Skip to main content
SpringerLink
Log in

Transdermal selegiline and intravenous cocaine: safety and interactions

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Because the dopamine system appears to be involved in both acute and chronic effects of cocaine, medication development efforts for cocaine addiction have focused largely on agents that interact with the dopamine system. Selegiline, a selective monoamine oxidase B inhibitor, indirectly modulates dopamine levels, and research suggests selegiline may modify subjective effects of cocaine.

Objectives

To evaluate further the safety and potential of transdermal selegiline as a treatment for cocaine dependence, interactions between transdermal selegiline and intravenous cocaine were studied in cocaine-dependent volunteers.

Methods

Pharmacokinetics and subjective, physiological, and endocrinological effects of intravenous cocaine (0,20 and 40 mg) were evaluated both before and during transdermal selegiline treatment (20 mg/day, 10 days) in 12 cocaine-dependent subjects. A transdermal selegiline formulation was used to avoid the risks associated with oral administration of MAO inhibitors.

Results

Selegiline attenuated some physiological (systolic blood pressure and heart rate) and subjective (good effects, liking, stimulated, high, desire for cocaine) effects of cocaine. Selegiline did not affect cocaine’s pharmacokinetics or cocaine-induced prolactin decrease and growth hormone increase.

Conclusions

The combined administration of the transdermal selegiline patch and up to 40 mg cocaine was well tolerated. Selegiline may reduce physiological and subjective effects of cocaine. A randomized trial is needed to evaluate the efficacy of selegiline for cocaine abuse.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Arnett CD, Fowler JS, MacGregor RR, Schlyer DJ, Wolf AP, Langstrom B, Halldin C (1987) Turnover of brain monoamine oxidase measured in vivo by positron emission tomography using l-[11C] Deprenyl. J Neurochem 49:522–527

    CAS  PubMed  Google Scholar 

  • Barroso N, Rodriguez M (1996) Action of beta-phenylethylamine and related amines on nigrostriatial dopamine neurotransmission. Eur J Pharmacol 297:195–203

    PubMed  Google Scholar 

  • Bartzokis G, Beckson M, Newton T, Mandelkern M, Mintz J, Foster JA, Ling W, Bridge TP (1999) Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria. Neuropsychopharmacology 20:582–590

    CAS  PubMed  Google Scholar 

  • Baumann MH, Rothman RB (1993) Effects of acute and chronic cocaine on the activity of tuberoinfundibular dopamine neurons in the rat. Brain Res 608:175–179

    Article  CAS  PubMed  Google Scholar 

  • Baumann MH, Raley TJ, Partilla JS, Rothman RB (1993) Biosynthesis of dopamine and serotonin in the rat brain after repeated cocaine injections: a microdissection mapping study. Synapse 14:40–50

    CAS  PubMed  Google Scholar 

  • Bergman J, Yasar Y, Winger G (2001) Psychomotor stimulant effects of beta-phenylethylamine in monkeys treated with MAO-B inhibitors. Psychopharmacology 159:21–30

    CAS  PubMed  Google Scholar 

  • Berlin I, de Brettes B, Aymard G, Diquet B, Arnult I, Puech AJ (2000) Dopaminergic drug response and the genotype (Taq IA polymorphism) of the dopamine D2 receptor. Int J Neuropsychopharmacol 3:35–43

    Article  CAS  PubMed  Google Scholar 

  • Campbell UC, Rodefer JS, Carroll ME (1999) Effects of dopamine receptor antagonists (D1 and D2) on the demand for smoked cocaine base in rhesus monkeys. Psychopharmacology 144:381–388

    Google Scholar 

  • Dackis CA, Gold MS (1985) New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev 9:469–477

    CAS  PubMed  Google Scholar 

  • De Wit H, Wise RA (1977) Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not the noradrenergic blockers phentolamine or phenyoxybenzamine. Can J Psychol 31:195–203

    CAS  PubMed  Google Scholar 

  • Di Paolo T, Rouillard C, Morissette M, Levesque D, Bedard PJ (1989) Endocrine and neurochemical actions of cocaine. Can J Pharmacol 67:1177–1181

    Google Scholar 

  • Emanuele NV, Levey AD, Li Q, Kirsteins L, van de Kar LD (1996) The impact of cocaine on plasma growth hormone levels in the adult male rats. Endocr Res 22:139–145

    CAS  PubMed  Google Scholar 

  • Evans SM, Walsh SL, Levin FR, Foltin RW, Fischman MW, Bigelow GE (2001) Effect of flupenthixol on subjective and cardiovascular responses to intravenous cocaine in humans. Drug Alcohol Depend 64:271–283

    CAS  PubMed  Google Scholar 

  • First MB, Spitzer RL, Gibbon M, Williams JBW (1997) Structured Clinical interview for DSM-IV axis I disorders—clinician version (SCID-CV). American Psychiatric Press, Washington D.C.

  • Gerra G, Zaimovic A, Moi G, Giusti F, Gardini S, Delsignore R, Laviola G, Macchia T, Brambilla F (2002) Effects of 3,4-methylene-dioxymethamphetamine (ecstacy) on dopamine system function in humans. Behav Brain Res 134:403–410

    Article  CAS  PubMed  Google Scholar 

  • Goeders NE, Smith JE (1986) Reinforcing properties of cocaine in the medial prefrontal cortex: primary action on presynaptic dopaminergic terminals. Pharmacol Biochem Behav 25:191–196

    CAS  PubMed  Google Scholar 

  • Haberny KA, Walsh SL, Ginn DH, Wilkins JN, Garner JE, Setoda D, Bigelow GE (1995) Absence of acute cocaine interactions with the MAO-B inhibitor selegiline. Drug Alcohol Depend 39:55–62

    Article  CAS  PubMed  Google Scholar 

  • Harris JE, Baldessarini RJ (1973) Uptake of [3H]-catecholamines by homogenates of rat corpus striatum and cerebral cortex: effects of amphetamine analogues. Neuropharmacology 12:659–679

    Article  Google Scholar 

  • Heesch CM, Negus BH, Bost JE, Keffer JH, Snyder RW, Eichhorn EJ (1996) Effects of cocaine on anterior pituitary and gonadal hormones. J Pharmacol Exp Ther 278:1195–1200

    CAS  PubMed  Google Scholar 

  • Heikkila RE, Orlanski H, Cohen G (1975) Studies on the distinction between uptake inhibition and release of [3H]-dopamine in rat brain and tissue slices. Biochem Pharmacol 103:241–248

    Google Scholar 

  • Hitri A, Casanova MF, Kleinman JE, Wyatt RJ (1994) Fewer dopamine transporter receptors in the prefrontal cortex of cocaine users. Am J Psychiatry 151:1074–1076

    CAS  PubMed  Google Scholar 

  • Houtsmuller E, Thornton JA, Stitzer ML. (2002) Effects of selegiline (l-deprenyl) during smoking and short-term abstinence. Psychopharmacology 163:213–220

    Article  CAS  PubMed  Google Scholar 

  • Hubner CB, Koob GF (1990) Bromocriptine produces decreases in cocaine self-administration in the rat. Neuropsychopharmacology 3:101–108

    CAS  PubMed  Google Scholar 

  • Karoum F, Fawcett RW, Wyatt RJ (1988) Chronic cocaine effects on peripheral biogenic amines: a long-term reduction in peripheral dopamine and phenylethylamine production. Eur J Pharmacol 148:381–388

    Article  CAS  PubMed  Google Scholar 

  • Karoum F, Suddath RL, Wyatt RJ (1990) Chronic cocaine and rat brain catecholamines: long-term reduction in hypothalamic and frontal cortex dopamine metabolism. Eur J Pharmacol 186:1–8

    Article  CAS  PubMed  Google Scholar 

  • Karoum F, Egan MF, Wyatt RJ (1994) Selective reduction in dopamine turnover in the rat frontal cortex and hypothalamus during withdrawal from repeated cocaine exposure. Eur J Pharmacol 254:127–132

    Article  CAS  PubMed  Google Scholar 

  • Kleven MS, Woolverton WL (1990) Effects of bromocriptine and desipramine on behavior maintained by cocaine or food presentation in rhesus monkeys. Psychopharmacology 101:208–213

    CAS  PubMed  Google Scholar 

  • Kleven MS, Woolverton WL, Seiden LS (1988) Lack of long-term monoamine depletions following repeated or continuous exposure to cocaine. Brain Res Bull 21:233–237

    Article  CAS  PubMed  Google Scholar 

  • Kleven MS, Perry BD, Woolverton WL, Seiden LS (1990) Effects of repeated injections of cocaine on D1 and D2 dopamine receptors in rat brain. Brain Res 532:265–270

    Article  CAS  PubMed  Google Scholar 

  • Knoll J (1983) Deprenyl (selegiline): the history of its development and pharmacological action. Acta Neurol Scand 95:57–80

    CAS  Google Scholar 

  • Kuhar MJ, Ritz MC, Boja JW (1991) The dopamine hypothesis of the reinforcing properties of cocaine. Trends Neurosci 14:299–302

    CAS  PubMed  Google Scholar 

  • Lee MA, Bowers MM, Nash JF, Meltzer HY (1990) Neuroendocrine measures of dopaminergic function in chronic cocaine users. Psychiatry Res 33:151–159

    Article  CAS  PubMed  Google Scholar 

  • Little KY, Umesh NP, Clark TB, Butts JD (1996) Alteration of brain dopamine and serotonin levels in cocaine users: a preliminary report. Am J Psychiatry 153:1216–1218

    CAS  PubMed  Google Scholar 

  • Mally J (1992) Some new aspects of the effect of (−)deprenyl in Parkinson’s disease−a retrospective study. J Neural Transm 4:155–164

    CAS  Google Scholar 

  • Mally J, Kovacs AB, Stone TW (1995) Delayed development of symptomatic improvement by (−)-deprenyl in Parkinson’s disease. J Neurol Sci 134:143–145

    Article  CAS  PubMed  Google Scholar 

  • Masserano JM, Venable D, Wyatt RJ (1994) Effects of chronic cocaine administration on [3H]dopamine uptake in the nucleus accumbens, striatum and frontal cortex of rats. J Pharmacol Exp Ther 270:133–141

    CAS  PubMed  Google Scholar 

  • McNair DM, Lorr M, Droppleman LF (1971) EITS manual for the profile of mood states. Educational and Industrial Testing Services, San Diego, Calif.

  • Nemeth-Coslett R, Henningfield JE, O’Keeffe MK, Griffiths RR (1986) Effects of mecamylamine on human cigarette smoking and subjective ratings. Psychopharmacology 88:420–425

    Google Scholar 

  • Newton T, Kalechstein A, Beckson M, Bartzokis G, Bridge TP, Ling W (1999) Effects of selegiline pretreatment on response to experimental cocaine administration. Psychiatry Res 87:101–106

    CAS  PubMed  Google Scholar 

  • Paterson IA, Juorio AV, Boulton AA (1990) 2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system? J Neurochem 55:1827–1837

    CAS  PubMed  Google Scholar 

  • Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237:1219–1223

    CAS  PubMed  Google Scholar 

  • Roberts DCS, Koob GF, Klonoff P, Fibiger HC (1980) Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens. Pharmacol Biochem Behav 12:781–787

    CAS  PubMed  Google Scholar 

  • Roy A, Berman J, Williams R, Kuhn C, Gonzales B. (2002) Higher levels of CSF homovanillic acid in recently abstinent cocaine-dependent patients. Am J Psychiatry 159:1053–1055

    Article  PubMed  Google Scholar 

  • Scheinin M, Karhuvara S, Ojala-Karlsson P, Kallio A, Koulu M (1991) Plasma 3,4-dihydroxiphenylglycol (DHPG) and MHPG are insensitive indicators of α2-adrenoceptor mediated regulation of norepinephrine release in healthy human volunteers. Life Sci 49:75–84

    CAS  PubMed  Google Scholar 

  • Schindler CW, Tella SR, Erzouki HK, Goldberg SR (1995) Pharmacological mechanisms in cocaine’s cardiovascular effects. Drug Alcohol Depend 37:183–191

    CAS  Google Scholar 

  • Sharpe LG, Pilotte NS, Mitchell WM, De Souza EB (1991) Withdrawal of repeated cocaine decreases autoradiographic [3H]mazindol-labelling of dopamine transporter in rat nucleus accumbens. Eur J Pharmacol 203:141–144

    Article  CAS  PubMed  Google Scholar 

  • Spealman RD, Bergman J, Rosenzweig-Lipson S (1997) Differential modulation of behavioral effects of cocaine by low- and high-efficacy D1 agonists. Psychopharmacology 133:283–292

    Article  CAS  PubMed  Google Scholar 

  • ThyagaRajan S, Quadri SK (1999) l-Deprenyl stimulates the release of catecholamines in the rat medial basal hypothalamus in vivo. Neurosci Lett 30:79–82

    Article  Google Scholar 

  • Tuomisto J, Mannisto P (1985) Neurotransmitter regulation of anterior pituitary hormones. Pharmacol Rev 37:249–332

    Google Scholar 

  • Volkow ND, Fowler JS, Wolff AP, Schlyer D, Shiue CY, Alpert R, Dewey SL, Logan J, Bendriem B, Christman D (1990) Effects of chronic cocaine abuse on postsynaptic dopamine receptors. Am J Psychiatry 147:719–724

    CAS  PubMed  Google Scholar 

  • Walsh SL, Sullivan JT, Preston KL, Garner JE, Bigelow GE (1996) Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans. J Pharmacol Exp Ther 279:524–538

    CAS  PubMed  Google Scholar 

  • Withers NW, Pulvirenti L, Koob GF, Gillin JC (1995) Cocaine abuse and dependence. J Clin Psychopharmacol 15:63–78

    CAS  Google Scholar 

  • Wu JC, Bell K, Najafi A, Widmark C, Keator D, Tang C, Klein E, Bunney BG, Fallon J, Bunney WE (1997) Decreasing striatal 6-FDOPA uptake with increasing duration of cocaine withdrawal. Neuropsychopharmacology 17:402–409

    Article  CAS  PubMed  Google Scholar 

  • Wyatt RJ, Karoum F, Suddath R, Fawcett R (1988) Persistently decreased brain dopamine levels and cocaine. JAMA 259:2996

    Article  CAS  Google Scholar 

  • Yasar S, Goldberg JP, Goldberg SR (1996) Are metabolites of l-deprenyl (selegiline) useful or harmful? Indications from preclinical research. J Neural Transm Suppl 48:61–73

    CAS  PubMed  Google Scholar 

  • Yeh SY, De Souza EB (1991) Lack of neurochemical evidence for neurotoxic effects of repeated cocaine administration in rats on brain monoamine neurons. Drug Alcohol Depend 27:51–61

    CAS  PubMed  Google Scholar 

  • Zimmer R (1990) Relationship between tyramine potentiation and monoamine oxidase (MAO) inhibition: comparison between moclobemide and other MAO inhibitors. Acta Psychiatr Scand Suppl 360:81–83

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Shirley Savage and John Yingling for technical services, Biopharmaceutical Research Consultants, Inc. (N01DA-6-8054) for data management and statistical support, and the University of California San Francisco (N01-DA48306) and University of Utah (N01-DA78074) for analytical support. This research was further supported by grants K05-DA00050 and RO1-DA 0-5196 (PI GEB) and Y01-DA50038, K08-DA00388, M01-RR00865. Selegiline patches were provided by Somerset Inc. through a CRADA with NIDA.

Author information

Authors and Affiliations

  1. Behavioral Pharmacology Research Unit, Johns Hopkins University School of Medicine, Bayview Medical Center, 5510 Nathan Shock Drive, Baltimore, MD, 21224-6823, USA

    Elisabeth J. Houtsmuller, Lisa D. Notes & George E. Bigelow

  2. Neuropsychiatric Institute, University of California at Los Angeles, Los Angeles, Calif., USA

    Thomas Newton & Nicolette van Sluis

  3. Medications Development Division, National Institute on Drug Abuse, Rockville, Md., USA

    Nora Chiang & Ahmed Elkashef

Authors
  1. Elisabeth J. Houtsmuller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lisa D. Notes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Newton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicolette van Sluis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nora Chiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ahmed Elkashef
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. George E. Bigelow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Elisabeth J. Houtsmuller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Houtsmuller, E.J., Notes, L.D., Newton, T. et al. Transdermal selegiline and intravenous cocaine: safety and interactions. Psychopharmacology 172, 31–40 (2004). https://doi.org/10.1007/s00213-003-1616-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-003-1616-6

Keywords

Search

Navigation