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Effects of Δ9-tetrahydrocannabinol in individuals with a familial vulnerability to alcoholism

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Abstract

Background and aims

A family history (FH) of alcoholism accounts for approximately 50 % of the risk of developing alcohol problems. Several lines of preclinical evidence suggest that brain cannabinoid receptor (CB1R) function may mediate the effects of alcohol and risk for developing alcoholism including the observations that reduced CB1R function decreases alcohol-related behaviors and enhanced CB1R function increases them. In this first human study, we probed CB1R function in individuals vulnerable to alcoholism with the exogenous cannabinoid Δ9-tetrahydrocannabinol (Δ9-THC).

Design, setting, and participants

Healthy volunteers (n = 30) participated in a three test day study during which they received 0.018 and 0.036 mg/kg of Δ9-THC, or placebo intravenously in a randomized, counterbalanced order under double-blind conditions.

Measurements

Primary outcome measures were subjective “high,” perceptual alterations, and memory impairment. Secondary outcome measures consisted of stimulatory and depressant subjective effects, attention, spatial memory, executive function, Δ9-THC and 11-hydroxy-THC blood levels, and other subjective effects. FH was calculated using the Family Pattern Density method and was used as a continuous variable.

Findings

Greater FH was correlated with greater “high” and perceptual alterations induced by Δ9-THC. This enhanced sensitivity with increasing FH was specific to Δ9-THC’s rewarding effects and persisted even when FH was calculated using an alternate method.

Conclusions

Enhanced sensitivity to the rewarding effects of Δ9-THC in high-FH volunteers suggests that alterations in CB1R function might contribute to alcohol misuse vulnerability.

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References

  • Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L (1986) Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev 38:21–43

    CAS  PubMed  Google Scholar 

  • CANTAB Cambridge Neuropsychological Test Automated Battery (CANTAB) http://www.cantab.com/camcog/default.asp

  • Carbuto M, Sewell RA, Williams A, Forselius-Bielen K, Braley G, Elander J, Pittman B, Schnakenberg A, Bhakta S, Perry E, Ranganathan M, D’Souza DC, Yale THCSG (2012) The safety of studies with intravenous delta-tetrahydrocannabinol in humans, with case histories. Psychopharmacol (Berl) 219:885–896

    Article  CAS  Google Scholar 

  • Cheer JF, Wassum KM, Heien ML, Phillips PE, Wightman RM (2004) Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats. J Neurosci 24:4393–4400

    Article  CAS  PubMed  Google Scholar 

  • Colombo G, Serra S, Brunetti G, Gomez R, Melis S, Vacca G, Carai MM, Gessa L (2002) Stimulation of voluntary ethanol intake by cannabinoid receptor agonists in ethanol-preferring sP rats. Psychopharmacol (Berl) 159:181–187

    Article  CAS  Google Scholar 

  • D’Souza DC, Ahn K, Bhakta S, Elander J, Singh N, Nadim H, Jatlow P, Suckow RF, Pittman B, Ranganathan M (2012) Nicotine Fails to Attenuate Ketamine-Induced Cognitive Deficits and Negative and Positive Symptoms in Humans: Implications for Schizophrenia. Biol Psychiatry

  • D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT, Braley G, Gueorguieva R, Krystal JH (2004) The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29:1558–1572

    Article  PubMed  Google Scholar 

  • Dawson DA, Harford TC, Grant BF (1992) Family history as a predictor of alcohol dependence. Alcohol Clin Exp Res 16:572–575

    Article  CAS  PubMed  Google Scholar 

  • Diana M, Melis M, Gessa GL (1998) Increase in meso-prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids. Eur J Neurosci 10:2825–2830

    Article  CAS  PubMed  Google Scholar 

  • Gallate JE, Saharov T, Mallet PE, McGregor IS (1999) Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur J Pharmacol 370:233–240

    Article  CAS  PubMed  Google Scholar 

  • Gardner EL (2005) Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav 81:263–284

    Article  CAS  PubMed  Google Scholar 

  • Giuffrida A, Parsons LH, Kerr TM, Rodriguez de Fonseca F, Navarro M, Piomelli D (1999) Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nat Neurosci 2:358–363

    Article  CAS  PubMed  Google Scholar 

  • Glass M, Felder CC (1997) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 17:5327–5333

    CAS  PubMed  Google Scholar 

  • Gueorguieva R, Krystal JH (2004) Move over ANOVA: progress in analyzing repeated-measures data and its reflection in papers published in the Archives of General Psychiatry. Arch Gen Psychiatry 61:310–317

    Article  PubMed  Google Scholar 

  • Holdstock L, King AC, de Wit H (2000) Subjective and objective responses to ethanol in moderate/heavy and light social drinkers. Alcohol Clin Exp Res 24:789–794

    Article  CAS  PubMed  Google Scholar 

  • Houchi H, Babovic D, Pierrefiche O, Ledent C, Daoust M, Naassila M (2005) CB1 Receptor knockout mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors. Neuropsychopharmacology 30:339–349

    Article  CAS  PubMed  Google Scholar 

  • Hungund BL, Basavarajappa BS (2000) Distinct differences in the cannabinoid receptor binding in the brain of C57BL/6 and DBA/2 mice, selected for their differences in voluntary ethanol consumption. J Neurosci Res 60:122–128

    Article  CAS  PubMed  Google Scholar 

  • Hungund BL, Basavarajappa BS, Vadasz C, Kunos G, Rodriguez de Fonseca F, Colombo G, Serra S, Parsons L, Koob GF (2002) Ethanol, endocannabinoids, and the cannabinoidergic signaling system. Alcohol Clin Exp Res 26:565–574

    Article  CAS  PubMed  Google Scholar 

  • Hungund BL, Szakall I, Adam A, Basavarajappa BS, Vadasz C (2003) Cannabinoid CB1 receptor knockout mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J Neurochem 84:698–704

    Article  CAS  PubMed  Google Scholar 

  • Jacob T, Waterman B, Heath A, True W, Bucholz KK, Haber R, Scherrer J, Fu Q (2003) Genetic and environmental effects on offspring alcoholism: new insights using an offspring-of-twins design. Arch Gen Psychiatry 60:1265–1272

    Article  PubMed  Google Scholar 

  • Le Strat Y, Grant BF, Ramoz N, Gorwood P (2010) A new definition of early age at onset in alcohol dependence. Drug Alcohol Depend 108:43–48

    Article  PubMed  Google Scholar 

  • Mackie K (2005) Cannabinoid receptor homo- and heterodimerization. Life Sci 77:1667–1673

    Article  CAS  PubMed  Google Scholar 

  • Mangieri RA, Hong KI, Piomelli D, Sinha R (2009) An endocannabinoid signal associated with desire for alcohol is suppressed in recently abstinent alcoholics. Psychopharmacology (Berl) 205:63–72

    Article  CAS  Google Scholar 

  • McGregor IS, Dam KD, Mallet PE, Gallate JE (2005) Delta9-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: comparison with midazolam, food deprivation and predator odour. Alcohol Alcohol 40:35–45

    Article  CAS  PubMed  Google Scholar 

  • Milne BJ, Moffitt TE, Crump R, Poulton R, Rutter M, Sears MR, Taylor A, Caspi A (2008) How should we construct psychiatric family history scores? A comparison of alternative approaches from the Dunedin Family Health History Study. Psychol Med 38:1793–1802

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Miyamoto A, Yamamoto T, Ohno M, Watanabe S, Tanaka H, Morimoto S, Shoyama Y (1996) Roles of dopamine D1 receptors in delta 9-tetrahydrocannabinol-induced expression of Fos protein in the rat brain. Brain Res 710:234–240

    Article  CAS  PubMed  Google Scholar 

  • Neumeister A, Normandin MD, Murrough JW, Henry S, Bailey CR, Luckenbaugh DA, Tuit K, Zheng MQ, Galatzer-Levy IR, Sinha R, Carson RE, Potenza MN, Huang Y (2012) Positron emission tomography shows elevated cannabinoid CB1 receptor binding in men with alcohol dependence. Alcohol Clin Exp Res 36:2104–2109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Patel S, Hillard CJ (2003) Cannabinoid-induced Fos expression within A10 dopaminergic neurons. Brain Res 963:15–25

    Article  CAS  PubMed  Google Scholar 

  • Pava MJ, Woodward JJ (2012) A review of the interactions between alcohol and the endocannabinoid system: implications for alcohol dependence and future directions for research. Alcohol 46:185–204

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Petrakis IL, Limoncelli D, Gueorguieva R, Jatlow P, Boutros NN, Trevisan L, Gelernter J, Krystal JH (2004) Altered NMDA glutamate receptor antagonist response in individuals with a family vulnerability to alcoholism. Am J Psychiatry 161:1776–1782

    Article  PubMed  Google Scholar 

  • Pickel VM, Chan J, Kearn CS, Mackie K (2006) Targeting dopamine D2 and cannabinoid-1 (CB1) receptors in rat nucleus accumbens. J Comp Neurol 495:299–313

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Prescott CA, Kendler KS (1999) Genetic and environmental contributions to alcohol abuse and dependence in a population-based sample of male twins. Am J Psychiatry 156:34–40

    CAS  PubMed  Google Scholar 

  • Rohsenow DJ, Marlatt GA (1981) The balanced placebo design: methodological considerations. Addict Behav 6:107–122

    Article  CAS  PubMed  Google Scholar 

  • Schuckit MA (1994) Alcohol sensitivity and dependence. EXS 71:341–348

    CAS  PubMed  Google Scholar 

  • Schuckit MA, Smith TL (1996) An 8-year follow-up of 450 sons of alcoholic and control subjects. Arch Gen Psychiatry 53:202–210

    Article  CAS  PubMed  Google Scholar 

  • Schuckit MA, Smith TL (2000) The relationships of a family history of alcohol dependence, a low level of response to alcohol and six domains of life functioning to the development of alcohol use disorders. J Stud Alcohol 61:827–835

    CAS  PubMed  Google Scholar 

  • Schuckit MA, Tsuang JW, Anthenelli RM, Tipp JE, Nurnberger JI Jr (1996) Alcohol challenges in young men from alcoholic pedigrees and control families: a report from the COGA project. J Stud Alcohol 57:368–377

    CAS  PubMed  Google Scholar 

  • Shaw LM, Edling-Owens J, Mattes R (1991) Ultrasensitive measurement of delta-9-tetrahydrocannabinol with a high energy dynode detector and electron-capture negative chemical-ionization mass spectrometry. Clin Chem 37:2062–2068

    CAS  PubMed  Google Scholar 

  • Stoltenberg SF, Mudd SA, Blow FC, Hill EM (1998) Evaluating measures of family history of alcoholism: density versus dichotomy. Addiction 93:1511–1520

    Article  CAS  PubMed  Google Scholar 

  • Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism.[comment]. Science 276:2048–2050

    Article  CAS  PubMed  Google Scholar 

  • Thanos PK, Dimitrakakis ES, Rice O, Gifford A, Volkow ND (2005) Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behav Brain Res 164:206–213

    Article  CAS  PubMed  Google Scholar 

  • Thanos PK, Gopez V, Delis F, Michaelides M, Grandy DK, Wang GJ, Kunos G, Volkow ND (2011) Upregulation of cannabinoid type 1 receptors in dopamine D2 receptor knockout mice is reversed by chronic forced ethanol consumption. Alcohol Clin Exp Res 35:19–27

    Article  PubMed Central  PubMed  Google Scholar 

  • Turner WM, Cutter HSG, Worobec TG, O’Farrell TJ, Bayog RD, Tsuang MT (2000) Family history models of alcoholism: age of onset, consequences and dependence. J Stud Alcohol Drugs Alcohol Res Doc Inc 1:164–171

    Google Scholar 

  • Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G (2003) Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci U S A 100:1393–1398

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to acknowledge support from the National Institute of Alcoholism and Alcohol Abuse (NIAAA), the National Institute of Mental Health (NIMH), the National Institute of Drug Abuse (NIDA), the Department of Veterans Affairs, the Yale Center for Clinical Investigation (YCCI), and the Center for the Translational Neuroscience of Alcoholism (CTNA). This research project was funded by NIAAA through R21 AA16311 to DCD. The authors also thank Angelina Genovese, R.N.C., M.B.A.; Michelle San Pedro, R.N.; Elizabeth O’Donnell, R.N.; Sonah Yoo, R.Ph.; Rachel Galvan, R.Ph.; and Willie Ford of the Neurobiological Studies Unit at the VA Connecticut Healthcare System, West Haven Campus for their central contributions to the success of this project. The authors thank John H. Krystal, MD for his contributions toward the initial conceptualization of the study hypothesis.

Financial disclosures

R. Andrew Sewell, Jacqueline Elander, Ashley Schnakenberg, Ashley Williams, and Rajiv Radhakrishnan report no financial relationships with commercial interests. Mohini Ranganathan has in the past 3 years received research grant support administered through the Yale University School of Medicine from Eli Lilly Inc. Deepak Cyril D’Souza has in the past 3 years and currently receives research grant support administered through the Yale University School of Medicine from Astra Zeneca, Abbott Laboratories, Eli Lilly Inc., Organon, Pfizer Inc., and Sanofi; he is also a consultant for Bristol Meyers Squibb.

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Authors and Affiliations

  1. Schizophrenia and Neuropharmacology Research Group, VA Connecticut Healthcare System, West Haven, CT, USA

    Mohini Ranganathan, R. Andrew Sewell, Michelle Carbuto, Jacqueline Elander, Ashley Schnakenberg, Rajiv Radhakrishnan, Brian Pittman & Deepak Cyril D’Souza

  2. Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, CT, USA

    Mohini Ranganathan, R. Andrew Sewell, Michelle Carbuto, Jacqueline Elander, Ashley Schnakenberg, Rajiv Radhakrishnan & Deepak Cyril D’Souza

  3. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Mohini Ranganathan, R. Andrew Sewell, Michelle Carbuto, Jacqueline Elander, Ashley Schnakenberg, Rajiv Radhakrishnan, Brian Pittman & Deepak Cyril D’Souza

  4. Psychiatry Service, 116A, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT, 06516, USA

    Deepak Cyril D’Souza

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  1. Mohini Ranganathan
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Correspondence to Deepak Cyril D’Souza.

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R. Andrew Sewell was deceased.

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Ranganathan, M., Sewell, R.A., Carbuto, M. et al. Effects of Δ9-tetrahydrocannabinol in individuals with a familial vulnerability to alcoholism. Psychopharmacology 231, 2385–2393 (2014). https://doi.org/10.1007/s00213-013-3402-4

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