ADRs seen at 10 mg dose typically used with L-dopa to treat Parkinson’s disease
It has been brought to our attention that deprenyl has been associated with ADRs at the higher doses (10 mg/day) typically used when it is taken in conjunction with L-dopa for the treatment of Parkinson’s disease, although not at the low doses (1 mg, 2-3 times/week) used for anti-aging purposes.
A study reviewing data submitted to the French Pharmacovigilance Database between 1989 through 1997 found a significant (OR=1.72) increase in cardiovascular-related mortality in patients with Parkinson’s disease taking selegiline (typical dosage 10 mg/day) with L-dopa.1
The United Kingdom Parkinson’s Disease Research Group trial also found an increase in mortality in patients with Parkinson’s disease randomized to receive selegiline (10 mg/day) and L-dopa compared with those taking L-dopa alone.
A small study (n=16) of patients taking selegiline (10 mg/day) and L-dopa found the combination may be associated with severe orthostatic hypotension not attributable to L-dopa alone, and that selegiline also has pronounced symptomatic motor effects in advanced Parkinson’s disease.
Study authors suggest these cardiovascular and motor effects may be due to the non-selective inhibition of MAO, which occurs when deprenyl is given at these higher doses.2
Potential for ADR with concomitant oral contraceptive use, but not with HRT
Significant potential for ADR was also seen in a small (n=8) four-period randomized study of women, 4 of whom were using oral contraceptives. In the women taking oral contraceptives, a single dose of 5 mg, 10 mg, 20 mg or 40 mg of selegiline HCl resulted in a 20-fold increase in its oral bioavailability, indicating that exogenous female sex steroids can reduce T-demethylation of selegiline.3
In addition, deprenyl does not appear to affect the metabolism of HRT, in which the dose of sex steriods is much lower than that used in oral contraceptives. In a randomized, double-blind, cross-over trial of 12 healthy female subjects, the women were given HRT (2 mg estradiol valerate and 250 micrograms levonorgestrel) or placebo for 10 days. On day 10, they took a single 10 mg dose of selegiline. Maximum plasma concentration (cMax) of selegiline was unchanged.4
No ADRs reported for deprenyl treatment for major depressive disorder and associated sexual dysfunction
A selegiline transdermal patch delivering 20 mg/day for up to 8 weeks was an effective and well tolerated treatment in patients with major depressive disorder. Side-effect profiles were similar to placebo.5,6
In research showing significant improvement in sexual function and satisfaction in women with major depressive disorder, selegiline in the form of a transdermal system delivering 6mg/24 hours was also well tolerated.7
No ADRs reported at the low doses used for anti-aging purposes
While ADRs are clearly a concern if deprenyl is given to women young enough to be taking oral contraceptives or when deprenyl is given in doses of 10 mg/day to treat Parkinson’s disease in conjunction with L-dopa, ADRs have not been reported at the much lower doses used for anti-aging purposes.
To protect cognitive function, dosage recommendations start at 1 mg, 1-2x/week for 30-35 year olds, and gradually increase with age to a maximum of up to 10mg/day for 80 year olds.8
ADRs are highly unlikely if anti-aging deprenyl treatment is initiated at a conservative level (1 mg/week). Monitor for side-effects (e.g., gastrointestinal symptoms, irritability, hyper-excitability, insomnia) while gradually increasing the dose to an age- and patient-appropriate level over several months.
Dosing delivery options
Deprenyl is currently available in tablet, transmucosal lozenge, transdermal patch, and liquid forms.
The oral tablet (10 mg, in doses of 1-2 tablets/day) is still most often chosen for concurrent use with L-dopa in the treatment of Parkinson’s disease, although a transmucosal lozenge (trade name, Zelapar) is gaining in popularity.
Developed to help avoid ADR issues, the transmucosal delivery system goes directly into the bloodstream, avoiding first pass liver detoxification and can therefore be given at much lower doses (1.25 mg daily for 6 weeks, then 1.25 mg b.i.d.).
The transdermal patch (trade name, Ensam), which is available to deliver doses of 6, 9 or 12 mg/day, is the form used in studies in which deprenyl has improved sexual function associated with major depression.
The liquid form, deprenyl citrate, is preferable for anti-aging purposes since it delivers 1 mg/drop and is bound to an organic molecule and thus likely to be better absorbed than the standard form, selegiline hydrocholoride, in which the agent is bound to an inorganic compound.
Montastruc JL, Chaumerliac C, Desboeuf K, et al. Adverse drug reactions to selegiline: a review of the French pharmacovigilance database. Clin Neuropharmacol. 2000 Sep-Oct;23(5):271-5. ↑
Churchyard A, Mathias CJ, Boonkongchuen P, et al. Autonomic effects of selegiline: possible cardiovascular toxicity in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1997 Aug;63(2):228-34. ↑
Laine K, Anttila M, Helminen A, et al. Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids. Br J Clin Pharmacol. 1999 Mar;47(3):249-54. ↑
Palovaara S, Anttila M, Nyman L, et al. Effect of concomitant hormone replacement therapy containing estradiol and levonorgestrel on the pharmacokinetics of selegiline. Eur J Clin Pharmacol. 2002 Jul;58(4):259-63. Epub 2002 May 22. ↑
Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry. 2002 Nov;159(11):1869-75. ↑
Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry. 2003 Feb;64(2):208-14. ↑
Clayton AH, Campbell BJ, Favit A, et al. Symptoms of sexual dysfunction in patients treated for major depressive disorder: a meta-analysis comparing selegiline transdermal system and placebo using a patient-rated scale. J Clin Psychiatry. 2007 Dec;68(12):1860-6. ↑
Knoll J. Antiaging compounds: (-)deprenyl (selegeline) and (-)1-(benzofuran-2-yl)-2-propylaminopentane, [(-)BPAP], a selective highly potent enhancer of the impulse propagation mediated release of catecholamine and serotonin in the brain. CNS Drug Rev. 2001 Fall;7(3):317-45. ↑