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PROPECIA: Disturbing Implications for Stress Management, OCD, and Substance Abuse

      It was found some time ago in a few studies that finasteride has a negative impact on the production of allopregnenolone-a neurosteriod essential to cognitive function and mood. As it turns out, several subsequent studies have corraborated this wounding effect on allopregnenolone, and have expanded the potential of negative effects to include impaired stress management, exacerbation of Obsessive compulsive disorder (OCD), and increased susceptibility to relapse in Cocaine addicts.

       In our opinion, it is these potential neurological effects, not sexual side effects per se, that loom most problematic.

      This study shows that finasteride actually prevented the decline and extinguishment of OCD behaviors treated with Prozac (Fluoxetine) in rats. One can reasonably assume that an underlying OCD condition would be even further exacerbated by finasteride in the absence of treatment with Prozac.

Prog Neuropsychopharmacol Biol Psychiatry. Oct 2009

Neurosteroids modulate compulsive and persistent behavior in rodents: implications for obsessive-compulsive disorder.

Neurosteroids are reported to modulate GABAergic and glutamatergic pathways that then influence serotonin and dopamine, the neurotransmitters implicated in pathophysiology of obsessive-compulsive disorder (OCD). Fluoxetine, a selective serotonin reuptake inhibitor clinically used in OCD is reported to increase the levels of neurosteroids like allopregnanolone, whereas OCD patients exhibit higher plasma levels of dehydroepiandrosterone 3-sulphate (DHEAS), a neuroactive steroid having opposite effects to that of allopregnanolone. Hence, it was contemplated that neurosteroids may influence obsessive-compulsive behavior. To test this possibility we studied the influence of various neurosteroids on two behavioral models of OCD, namely marble-burying behavior in mice and 8-OH-DPAT induced disruption of spontaneous alternation behavior (SAB) in rats. The results revealed that allopregnanolone (1 microg/mouse, i.c.v) and progesterone (20mg/kg, s.c.) reduced the marble-burying behavior in mice, whereas dehydroisoandrosterone 3-sulphate (DHAS) (5mg/kg, i.p.) exacerbated the same. The effects of allopregnanolone were comparable to that of fluoxetine (10mg/kg, i.p.). In view of the report that restraint stress increases the levels of allopregnanolone and isolation stress decreases the same, we studied the effect of these stressors on marble-burying behavior; wherein it was found to be less in restraint stress exposed mice, and higher in socially isolated mice. Restrain stress-induced attenuation of marble-burying behavior was blocked by finasteride, a neurosteroid biosynthesis blocker. In rat model of SAB disruption, acute and chronic treatment with allopregnanolone (1 microg/mouse, i.c.v.) reduced 8-OH-DPAT-induced persistent behavior, whereas treatment with DHAS (5mg/kg, i.p.) had an opposite effect. In conclusion, the studies indicate that neurosteroids can modulate obsessive-compulsive behavior in a bidirectional manner, and could serve as an effective target in the management of OCD.

      In this study Allopregnenolone diminished cocaine seeking behaviors in rats, while the administration of finasteride prevented this apparent attenuating effect. Again, Cocaine seeking behaviors would likely be further exacerbated by finasteride in the absence of concurrent Pregnenolone administration.

Psychopharmacology (Berl). Mar. 2009

Effects of allopregnanolone on the reinstatement of cocaine-seeking behavior in male and female rats.

Anker JJ, Holtz NA, Zlebnik N, Carroll ME.

Department of Psychiatry, University of Minnesota, MMC 392, Minneapolis, MN, 55455, USA. anke0022@umn.edu

RATIONALE: Previous research indicates that progesterone (PROG) decreased cocaine-seeking behavior in female rats. This effect of PROG may be in part due to its metabolite allopregnanolone (ALLO), which has been shown to decrease the sensitizing effects of cocaine and reduce lethality associated with cocaine overdose in mice. OBJECTIVE: The purpose of the present study was to examine the effects of ALLO on the reinstatement of cocaine-seeking behavior in female and male rats. METHODS: Rats were trained to lever press for i.v. infusions of cocaine (0.4 mg/kg per infusion) during 2-h sessions, and once acquisition criteria were met, cocaine self-administration continued for 14 days. Cocaine was then replaced with saline, and lever pressing was allowed to extinguish over 21 days. After the extinction phase, rats received s.c. ALLO (15 or 30 mg/kg), PROG (0.5 mg/kg), PROG (0.5 mg/kg) plus the 5-alpha reductase inhibitor finasteride (25 mg/kg), or vehicle pretreatment for 3 days. Rats were then tested during reinstatement with three doses of cocaine (5, 10, and 15 mg/kg, i.p. in mixed order). RESULTS: PROG, and to a greater extent ALLO, decreased cocaine-primed reinstatement in females, while finasteride blocked the attenuating effects of PROG on reinstatement. ALLO had no effect on cocaine-primed reinstatement in males. CONCLUSION: These findings suggest that ALLO may explain part of PROG's inhibitory effect on cocaine-primed reinstatement, and it may serve as a novel approach for preventing relapse in female cocaine abusers.

      One interesting finding that is likely relevant to humans showed finasteride actually reduced alcohol cravings due to its negative impact on AlloPregnenolone.

Alcohol Clin Exp Res. Aug 2008

Inhibition of 5alpha-reduced steroid biosynthesis impedes acquisition of ethanol drinking in male C57BL/6J mice.

Ford MM, Yoneyama N, Strong MN, Fretwell A, Tanchuck M, Finn DA

Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239-3098, USA. fordma@ohsu.edu

      BACKGROUND: Allopregnanolone (ALLO) is a physiologically relevant neurosteroid modulator of GABA(A) receptors, and it exhibits a psychopharmacological profile that closely resembles the post-ingestive effects of ethanol. The 5alpha-reductase inhibitor finasteride (FIN), which inhibits biosynthesis of ALLO and structurally related neurosteroids, was previously demonstrated to reduce the maintenance of limited-access ethanol consumption. The primary aim of the current work was to determine whether FIN would reduce the acquisition of drinking in ethanol-naÔve mice. METHODS: Male C57BL/6J (B6) mice were acclimated to a reverse light/dark schedule, and were provided ad libitum access to chow and water. Following habituation to vehicle injections (VEH; 20% w/v beta-cyclodextrin; i.p.) administered 22-hour prior to drinking sessions with water only, mice were divided into 3 treatment groups: vehicle control (VEH), 50 mg/kg FIN (FIN-50), and 100 mg/kg FIN (FIN-100). Twenty-two hours after the first treatment, mice were permitted the inaugural 2-hour limited access to a 10% v/v ethanol solution (10E) and water. The acquisition of 10E consumption and underlying drinking patterns were assessed during FIN treatment (7 days) and subsequent FIN withdrawal (13 days) phases. RESULTS: FIN dose-dependently blocked the acquisition of 10E drinking and prevented the development of ethanol preference, thereby suggesting that the GABAergic neurosteroids may be important in the establishment of stable drinking patterns. FIN-elicited reductions in 10E intake were primarily attributable to selective and marked reductions in bout frequency, as no changes were observed in bout size, duration, or lick rates following FIN treatment. FIN-treated mice continued to exhibit attenuated ethanol consumption after 2 weeks post-treatment, despite a full recovery in brain ALLO levels. A second study confirmed the rightward and downward shift in the acquisition of ethanol intake following 7 daily FIN injections. While there were no significant group differences in brain ALLO levels following the seventh day of ethanol drinking, ALLO levels were decreased by 28% in the FIN-50 group. CONCLUSIONS: Although the exact mechanism is unclear, FIN and other pharmacological interventions that modulate the GABAergic system may prove useful in curbing ethanol intake acquisition in at-risk individuals.

Editor's Comment:

      To use or not to use finasteride, (Propecia/Proscar) for the treatment of hair loss is a personal choice. In fairness, while it is no miracle drug, the majority of users get a transient stabilization of hair loss that last two years or longer, and some get a modicum of hair regrowth. For a certain percentage the hair loss stabilization effect appears to last over 5 years.

      The incidence of sexual side effects is likely much more than the 2% reported in the PDR, and are *usually* reversible upon discontinuation. Gynecomastia (breast enlargement in males, usually reversible only with surgery) has been added as a finasteride side effect in recent years. The prevention of the onset of Gynocemastia and sexual side effects have been controlled with some measure of success by the concurrent administration of plant based and pharmaceutical Aromatase inhibitors, such as Grape Seed Extract, Pomegranate Extract, Green Tea Extract and Arimidex, while still preserving its positive effects on hair growth.

      The side effects that loom most ominous arenít listed in the Physicianís Desk Reference, and that is the cognitive/behavioral/affective effects associated with finasterideís impact on alloppregnenolone. Whether or nor this potential effect on mood and cognitive function could be ameliorated with the concurrent usage of supplemental Pregnenolone remains unclear. A few anecdotal accounts indicate that Pregnenolone is helpful in clearing up the oft reported brain fog with Propecia, and this would make sense, however no controlled data exist to evaluate this interaction. Nevertheless, it would appear reasonable to use both a high dose of Pregnenolone (100+ mg) and an aromatase inhibitor while on finasteride.

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