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Current Neuropharmacology

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ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

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Review Article

Effects of β -caryophyllene, A Dietary Cannabinoid, in Animal Models of Drug Addiction

Author(s): Laila Asth*, Leonardo Cardoso Cruz, Nicholas Soyombo, Pedro Rigo and Fabrício A. Moreira

Volume 21, Issue 2, 2023

Published on: 05 December, 2022

Page: [213 - 218] Pages: 6

DOI: 10.2174/1570159X20666220927115811

Price: $65

Abstract

Background: β-caryophyllene (BCP) is a natural bicyclic sesquiterpene found in Cannabis and other plants. BCP is currently used as a food additive, although pharmacological studies suggest its potential therapeutic application for the treatment of certain brain disorders. The mechanisms of action of BCP remain uncertain, possibly including full agonism at the cannabinoid CB2 receptor (CB2R).

Objective: The study aims to investigate BCP’s potential as a new drug for the treatment of substance use disorders by reviewing preclinical studies with animal models.

Results: BCP has been investigated in behavioral paradigms, including drug self-administration, conditioned place preference, and intracranial self-stimulation; the drugs tested were cocaine, nicotine, alcohol, and methamphetamine. Remarkably, BCP prevented or reversed behavioral changes resulting from drug exposure. As expected, the mechanism of action entails CB2R activation, although this is unlikely to constitute the only molecular target to explain such effects. Another potential target is the peroxisome proliferator-activated receptor.

Conclusion: Preclinical studies have reported promising results with BCP in animal models of substance use disorders. Further research, including studies in humans, are warranted to establish its therapeutic potential and its mechanisms of action.

Keywords: Cannabinoids, Cannabis, drugs, addiction, abuse, β-caryophyllene.

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[1]
Association, A.P. Diagnostic and statistical manual of mental disorders: DSM-5. Arlington, VA 2013. Available from: https://www.amberton.edu/media/Syllabi/Fall%202021/Graduate/CSL6798_E1.pdf
[2]
Wise, R.A.; Koob, G.F. The development and maintenance of drug addiction. Neuropsychopharmacology, 2014, 39(2), 254-262.
[http://dx.doi.org/10.1038/npp.2013.261] [PMID: 24121188]
[3]
Everitt, B.J.; Robbins, T.W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat. Neurosci., 2005, 8(11), 1481-1489.
[http://dx.doi.org/10.1038/nn1579] [PMID: 16251991]
[4]
Koob, G.F.; Volkow, N.D. Neurobiology of addiction: a neurocircuitry analysis. Lancet Psychiatry, 2016, 3(8), 760-773.
[http://dx.doi.org/10.1016/S2215-0366(16)00104-8] [PMID: 27475769]
[5]
Koob, G.F.; Le Moal, M. Addiction and the brain antireward system. Annu. Rev. Psychol., 2008, 59(1), 29-53.
[http://dx.doi.org/10.1146/annurev.psych.59.103006.093548] [PMID: 18154498]
[6]
Liu, J.; Li, J. Drug addiction: a curable mental disorder? Acta Pharmacol. Sin., 2018, 39(12), 1823-1829.
[http://dx.doi.org/10.1038/s41401-018-0180-x] [PMID: 30382181]
[7]
Volkow, N.D.; Boyle, M. Neuroscience of addiction: Relevance to prevention and treatment. Am. J. Psychiatry, 2018, 175(8), 729-740.
[http://dx.doi.org/10.1176/appi.ajp.2018.17101174] [PMID: 29690790]
[8]
Li, X.; Hempel, B.J.; Yang, H.J.; Han, X.; Bi, G.H.; Gardner, E.L.; Xi, Z.X. Dissecting the role of CB1 and CB2 receptors in cannabinoid reward versus aversion using transgenic CB1- and CB2-knockout mice. Eur. Neuropsychopharmacol., 2021, 43, 38-51.
[http://dx.doi.org/10.1016/j.euroneuro.2020.11.019] [PMID: 33334652]
[9]
Asth, L.; Santos, A.C.; Moreira, F.A. The endocannabinoid system and drug-associated contextual memories. Behav. Pharmacol., 2022, 33(2&3), 90-104.
[http://dx.doi.org/10.1097/FBP.0000000000000621] [PMID: 33491992]
[10]
Mechoulam, R.; Hanuš, L.O.; Pertwee, R.; Howlett, A.C. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat. Rev. Neurosci., 2014, 15(11), 757-764.
[http://dx.doi.org/10.1038/nrn3811] [PMID: 25315390]
[11]
Herkenham, M.; Lynn, A.B.; Little, M.D.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA, 1990, 87(5), 1932-1936.
[http://dx.doi.org/10.1073/pnas.87.5.1932] [PMID: 2308954]
[12]
Herkenham, M.; Lynn, A.B.; Johnson, M.R.; Melvin, L.S.; de Costa, B.R.; Rice, K.C. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J. Neurosci., 1991, 11(2), 563-583.
[http://dx.doi.org/10.1523/JNEUROSCI.11-02-00563.1991] [PMID: 1992016]
[13]
Tsou, K.; Brown, S.; Sañudo-Peña, M.C.; Mackie, K.; Walker, J.M. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience, 1998, 83(2), 393-411.
[http://dx.doi.org/10.1016/S0306-4522(97)00436-3] [PMID: 9460749]
[14]
Le Foll, B.; Goldberg, S.R. Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence. J. Pharmacol. Exp. Ther., 2005, 312(3), 875-883.
[http://dx.doi.org/10.1124/jpet.104.077974] [PMID: 15525797]
[15]
Moreira, F.A.; Jupp, B.; Belin, D.; Dalley, J.W. Endocannabinoids and striatal function. Behav. Pharmacol., 2015, 26(1 and 2 - Special Issue), 59-72.
[http://dx.doi.org/10.1097/FBP.0000000000000109] [PMID: 25369747]
[16]
Parsons, L.H.; Hurd, Y.L. Endocannabinoid signalling in reward and addiction. Nat. Rev. Neurosci., 2015, 16(10), 579-594.
[http://dx.doi.org/10.1038/nrn4004] [PMID: 26373473]
[17]
Manzanares, J.; Cabañero, D.; Puente, N.; García-Gutiérrez, M.S.; Grandes, P.; Maldonado, R. Role of the endocannabinoid system in drug addiction. Biochem. Pharmacol., 2018, 157, 108-121.
[http://dx.doi.org/10.1016/j.bcp.2018.09.013] [PMID: 30217570]
[18]
Le Foll, B.; Gorelick, D.A.; Goldberg, S.R. The future of endocannabinoid-oriented clinical research after CB1 antagonists. Psychopharmacology (Berl.), 2009, 205(1), 171-174.
[http://dx.doi.org/10.1007/s00213-009-1506-7] [PMID: 19300982]
[19]
Munro, S.; Thomas, K.L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature, 1993, 365(6441), 61-65.
[http://dx.doi.org/10.1038/365061a0] [PMID: 7689702]
[20]
Zhang, H.Y.; Gao, M.; Shen, H.; Bi, G.H.; Yang, H.J.; Liu, Q.R.; Wu, J.; Gardner, E.L.; Bonci, A.; Xi, Z.X. Expression of functional cannabinoid CB 2 receptor in VTA dopamine neurons in rats. Addict. Biol., 2017, 22(3), 752-765.
[http://dx.doi.org/10.1111/adb.12367] [PMID: 26833913]
[21]
Zhang, H.Y.; Gao, M.; Liu, Q.R.; Bi, G.H.; Li, X.; Yang, H.J.; Gardner, E.L.; Wu, J.; Xi, Z.X. Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc. Natl. Acad. Sci. USA, 2014, 111(46), E5007-E5015.
[http://dx.doi.org/10.1073/pnas.1413210111] [PMID: 25368177]
[22]
Gong, J.P.; Onaivi, E.S.; Ishiguro, H.; Liu, Q.R.; Tagliaferro, P.A.; Brusco, A.; Uhl, G.R. Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain. Brain Res., 2006, 1071(1), 10-23.
[http://dx.doi.org/10.1016/j.brainres.2005.11.035] [PMID: 16472786]
[23]
Onaivi, E.S.; Ishiguro, H.; Gong, J.P.; Patel, S.; Meozzi, P.A.; Myers, L.; Perchuk, A.; Mora, Z.; Tagliaferro, P.A.; Gardner, E.; Brusco, A.; Akinshola, B.E.; Hope, B.; Lujilde, J.; Inada, T.; Iwasaki, S.; Macharia, D.; Teasenfitz, L.; Arinami, T.; Uhl, G.R. Brain neuronal CB2 cannabinoid receptors in drug abuse and depression: from mice to human subjects. PLoS One, 2008, 3(2), e1640.
[http://dx.doi.org/10.1371/journal.pone.0001640] [PMID: 18286196]
[24]
Jordan, C.J.; Xi, Z.X. Progress in brain cannabinoid CB2 receptor research: From genes to behavior. Neurosci. Biobehav. Rev., 2019, 98, 208-220.
[http://dx.doi.org/10.1016/j.neubiorev.2018.12.026] [PMID: 30611802]
[25]
Gobira, P.H.; Oliveira, A.C.; Gomes, J.S.; da Silveira, V.T.; Asth, L.; Bastos, J.R.; Batista, E.M.; Issy, A.C.; Okine, B.N.; de Oliveira, A.C.; Ribeiro, F.M.; Del Bel, E.A.; Aguiar, D.C.; Finn, D.P.; Moreira, F.A. Opposing roles of CB 1 and CB 2 cannabinoid receptors in the stimulant and rewarding effects of cocaine. Br. J. Pharmacol., 2019, 176(10), 1541-1551.
[http://dx.doi.org/10.1111/bph.14473] [PMID: 30101419]
[26]
Al Mansouri, S.; Ojha, S.; Al Maamari, E.; Al Ameri, M.; Nurulain, S.M.; Bahi, A. The cannabinoid receptor 2 agonist, β-caryophyllene, reduced voluntary alcohol intake and attenuated ethanol-induced place preference and sensitivity in mice. Pharmacol. Biochem. Behav., 2014, 124, 260-268.
[http://dx.doi.org/10.1016/j.pbb.2014.06.025] [PMID: 24999220]
[27]
Martín-Sánchez, A.; Warnault, V.; Montagud-Romero, S.; Pastor, A.; Mondragón, N.; De La Torre, R.; Valverde, O. Alcohol-induced conditioned place preference is modulated by CB2 cannabinoid receptors and modifies levels of endocannabinoids in the mesocorticolimbic system. Pharmacol. Biochem. Behav., 2019, 183, 22-31.
[http://dx.doi.org/10.1016/j.pbb.2019.06.007] [PMID: 31220547]
[28]
Ortega-Álvaro, A.; Ternianov, A.; Aracil-Fernández, A.; Navarrete, F.; García-Gutiérrez, M.S.; Manzanares, J. Role of cannabinoid CB 2 receptor in the reinforcing actions of ethanol. Addict. Biol., 2015, 20(1), 43-55.
[http://dx.doi.org/10.1111/adb.12076] [PMID: 23855434]
[29]
Bahi, A. Al Mansouri, S.; Al Memari, E.; Al Ameri, M.; Nurulain, S.M.; Ojha, S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol. Behav., 2014, 135, 119-124.
[http://dx.doi.org/10.1016/j.physbeh.2014.06.003] [PMID: 24930711]
[30]
Sharma, C.; Al Kaabi, J.M.; Nurulain, S.M.; Goyal, S.N.; Kamal, M.A.; Ojha, S. Polypharmacological properties and therapeutic potential of β-caryophyllene: A dietary phytocannabinoid of pharmaceutical promise. Curr. Pharm. Des., 2016, 22(21), 3237-3264.
[http://dx.doi.org/10.2174/1381612822666160311115226] [PMID: 26965491]
[31]
Ben-Shabat, S.; Fride, E.; Sheskin, T.; Tamiri, T.; Rhee, M.H.; Vogel, Z.; Bisogno, T.; De Petrocellis, L.; Di Marzo, V.; Mechoulam, R. An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity. Eur. J. Pharmacol., 1998, 353(1), 23-31.
[http://dx.doi.org/10.1016/S0014-2999(98)00392-6] [PMID: 9721036]
[32]
Gertsch, J.; Leonti, M.; Raduner, S.; Racz, I.; Chen, J.Z.; Xie, X.Q.; Altmann, K.H.; Karsak, M.; Zimmer, A. Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. USA, 2008, 105(26), 9099-9104.
[http://dx.doi.org/10.1073/pnas.0803601105] [PMID: 18574142]
[33]
Galaj, E.; Bi, G.H.; Moore, A.; Chen, K.; He, Y.; Gardner, E.; Xi, Z.X. Beta-caryophyllene inhibits cocaine addiction-related behavior by activation of PPARα and PPARγ repurposing a FDA-approved food additive for cocaine use disorder. Neuropsychopharmacology, 2021, 46(4), 860-870.
[http://dx.doi.org/10.1038/s41386-020-00885-4] [PMID: 33069159]
[34]
Schmitt, D.; Levy, R.; Carroll, B. Toxicological evaluation of β-caryophyllene oil. Int. J. Toxicol., 2016, 35(5), 558-567.
[http://dx.doi.org/10.1177/1091581816655303] [PMID: 27358239]
[35]
Klauke, A.L.; Racz, I.; Pradier, B.; Markert, A.; Zimmer, A.M.; Gertsch, J.; Zimmer, A. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. Eur. Neuropsychopharmacol., 2014, 24(4), 608-620.
[http://dx.doi.org/10.1016/j.euroneuro.2013.10.008] [PMID: 24210682]
[36]
Hashiesh, H.M.; Sharma, C.; Goyal, S.N.; Sadek, B.; Jha, N.K.; Kaabi, J.A.; Ojha, S. A focused review on CB2 receptor-selective pharmacological properties and therapeutic potential of β-caryophyllene, a dietary cannabinoid. Biomed. Pharmacother., 2021, 140, 111639.
[http://dx.doi.org/10.1016/j.biopha.2021.111639] [PMID: 34091179]
[37]
Oppong-Damoah, A.; Blough, B.E.; Makriyannis, A.; Murnane, K.S. The sesquiterpene beta-caryophyllene oxide attenuates ethanol drinking and place conditioning in mice. Heliyon, 2019, 5(6), e01915.
[http://dx.doi.org/10.1016/j.heliyon.2019.e01915] [PMID: 31245644]
[38]
He, Y. Galaj, E.; Bi, G.H.; Wang, X.F.; Gardner, E.; Xi, Z.X. β‐Caryophyllene, a dietary terpenoid, inhibits nicotine taking and nicotine seeking in rodents. Br. J. Pharmacol., 2020, 177(9), 2058-2072.
[http://dx.doi.org/10.1111/bph.14969] [PMID: 31883107]
[39]
He, X.H. Galaj, E.; Bi, G.H.; He, Y.; Hempel, B.; Wang, Y.L.; Gardner, E.L.; Xi, Z.X. β-caryophyllene, an FDA-approved food additive, inhibits methamphetamine-taking and methamphetamine-seeking behaviors possibly via CB2 and Non-CB2 receptor mechanisms. Front. Pharmacol., 2021, 12, 722476.
[http://dx.doi.org/10.3389/fphar.2021.722476] [PMID: 34566647]
[40]
Oliveira, G.L.S.; Machado, K.C.; Machado, K.C.; da Silva, A.P.S.C.L.; Feitosa, C.M.; de Castro Almeida, F.R. Non-clinical toxicity of β -caryophyllene, a dietary cannabinoid: Absence of adverse effects in female Swiss mice. Regul. Toxicol. Pharmacol., 2018, 92, 338-346.
[http://dx.doi.org/10.1016/j.yrtph.2017.12.013] [PMID: 29258925]
[41]
Rose, J.E.; Behm, F.M. Inhalation of vapor from black pepper extract reduces smoking withdrawal symptoms. Drug Alcohol Depend., 1994, 34(3), 225-229.
[http://dx.doi.org/10.1016/0376-8716(94)90160-0] [PMID: 8033760]
[42]
Xi, Z.X.; Peng, X.Q.; Li, X.; Song, R.; Zhang, H.Y.; Liu, Q.R.; Yang, H.J.; Bi, G.H.; Li, J.; Gardner, E.L. Brain cannabinoid CB2 receptors modulate cocaine’s actions in mice. Nat. Neurosci., 2011, 14(9), 1160-1166.
[http://dx.doi.org/10.1038/nn.2874] [PMID: 21785434]
[43]
Lopes, J.B.; Bastos, J.R.; Costa, R.B.; Aguiar, D.C.; Moreira, F.A. The roles of cannabinoid CB1 and CB2 receptors in cocaine-induced behavioral sensitization and conditioned place preference in mice. Psychopharmacology (Berl.), 2020, 237(2), 385-394.
[http://dx.doi.org/10.1007/s00213-019-05370-5] [PMID: 31667531]
[44]
Navarrete, F.; García-Gutiérrez, M.S.; Gasparyan, A.; Navarro, D.; Manzanares, J. CB2 receptor involvement in the treatment of substance use disorders. Biomolecules, 2021, 11(11), 1556.
[http://dx.doi.org/10.3390/biom11111556] [PMID: 34827554]
[45]
García-Gutiérrez, M.S.; García-Bueno, B.; Zoppi, S.; Leza, J.C.; Manzanares, J. Chronic blockade of cannabinoid CB2 receptors induces anxiolytic-like actions associated with alterations in GABAA receptors. Br. J. Pharmacol., 2012, 165(4), 951-964.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01625.x] [PMID: 21838753]
[46]
Navarrete, F.; Pérez-Ortiz, J.M.; Manzanares, J. Cannabinoid CB2 receptor-mediated regulation of impulsive-like behaviour in DBA/2 mice. Br. J. Pharmacol., 2012, 165(1), 260-273.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01542.x] [PMID: 21671903]
[47]
Youssef, D.A.; El-Fayoumi, H.M.; Mahmoud, M.F. Beta-caryophyllene alleviates diet-induced neurobehavioral changes in rats: The role of CB2 and PPAR-γ receptors. Biomed. Pharmacother., 2019, 110, 145-154.
[http://dx.doi.org/10.1016/j.biopha.2018.11.039] [PMID: 30469079]
[48]
Mascia, P.; Pistis, M.; Justinova, Z.; Panlilio, L.V.; Luchicchi, A.; Lecca, S.; Scherma, M.; Fratta, W.; Fadda, P.; Barnes, C.; Redhi, G.H.; Yasar, S.; Le Foll, B.; Tanda, G.; Piomelli, D.; Goldberg, S.R. Blockade of nicotine reward and reinstatement by activation of alpha-type peroxisome proliferator-activated receptors. Biol. Psychiatry, 2011, 69(7), 633-641.
[http://dx.doi.org/10.1016/j.biopsych.2010.07.009] [PMID: 20801430]
[49]
Haile, C.N.; Kosten, T.A. The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration in rats. Neuropharmacology, 2017, 116, 364-370.
[http://dx.doi.org/10.1016/j.neuropharm.2017.01.007] [PMID: 28088358]
[50]
de Guglielmo, G.; Melis, M.; De Luca, M.A.; Kallupi, M.; Li, H.W.; Niswender, K.; Giordano, A.; Senzacqua, M.; Somaini, L.; Cippitelli, A.; Gaitanaris, G.; Demopulos, G.; Damadzic, R.; Tapocik, J.; Heilig, M.; Ciccocioppo, R. PPARγ activation attenuates opioid consumption and modulates mesolimbic dopamine transmission. Neuropsychopharmacology, 2015, 40(4), 927-937.
[http://dx.doi.org/10.1038/npp.2014.268] [PMID: 25311134]
[51]
Melis, M.; Carta, G.; Pistis, M.; Banni, S. Physiological role of peroxisome proliferator-activated receptors type α on dopamine systems. CNS Neurol. Disord. Drug Targets, 2013, 12(1), 70-77.
[http://dx.doi.org/10.2174/1871527311312010012] [PMID: 23394525]
[52]
Nutt, D.J.; Lingford-Hughes, A.; Erritzoe, D.; Stokes, P.R.A. The dopamine theory of addiction: 40 years of highs and lows. Nat. Rev. Neurosci., 2015, 16(5), 305-312.
[http://dx.doi.org/10.1038/nrn3939] [PMID: 25873042]
[53]
Solinas, M.; Belujon, P.; Fernagut, P.O.; Jaber, M.; Thiriet, N. Dopamine and addiction: what have we learned from 40 years of research. J. Neural Transm. (Vienna), 2019, 126(4), 481-516.
[http://dx.doi.org/10.1007/s00702-018-1957-2] [PMID: 30569209]

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