouridou V, Papadimitriou E, Roussos C, Kolisis FN, Papapetropoulos A. Perillyl alcohol is an angiogenesis inhibitor. J Pharmacol Exp Ther. 2004 Jun 21
  10. 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.
  11. Xu M, Floyd HS, Greth SM, et al. Perillyl alcohol-mediated inhibition of lung cancer cell line proliferation: potential mechanisms for its chemotherapeutic effects. Toxicol Appl Pharmacol. 2004 Mar 1;195(2):232-46.
  12. Fernandes J, da Fonseca CO, Teixeira A, Gattass CR. Perillyl alcohol induces apoptosis in human glioblastoma multiforme cells. Oncol Rep. 2005 May;13(5):943-7.
  13. Stratton SP, Alberts DS, Einspahr JG, et al. A phase 2a study of topical perillyl alcohol cream for chemoprevention of skin cancer. Cancer Prev Res (Phila). 2010 Feb;3(2):160-9.
  14. Bailey HH, Attia S, Love RR, et al. Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer. Cancer Chemother Pharmacol. 2008 Jun;62(1):149-57.
  15. da Fonseca CO, Schwartsmann G, Fischer J, et al. Preliminary results from a phase I/II study of perillyl alcohol intranasal administration in adults with recurrent malignant gliomas. Surg Neurol. 2008 Sep;70(3):259-66; discussion 266-7.
  16. Koyama M, Sowa Y, Hitomi T, et al. Perillyl alcohol causes G1 arrest through p15(INK4b) and p21(WAF1/Cip1) induction.Oncol Rep. 2013 Feb;29(2):779-84.
  17. Sultana S, Nafees S, Khan A. Perillyl alcohol as a protective modulator against rat hepatocarcinogenesis via amelioration of oxidative damage and cell proliferation.Hum Exp Toxicol. 2013 Mar 27. [Epub ahead of print]

Consumer Information

How It Works

Bottom Line: Perillyl alcohol has not been shown to treat cancer in humans.

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.

Purported Uses
  • To prevent and treat cancer
    Although evidence from laboratory and animal experiments suggests that perillyl alcohol has anti-tumor activity against a number of cancers, such in vitro results often do not translate to the human body. A few phase I clinical trials and one phase II clinical trial do not support the use of perillyl alcohol to treat cancer. Preliminary results from one study reported benefits with perillyl alcohol. More research is needed.
Research Evidence

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 the 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.

Side Effects
  • Nausea
  • Unpleasant taste
  • Early satiety
  • Fatigue
  • At high doses (> 2800 mg/m2/day) toxicity can develop, including nausea, fatigue, diarrhea, hypokalemia (dangerously low blood potassium levels), stomatitis (inflammation of the mucous membranes of the mouth), and loss of appetite.
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