Could immunotherapy be a hope for addiction treatment?

Substance use disorder (SUD) or addiction is defined as a chronic illness in which there is physical and psychological dependence on psychoactive substances. It is characterized by compulsive drug-seeking behavior, lack of self-control during use, and negative physiological and psychological changes (e.g., irritability, anxiety, and dysphoria) in the absence of the substance.¹,²

According to the World Drug Report 2023, it is estimated that 296 million people used psychoactive substances in 2021 and approximately 40 million have developed substance use disorder.³ Moreover, the number of deaths resulting from psychoactive substance misuse reached around 500.000 in 2019. Finally, even if it does not lead to death, in 2021, the use of drugs generated a “loss of healthy life” of approximately 32 million years.³

Despite the deleterious effects of drug use being widely known, the prevalence of people who use drugs remains high, which is intrinsically related to the mechanism of action of drugs of abuse. According to DSM-5, psychoactive substances encompass ten distinct classes of drugs: stimulants, caffeine, alcohol, tobacco, marihuana, opioids, anxiolytics, sedatives and hypnotics, inhalants, hallucinogens, and other unknown substances.¹ Despite being divided into different categories and presenting various neuropharmacological properties, the psychoactive substances act directly on the reward system,⁴ which is formed mainly by the Ventral Tegmental Area (VTA), the Nucleus Accumbens (NAc) and the Prefrontal Cortex (PFC),⁵ promoting an imbalance in the levels of neurotransmitters in the mesocorticolimbic dopaminergic and in the corticolimbic glutamatergic pathways.²,⁶,⁷ Consequently, psychoactive substances reorganize and promote plastic changes in these circuits of the Central Nervous System (CNS), “hijacking” neural adaptive motivational mechanisms,⁸,⁹,¹⁰ and leading to the dysfunctional pattern of behavior that characterizes drug addiction.¹

Importantly, these neuroplastic changes that occur after drug exposure are so forceful that, even after extensive periods of abstinence, the drug’s reinforcing effects are still present, leading to high rates of relapse and being a challenge to treat.¹¹ In fact, there are very few pharmacological options to treat alcohol, nicotine, and opioid use disorder, and no pharmacotherapies for substances such as psychostimulants (cocaine, methamphetamines) and marijuana/synthetic cannabinoids. In addition, the treatment adherence rate is extremely low, with a dropout prevalence of almost 90%.¹²,¹³ Thus, there is an urgent clinical need for extensive research to develop new molecular targets and pharmacological options.

Although alterations in the dopaminergic and glutamatergic systems are considered key in the neurobiological changes that regulate motivated behavior, it is known that psychoactive substances can also alter other molecular pathways, including immunologic signaling.¹⁴,¹⁵,¹⁶ For example, alcohol, opioids, and psychostimulants can alter microglia morphology, microglial activation markers, and cytokines levels in preclinical and clinical studies.¹⁷,¹⁸,¹⁹ During the years, glial cells were described as supportive cells for neurons. However, a growing body of evidence now indicates that both microglia and astrocytes can regulate neuronal circuits, actively participating in processes such as neurogenesis, neurotransmitter release, modulation of synaptic morphology, and neuronal connectivity.²⁰,²¹ In this sense, the interaction between psychoactive substances and the microglia and astrocytes could, directly or indirectly, contribute to the alterations in brain function and the behavioral changes that occur in substance use disorder. For example, a study using the radioligand [11C](R)-PK11195 showed increased microglial activity in the midbrain, striatum, thalamus, and the orbitofrontal and insular cortex from abstinent METH abusers, which was negatively correlated with the duration of abstinence.²² In addition, increased IL-1β production due to polymorphisms in IL1B gene is associated with an increased risk of opioid and alcohol dependence in humans,²³ while IL-6 is associated with METH-induced mesocorticolimbic functional connectivity.²⁴ Once these cytokines can be produced by the glial cells and are important for CNS neuroplasticity, could the inhibition of drug-induced neuroinflammation be a pharmacological approach against addiction?

Although the literature is still scarce, some studies have shown the beneficial effects of immunomodulators in substance use disorder treatment. Inhibition of microglial activation by minocycline, a tetracycline antibiotic widely used as a microglial inhibitor, reverses the behavioral alterations and dopamine release induced by cocaine²⁵,²⁶ and methamphetamine²⁷,²⁸ in mice. Ibudilast, an anti-inflammatory drug, also reduces the behavioral sensitization and the self-administration of cocaine by rats²⁹,³⁰ and ethanol intake in three different rodent models of alcohol use disorder.³¹ Chronic ethanol intake and relapse are also reduced by aspirin, a non-steroidal anti-inflammatory drug, in rats.³² Finally, the selective COX-2 inhibitors - valdecoxib and LM-4131 – attenuated nicotine preference,³³ while rofecoxib and nimesulide protected against withdrawal symptoms induced by alcohol.³⁴

Some clinical studies have also evaluated the potential of antiinflammatory/immunomodulators in the SUD. Minocycline improved the psychotic symptoms of METH use disorder in a female patient. Besides, this drug also reduced some of the subjective reinforcing effects of D-amphetamine,³⁵ oxycodone³⁶ and the craving for cigarettes.³⁷ The anti-inflammatory ibudilast decreased some reward-related as well as peripheral inflammatory markers in METH-dependent volunteers.³⁸,³⁹ Also, it reduced cocaine and heroin craving in human volunteers diagnosed with opioid dependence,³⁰,⁴⁰,⁴¹ decreased withdrawal symptoms in heroin-dependent patients,⁴² decreased the positive subjective and reinforcing effects in opioid-dependent.⁴⁰ Ibudilast also decreased craving for alcohol in a small, randomized, placebo-controlled, and human laboratory trial. The authors suggest that this effect may be due to the anti-inflammatory properties of this drug.⁴³,⁴⁴

In general, minocycline and ibudilast are inexpensive drugs that are also well-tolerated and induce only moderate side effects. For example, in a methamphetamine clinical trial, there is no difference in the rate of adverse effects between Ibudilast placebo and groups.⁴⁵ Despite this promising data and the potential benefits of these compounds, more studies are necessary for a better comprehension of the clinical use of immunomodulators in substance use disorder.

In summary, alterations in neuroimmune signaling are emerging as an important contributing factor in the neurobiology of substance use disorder. The understanding of how glial and neuroinflammatory responses modulate the development and maintenance of this disease could provide novel insights and contribute to the development of new pharmacological targets.

References

• ¹
  Volkow ND, Blanco C. Substance use disorders: a comprehensive update of classification, epidemiology, neurobiology, clinical aspects, treatment and prevention. World Psychiatry 2023;22(2):203-29.
• ²
  Volkow ND, Michaelides M, Baler R. The neuroscience of drug reward and addiction. Physiol Rev2019;99(4):2115–40.
• ³
  Executive Summary - World Drug Report 2023 n.d. https://www.unodc.org/unodc/en/data-and-analysis/Exsum_wdr2023.html (accessed September 27, 2023).
  » https://www.unodc.org/unodc/en/data-and-analysis/Exsum_wdr2023.html
• ⁴
  Di Chiara G, Imperato A. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci U S A 1988;85(14):5274-8.
• ⁵
  Koob GF, Volkow ND. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry 2016;3(8):760.
• ⁶
  Hasbi A, Perreault ML, Shen MYF, Fan T, Nguyen T, Alijaniaram M, et al. Activation of dopamine D1-D2 receptor complex attenuates cocaine reward and reinstatement of cocaine-seeking through inhibition of DARPP-32, ERK, and AFosB. Front Pharmacol 2018;8:924.
• ⁷
  Fischer KD, Knackstedt LA, Rosenberg PA. Glutamate homeostasis and dopamine signaling: implications for psychostimulant addiction behavior. Neurochem Int 2021;144:104896.
• ⁸
  Luscher C, Bellone C. Cocaine-evoked synaptic plasticity: a key to addiction? Nat Neurosci 2008;11(7):737-8.
• ⁹
  Dong Y, Taylor JR, Wolf ME, Shaham Y. Circuit and synaptic plasticity mechanisms of drug relapse. J Neurosci 2017;37(45):10867-76.
• ¹⁰
  Luscher C, Janak PH. Consolidating the circuit model for addiction. Annu Rev Neurosci 2021;44:173-95.
• ¹¹
  Heilig M, MacKillop J, Martinez D, Rehm J, Leggio L, Vanderschuren LJMJ. Addiction as a brain disease revised: why it still matters, and the need for consilience. Neuropsychopharmacol 2021;46(10):1715-23.
• ¹²
  Chan B, Kondo K, Ayers C, Freeman M, Montgomery J, Paynter R, et al. Pharmacotherapy for stimulant use disorders: a systematic review. Pharmacother Stimul Use Disord A Syst Rev 2018 https://pubmed.ncbi.nlm.nih.gov/30715830/
  » https://pubmed.ncbi.nlm.nih.gov/30715830/
• ¹³
  Sinha R. New findings on biological factors predicting addiction relapse vulnerability. Curr Psychiatry Rep 2011;13(5):398-405.
• ¹⁴
  Doggui R, Elsawy W, Conti AA, Baldacchino A. Association between chronic psychoactive substances use and systemic inflammation: a systematic review and meta-analysis. Neurosci Biobehav Rev 2021;125:208-20.
• ¹⁵
  Stamatovich SN, Lopez-Gamundi P, Suchting R, Colpo GD, Walss-Bass C, Lane SD, et al. Plasma pro- and anti-inflammatory cytokines may relate to cocaine use, cognitive functioning, and depressive symptoms in cocaine use disorder. Am J Drug Alcohol Abuse 2021;47(1):52-64.
• ¹⁶
  Stolyarova A, Thompson AB, Barrientos RM, Izquierdo A. Reductions in frontocortical cytokine levels are associated with long-lasting alterations in reward valuation after methamphetamine. Neuropsychopharmacol 2015;40(5):1234-42.
• ¹⁷
  Gano A, Deak T, Pautassi RM. A review on the reciprocal interactions between neuroinflammatory processes and substance use and misuse, with a focus on alcohol misuse. Am J Drug Alcohol Abuse 2023;49(3):269-82.
• ¹⁸
  Zhang H, Largent-Milnes TM, Vanderah TW. Glial neuroimmune signaling in opioid reward. Brain Res Bull 2020;155:102-11.
• ¹⁹
  da Silva MCM, Iglesias LP, Candelario-Jalil E, Khoshbouei H, Moreira FA, de Oliveira ACP. Role of microglia in psychostimulant addiction. Curr Neuropharmacol 2023;21 (2):235-59.
• ²⁰
  Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR, Lafaille JJ, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013;155(7):1596-609.
• ²¹
  Weinhard L, Di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat Commun 2018;9(1):1228.
• ²²
  Sekine Y, Ouchi Y, Sugihara G, Takei N, Yoshikawa E, Nakamura K, et al. Methamphetamine causes microglial activation in the brains of human abusers. J Neurosci 2008;28(22):5756-61.
• ²³
  Liu L, Hutchinson MR, White JM, Somogyi AA, Coller JK. Association of IL-1B genetic polymorphisms with an increased risk of opioid and alcohol dependence. Pharmacogenet Genomics 2009;19(11):869-76.
• ²⁴
  Kohno M, Loftis JM, Huckans M, Dennis LE, McCready H, Hoffman WF. The relationship between interleukin-6 and functional connectivity in methamphetamine users. Neurosci Lett 2018;677:49-54.
• ²⁵
  Northcutt AL, Hutchinson MR, Wang X, Baratta MV, Hiranita T, Cochran TA, et al. DAT isn’t all that: cocaine reward and reinforcement require Toll-like receptor 4 signaling. Mol Psychiatry 2015;20(12):1525-37.
• ²⁶
  Chen H, Uz T, Manev H. Minocycline affects cocaine sensitization in mice. Neurosci Lett2009;452(3):258-61.
• ²⁷
  Attarzadeh-Yazdi G, Arezoomandan R, Haghparast A. Minocycline, an antibiotic with inhibitory effect on microglial activation, attenuates the maintenance and reinstatement of methamphetamine-seeking behavior in rat. Prog Neuropsychopharmacol Biol Psychiatry 2014;53:142-8.
• ²⁸
  Fujita Y, Kunitachi S, Iyo M, Hashimoto K. The antibiotic minocycline prevents methamphetamine-induced rewarding effects in mice. Pharmacol Biochem Behav 2012;101(2):303-6.
• ²⁹
  Poland RS, Hahn YK, Knapp PE, Beardsley PM, Bowers MS. Ibudilast attenuates expression of behavioral sensitization to cocaine in male and female rats. Neuropharmacology 2016;109:281-92.
• ³⁰
  Mu L, Liu X, Yu H, Hu M, Friedman V, Kelly TJ, et al. Ibudilast attenuates cocaine selfadministration and prime- and cue-induced reinstatement of cocaine seeking in rats. Neuropharmacology 2021;201:108830.
• ³¹
  Bell RL, Lopez MF, Cui C, Egli M, Johnson KW, Franklin KM, et al. Ibudilast reduces alcohol drinking in multiple animal models of alcohol-dependence. Addict Biol 2015;20(1):38-42.
• ³²
  Israel Y, Quintanilla ME, Ezquer F, Morales P, Santapau D, Berríos-Cárcamo P, et al. Aspirin and N-acetylcysteine co-administration markedly inhibit chronic ethanol intake and block relapse binge drinking: role of neuroinflammation-oxidative stress self-perpetuation. Addict Biol 2021;26(1):e12853.
• ³³
  Muldoon PP, Akinola LS, Schlosburg JE, Lichtman AH, Sim-Selley LJ, Mahadevan A, et al. Inhibition of monoacylglycerol lipase reduces nicotine reward in the conditioned place preference test in male mice. Neuropharmacology 2020;176:108170.
• ³⁴
  Dhir A, Naidu PS, Kulkarni SK. Protective effect of cyclooxygenase-2 (COX-2) inhibitors but not non-selective cyclooxygenase (COX)-inhibitors on ethanol withdrawalinduced behavioural changes. Addict Biol 2005;10(4):329-35.
• ³⁵
  Sofuoglu M, Mooney M, Kosten T, Waters A, Hashimoto K. Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans. Psychopharmacology (Berl) 2011;213(1):61-8.
• ³⁶
  Mogali S, Comer SD. Effects of minocycline on oxycodone-induced responses in humans. FASEB J 2013;27:lb530.. -lb530.
• ³⁷
  Sofuoglu M, Waters AJ, Mooney M, O’Malley SS. Minocycline reduced craving for cigarettes but did not affect smoking or intravenous nicotine responses in humans. Pharmacol Biochem Behav 2009;92(1):135-40.
• ³⁸
  Worley MJ, Heinzerling KG, Roche DJO, Shoptaw S. Ibudilast attenuates subjective effects of methamphetamine in a placebo-controlled inpatient study. Drug Alcohol Depend 2016;162:245-50.
• ³⁹
  Li MJ, Briones MS, Heinzerling KG, Kalmin MM, Shoptaw SJ. Ibudilast attenuates peripheral inflammatory effects of methamphetamine in patients with methamphetamine use disorder. Drug Alcohol Depend 2020;206:107776.
• ⁴⁰
  Metz VE, Jones JD, Manubay J, Sullivan MA, Mogali S, Segoshi A, et al. Effects of ibudilast on the subjective, reinforcing, and analgesic effects of oxycodone in recently detoxified adults with opioid dependence. Neuropsychopharmacology 2017;42(9):1825-32.
• ⁴¹
  Poland RS, Hahn YK, Knapp PE, Beardsley PM, Bowers MS. Ibudilast attenuates expression of behavioral sensitization to cocaine in male and female rats. Neuropharmacology 2016;109:281-92.
• ⁴²
  Cooper ZD, Johnson KW, Vosburg SK, Sullivan MA, Manubay J, Martinez D, et al. Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioiddependent volunteers. Drug Alcohol Depend 2017;178:340-7.
• ⁴³
  Grodin EN, Nieto SJ, Meredith LR, Burnette E, O’Neill J, Alger J, et al. Effects of ibudilast on central and peripheral markers of inflammation in alcohol use disorder: a randomized clinical trial. Addict Biol 2022;27(4):e13182.
• ⁴⁴
  Ray LA, Bujarski S, Shoptaw S, Roche DJ, Heinzerling K, Miotto K. Development of the neuroimmune modulator ibudilast for the treatment of alcoholism: a randomized, placebo-controlled, human laboratory trial. Neuropsychopharmacology 2017;42(9):1776-88.
• ⁴⁵
  DeYoung DZ, Heinzerling KG, Swanson AN, Tsuang J, Furst BA, Yi Y, et al. Safety of intravenous methamphetamine administration during ibudilast treatment. J Clin Psychopharmacol 2016;36(4):347-54.

Publication Dates

• Publication in this collection
  24 May 2024
• Date of issue
  2024

History

• Received
  5 Dec 2023
• revised
  26 Jan 2024
• Accepted
  10 Mar 2024