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Amphetamine induced activation of the opioid system: a focused review of animal and human studies

Iliyan Ivanov, Chang Wang, Abigail Cohen


Stimulants are commonly prescribed as first line medications for ADHD and also used as adjunct treatment in other psychiatric conditions. While much is known about stimulants’ influence on brain neurochemistry, particularly on the dopaminergic neurotransmission, there has been less research into prescription stimulants’ effects on the endogenous opioid system. What we know about the mechanisms underlying the effects of stimulants on the opioid system come predominantly from animal studies and a relatively small number of studies in humans using positron emission tomography (PET) to examine the activation of the endogenous opioid system as evidenced by radioligand binding to opioid receptors. This paper is a focused review of the currently available literature on both animal and human studies examining the effects of stimulant administration on the endogenous opioid system, which suggest that stimulant administration results in increased occupancy of the opioid receptors in a widespread network of brain regions. We discuss the possible underlying mechanisms of this interaction, it’s potential impact on our understanding of substance abuse and addiction, particularly as viewed through the model of behavioral sensitization, and possible clinical implications.


attention deficit hyperactivity disorder (ADHD), positron emission tomography (PET) imaging, amphetamine, opioid receptors

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Arnold, L. E. (1972). Levoamphetamine and dextroamphetamine: Comparative efficacy in the hyperkinetic syndrome. Arch General Psychiatry 27(6): 816. https://

Berman, S. M., Kuczenski, R., McCracken, J. T., London, ED. (2009). Potential adverse effects of amphetamine treatment on brain and behavior: a review. Mol Psychi- atry, 14(2): 123–142. mp.2008.90

Bernstein, H-G., Henning, H., Seliger, N., Baumann, B., Bogerts, B. (1996). Remarkable β-endorphinergic innervation of human cerebral cortex as revealed by immunohistochemistry. Neurosci Lett 215(1): 33–36.

Boileau, I., Dagher, A., Leyton, M., Gunn, R. N., Baker,

G. B., Diksic, et al. (2006). Modeling sensitization to stimulants in humans. Arch General Psychiatry 63(12). archpsyc.63.12.1386.

Boileau I, Payer D, Chunagi B, Lobo D, Behzadi A, Rusian P, et al. (2013) The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [11C]-(+)-propyl-hexahydro-naphtho-oxazin and [11C]raclopride. Addiction 108(5):953-63. doi: 10.1111/add.12066.

Bourdy, R., Barrot, M. (2012). A new control center for dopaminergic systems: Pulling the VTA by the tail. Trends Neurosci 35(11):681–690. tins.2012.06.007.

Cao, D.-N., Shi, J.-J., Hao, W., Wu, N., Li, J. (2016).

Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction. European Journal of Pharmacology, 780, 129–135. https://doi. org/10.1016/j.ejphar.2016.03.040.

Chang, Z., Ghirardi, L., Quinn, P. D., Asherson, P., D’Onofrio, B. M., Larsson, H. (2019). Risks and benefits of attention-deficit/hyperactivity disorder medication on behavioral and neuropsychiatric outcomes: A qualitative review of pharmacoepidemiology studies using linked prescription databases. Biol Psychiatry, 86(5), 335–343.

Chiu, C. T., Ma, T., Ho, I. K. (2005). Attenuation of meth- amphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone. Brain research bulletin, 67(1-2), 100–109. brainresbull.2005.05.028

Colasanti, A., Searle, G. E., Long, C. J., Hill, S. P., Reiley,

R. R., Quelch, D., et al. (2012). Endogenous opioid release in the human brain reward system induced by acute amphetamine administration. Biol Psychiatry 72(5), 371– 377.

Di Chiara G, Imperato A. (1988) Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther. 244:1067–1080.

Doron R, Fridman L, Yadid G (2006). Dopamine-2 receptors in the arcuate nucleus modulate cocaine-seeking behavior. Neuroreport 17: 1633–1636.

Dudás, B., Merchenthaler, I. (2004). Close anatomical associations between β- endorphin and luteinizing hormone-releasing hormone neuronal systems in the human diencephalon. Neuroscience 124(1), 221–229. https://doi. org/10.1016/j.neuroscience.2003.11.021.

Erritzoe, D., Tziortzi, A., Bargiela, D., Colasanti, A., Searle, G. E., Gunn, R. N., et al. (2014). In vivo imaging of cerebral dopamine D3 receptors in alcoholism. Neuropsychopharmacology, 39(7), 1703–1712. https://

Gramsch, C., Hölt, V., Mehraein, P., Pasi, A., Herz, A. (1979). Regional distribution of methionine-enkephalin- and beta-endorphin-like immunoreactivity in human brain and pituitary. Brain Res 71(2), 261–270. https:// 8993(79)90332-9.

Gonzalez-Nicolini, M. V., Berglind, W., Cole, K. S., Keogh, C. L., & McGinty, J. F. (2003). Local μ and δ opioid receptors regulate amphetamine-induced behavior and neuropeptide mrna in the striatum. Neuroscience, 121(2), 387–398. 3.

Gray, A. M., Rawls, S. M., Shippenberg, T. S., McGinty, J.

F. (1999). The kappa- opioid agonist, U-69593, decreases acute amphetamine-evoked behaviors and calcium- dependent dialysate levels of dopamine and glutamate in the ventral striatum. J Neurochem73(3), 1066–1074. https:// 4159.1999.0731066.x

Guterstram J, Jayaram-Lindstrom N, Cervenka S, Frost J, Farde L, Halldin C, Franck J. Effects of amphetamine on the human brain opioid system--a positron emission tomography study. (2013) Int J Neuropsychopharmacol 16(4):763-9. doi: 10.1017/S1461145712000818.

Häggkvist J, Lindholm S, Franck, J. (2009a). The effect of naltrexone on amphetamine-induced conditioned place preference and locomotor behaviour in the rat. Addiction Biol 14(3), 260–269.


Haggkvist, J, Lindholm S, Franck, J. (2009b). The opioid receptor antagonist naltrexone attenuates reinstatement of amphetamine drug-seeking in the rat. Behavioural Brain Research, 197(1), 219–224. bbr.2008.08.021.

Haggkvist, J, Bjorkholm C, Steensland P, Lindholm, S, Franck, J, Schilstrom B. (2011) Naltrexone attenuates amphetamine-induced locomotor sensitization in rats. Addict Biol 16(1): 20-29.

Heal, DJ., Smith, S. L., Gosden, J., Nutt, DJ. (2013). Amphetamine, past and present – a pharmacological and clinical perspective. J Psychopharmacol 27(6), 479– 496.

Ivanov I, Bjork J, Blair, RJ, Newcorn J. (2022). Sensitization-based risk for substance abuse in vulnerable individuals with ADHD: Review and re-examination of evidence. Neurosci Biobehav Rev 104575

Jayaram-Lindström, N., Wennberg, P., Hurd, Y. L., Franck, J. (2004). Effects of naltrexone on the subjective response to amphetamine in healthy volunteers. J Clin Psychopharmacol 24(6), 665–669. https://doi. org/10.1097/

Jayaram-Lindström, N., Konstenius, M., Eksborg, S., Beck, O., Hammarberg, A., Franck, J. (2007). Naltrexone attenuates the subjective effects of amphetamine in patients with amphetamine dependence. Neuropsychopharmacology, 33(8), 1856–1863. sj.npp.1301572.

Jayaram-Lindström, N., Guterstam, J., Häggkvist, J., Ericson, M., Malmlöf, T., Schilström, B., Halldin, C., Cervenka, S., Saijo, T., Nordström, A.-L., & Franck, J. (2017). Naltrexone modulates dopamine release follow- ing chronic, but not acute amphetamine administration: A translational study. Translational Psychiatry, 7(4). https://

Jimenez-Gomez, C., Winger, G., Dean, R. L., Deaver,

D. R., & Woods, J. H. (2011). Naltrexone decreases D-amphetamine and ethanol self-administration in Rhesus Monkeys. Behavioural Pharmacology, 22(1), 87–90.

Kollins S. (2003) Comparing the abuse potential of methylphenidate versus other stimulants: A review of available evidence and relevance to the ADHD patient. The Journal of Clinical Psychiatry 64 Suppl 11(Suppl 11):14-8

Kotlinska, J., Rafalski, P., Biala, G., Dylag, T., Rolka, K., Silberring, J. (2003). Nociceptin inhibits acquisition of amphetamine-induced place preference and sensitization to stereotypy in rats. Eur J Pharmacol 474(2-3), 233–239.

Kuczenski, R., Segal, D. S. (2005). Stimulant actions in rodents: Implications for attention-deficit/hyperactiv- ity disorder treatment and potential substance abuse. Biological Psychiatry, 57(11), 1391–1396. https://doi. org/10.1016/j.biopsych.2004.12.036.

Lan, K.-C., Ma, T., Lin-Shiau, S.-Y., Liu, S.-H., Ho, I.-K. (2007). Methamphetamine-elicited alterations of dopamine- and serotonin-metabolite levels within μ-opioid receptor knockout mice: a microdialysis study. J Biomed Sci 15(3), 391–403. s11373-007-9218-7

Le Merrer, J., Becker, J. A., Befort, K., Kieffer, B. L. (2009). Reward processing by the opioid system in the brain. Physiol Rev 89(4), 1379–1412. https://doi. org/10.1152/physrev.00005.2009.

Leith, N. J., & Kuczenski, R. (1982). Two dissociable components of behavioral sensitization following repeated amphetamine administration. Psychopharmacol- ogy, 76(4), 310–315.

Lett, B. T. (1989). Repeated exposures intensify rather than diminish the rewarding effects of amphetamine, morphine, and cocaine. Psychopharmacology, 98(3), 357–362.

Mick I, Myers J, Stokes P, Erritzoe D, Colasanto A, Bowden-Jones H, et al. (2014) Amphetamine induced endogenous opioid release in the human brain detected with [¹¹C]carfentanil PET: replication in an independent cohort. Int J Neuropsychopharmacol 17(12):2069-74. doi: 10.1017/S1461145714000704.

Mick I, Myers J, Ramos A, Stokes P, Erritzoe D, et al. (2016) Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers. Neuropsychopharmacology 41(7):1742-50. doi: 10.1038/ npp.2015.340.

Piazza, P. V., Deminiere, J. M., le Moal, M., Simon, H. (1990). Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration. Brain Res 514(1), 22–26.

Pierce, R. C., & Kumaresan, V. (2006). The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse? Neurosci Biobehav Rev 30(2), 215–238. orev.2005.04.016

Quinn P, Chand Z, Hur K, Gibbons R, Lahey B, Rickert M, et al (2017) ADHD Medication and Substance-Related Problems. Am J Psychiatry 174(9):877-885.

Robinson, T. E., Berridge, K. C. (2000). The Psychology and Neurobiology of addiction: An incentive-sensitization view. Addiction, 95(8s2), 91–117. https://doi. org/10.1046/j.1360-0443.95.8s2.19.x

Robinson, T. E., Berridge, K. C. (2008). The incentive sensitization theory of addiction: Some current issues. Philosoph Transac Royal Soc B: Biol Sci 363(1507), 3137–3146.

Shen, X., Purser, C., Tien, L.-T., Chiu, C.-T., Paul, I. A., Baker, R., et al. (2010). Μ-opioid receptor knockout mice are insensitive to methamphetamine-induced behavioral sensitization. J Neurosci Res 88(10), 2294–2302. https://

Spanagel, R., Herz, A., Shippenberg, T. S. (1992). Oppos- ing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci USA 89(6), 2046–2050. pnas.89.6.2046

Smith, A. J. W., McGinty, J. F. (1994). Acute amphetamine or methamphetamine alters opioid peptide mrna expression in rat striatum. Mol Brain Res 21(3-4):359–362.

Soderman AR, Unterwald EM (2009). Cocaine-induced mu opioid receptor occupancy within the striatum is mediated by dopamine D2 receptors. Brain Res 1296: 63–71.

Souza, D. Z., Boehl, P. O., Comiran, E., Prusch, D. S., Zancanaro, I., et al. (2012). Which amphetamine-type stimulants can be detected by oral fluid immunoassays? Ther Drug Monit 34(1): 98–109. ftd.0b013e31823d8e8d

Tanimura, Y., Ogoegbunam, F. C., Lewis, M. H. (2009). Amphetamine-induced sensitization and spontaneous stereotypy in Deer mice. Pharmacol Bio- chem Behav 92(4):670–675. pbb.2009.03.006

Tien, L. T., Ho, I. K., Loh, H. H., & Ma, T. (2007). Role of mu-opioid receptor in modulation of preproenkephalin mRNA expression and opioid and dopamine receptor binding in methamphetamine-sensitized mice. J Neu- rosci Res 85(3), 673–680. https://doi. org/10.1002/ jnr.21145

Trigo, J. M., Martin-García, E., Berrendero, F., Robledo, P., Maldonado, R. (2010). The endogenous opioid system: A common substrate in drug addiction. Drug Alcohol Depend 108(3), 183–194. https://doi. org/ 10.1016/j.drugalcdep.2009.10.011

Trujillo, K. A., Belluzzi, J. D., Stein, L. (1991). Naloxone blockade of amphetamine place preference conditioning. Psychopharmacology, 104(2), 265–274.

Turton S, Myers J, Mick I, Colasanti A, Venkatarman A,

Durant C, Waldman A, Brailsford A, Parkin M, Dawe G, Rabiner E, Gunn R, Lightman S, Nutt D. (2020) Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol-dependent indi- viduals. Mol Psychiatry. 25(8):1749-1758. doi: 10.1038/ s41380-018-0107-4.

Tzaferis, J. A., & McGinty, J. F. (2001). Kappa opioid receptor stimulation decreases amphetamine-induced behavior and neuropeptide mrna expression in the striatum. Molecular Brain Research, 93(1), 27–35. https://

Wang, J. Q., Smith, A. J. W., & McGinty, J. F. (1995). A single injection of amphetamine or methamphetamine induces dynamic alterations in c-fos,ZIF/268 and preprodynorphin messenger RNA expression in rat forebrain. Neuroscience, 68(1), 83– 95. https://doi. org/10.1016/0306-4522(95)00100-w

Webber, H. E., Lopez-Gamundi, P., Stamatovich, S. N., de Wit, H., & Wardle, M. C. (2021). Using pharmacological manipulations to study the role of dopamine in human reward functioning: A review of studies in healthy adults. Neurosci Biobehav Rev 120, 123–158. 10.1016/j.neubiorev.2020.11.004

Xia, Y.-fang, He, L., Whistler, JL., Hjelmstad, G. O. (2007). Acute amphetamine exposure selectively desensitizes κ-opioid receptors in the nucleus accumbens. Neuropsychopharmacology, 33(4), 892–900. https:// doi. org/10.1038/sj.npp.1301463

Zadina, J. E. (2002). Recent advances in the search for the N-opioidergic system: Isolation and distribution of Endomorphins in the Central Nervous System. Jap J Pharmacol 89(3), 203–208. https://doi. org/10.1254/ jjp.89.203



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About The Authors

Iliyan Ivanov
Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, NY
United States

Chang Wang
Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, NY
United States

Abigail Cohen
Icahn School of Medicine at Mount Sinai, Department of Psychiatry, New York, NY
United States

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