Skip to main content

Advertisement

Log in

Intermediate cannabis dependence phenotypes and the FAAH C385A variant: an exploratory analysis

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

Abstract

Rationale

Cannabis dependence is a growing problem among individuals who use marijuana frequently, and genetic differences make some users more liable to progress to dependence. The identification of intermediate phenotypes of cannabis dependence may aid candidate genetic analysis. Promising intermediate phenotypes include craving for marijuana, withdrawal symptoms after abstinence, and sensitivity to its acute effects. A single nucleotide polymorphism (SNP) in the gene encoding for fatty acid amide hydrolase (FAAH) has demonstrated association with substance use disorder diagnoses, but has not been studied with respect to these narrower phenotypes. FAAH is an enzyme that inactivates anandamide, an endogenous agonist for CB1 receptors (to which Δ9-tetrahydrocannabinol binds). CB1 binding modulates mesocorticolimbic dopamine release, which underlies many facets of addiction.

Objectives

The SNP, FAAH C385A (rs324420), was examined to determine whether its variance was associated with changes in craving and withdrawal after marijuana abstinence, craving after cue exposure, or sensitivity to the acute effects of marijuana.

Materials and methods

Forty daily marijuana users abstained for 24 h, were presented with a cue-elicited craving paradigm and smoked a marijuana cigarette in the laboratory.

Results

C385A variance was significantly associated with changes in withdrawal after abstinence, and happiness after smoking marijuana in the predicted directions, was associated with changes in heart rate after smoking in the opposite of the predicted direction, and was not associated with changes in craving or other acute effects.

Conclusions

These data lend support to some previous association studies of C385A, but suggest that further refinement of these intermediate phenotypes is necessary.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • American Psychatric Association (APA) (1994) Diagnostic and statistical manual of mental disorders, 4th edn. APA, Washington, DC

    Google Scholar 

  • Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Brain Res Rev 28:309–369

    Article  CAS  PubMed  Google Scholar 

  • Budney AJ, Novy PL, Hughes JR (1999) Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction 94:1311–1321

    Article  CAS  PubMed  Google Scholar 

  • Budney AJ, Moore BA, Vandrey RG, Hughes JR (2003) The time course and significance of cannabis withdrawal. J Abnorm Psychol 112:393–402

    Article  PubMed  Google Scholar 

  • Budney AJ, Hughes JR, Moore BA, Vandrey R (2004) Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 161:1967–1977

    Article  PubMed  Google Scholar 

  • Chiang KP, Gerber AL, Sipe JC, Cravatt BF (2004) Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: Evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet 13:2113–2119

    Article  CAS  PubMed  Google Scholar 

  • Compton WM, Grant BF, Colliver JD, Glantz MD, Stinson FS (2004) Prevalence of marijuana use disorders in the United States, 1991–1992 and 2001–2002. JAMA 291:2114–2121

    Article  CAS  PubMed  Google Scholar 

  • Conrod PJ, Pihl RO, Vassileva J (1998) Differential sensitivity to alcohol reinforcement in groups of men at risk for distinct alcoholism subtypes. Alcohol Clin Exp Res 22:585–597

    Article  CAS  PubMed  Google Scholar 

  • Cooper ZD, Haney M (2008) Cannabis reinforcement and dependence: role of the cannabinoid CB1 receptor. Addict Biol 13:188–195

    Article  CAS  PubMed  Google Scholar 

  • Cornelius JR, Chung T, Martin C, Wood DS, Clark DB (2008) Cannabis withdrawal is common among treatment-seeking adolescents with cannabis dependence and major depression, and is associated with rapid relapse to dependence. Addict Behav 33:1500–1505

    Article  PubMed  Google Scholar 

  • Cravatt BF, Lichtman AH (2003) Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol 7:469–475

    Article  CAS  PubMed  Google Scholar 

  • Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin MR et al (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376

    Article  CAS  PubMed  Google Scholar 

  • Diana M, Melis M, Muntoni AL, Gessa GL (1998) Mesolimbic dopaminergic decline after cannabinoid withdrawal. Proc Natl Acad Sci USA 95:10269–10273

    Article  CAS  PubMed  Google Scholar 

  • Erblich J, Earleywine M (1995) Distraction does not impair memory during intoxication: support for the attention-allocation model. J Stud Alcohol 56:444–448

    CAS  PubMed  Google Scholar 

  • Fergusson DM, Horwood J, Lynskey MT, Madden PAF (2003) Early reactions to cannabis predict later dependence. Arch Gen Psychiatry 60:1033–1039

    Article  PubMed  Google Scholar 

  • Flanagan JM, Gerber AL, Cadet JL, Beutler E, Sipe J (2006) The fatty acid amide hydrolase 385 A/A (P129T) variant: Haplotype analysis of an ancient missense mutation and validation of risk for drug addiction. Hum Genet 120:581–588

    Article  CAS  PubMed  Google Scholar 

  • Gessa GL, Melis M, Muntoni AL, Diana M (1998) Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors. Eur J Pharmacol 341:39–44

    Article  CAS  PubMed  Google Scholar 

  • Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: Etymology and strategic intentions. Am J Psychiatry 160:636–645

    Article  PubMed  Google Scholar 

  • Gynther LM, Carey G, Gottesman II, Vogler GP (1995) A twin study of non-alcohol substance dependence. Psychiatry Res 56:213–220

    Article  CAS  PubMed  Google Scholar 

  • Hart CL, van Gorp W, Haney M, Foltin RW, Fischman MW (2001) Effects of acute smoked marijuana on complex cognitive performance. Neuropsychopharmacology 25:757–765

    Article  CAS  PubMed  Google Scholar 

  • Hart CL, Ward AS, Haney M, Comer SD, Foltin RW, Fischman MW (2002) Comparison of smoked marijuana and oral Delta(9)-tetrahydrocannabinol in humans. Psychopharmacology 164:407–415

    Article  CAS  PubMed  Google Scholar 

  • Haughey HM, Marshall E, Schacht JP, Louis A, Hutchison KE (2008) Marijuana withdrawal and craving: Influence of the CNR1 and FAAH genes. Addiction 103:1678–1686

    Article  PubMed  Google Scholar 

  • Heishman SJ, Singleton EG, Liguori A (2001) Marijuana Craving Questionnaire: development and initial validation of a self-report instrument. Addiction 96:1023–1034

    Article  CAS  PubMed  Google Scholar 

  • Hutchison KE, Stallings M, McGeary J, Bryan A (2004) Population stratification in the candidate gene study: fatal threat or red herring? Psychol Bull 130:66–79

    Article  PubMed  Google Scholar 

  • Johanson CE, Uhlenhuth EH (1980) Drug preference and mood in humans: d-amphetamine. Psychopharmacology 71:275–279

    Article  CAS  PubMed  Google Scholar 

  • Johnson BA, Chen YR, Schmitz J, Bordnick P, Schafer A (1998) Cue reactivity in cocaine-dependent subjects: effects of cue type and cue reactivity. Addict Behav 23:7–15

    Article  CAS  PubMed  Google Scholar 

  • Kalivas PW, Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413

    Article  PubMed  Google Scholar 

  • Kanakis C, Pouget JM, Rosen KM (1976) The effects of delta-9-tetrahydrocannabinol (cannabis) on cardiac performance with and without beta blockade. Circulation 53:703–707

    CAS  PubMed  Google Scholar 

  • Lukas SE, Orozco S (2001) Ethanol increases plasma Delta(9)-tetrahydrocannabinol (THC) levels and subjective effects after marihuana smoking in human volunteers. Drug Alcohol Depend 64:143–149

    Article  CAS  PubMed  Google Scholar 

  • Lyons MJ, Toomey R, Meyer JM, Green AI, Eisen SA, Goldberg J et al (1997) How do genes influence marijuana use? The role of subjective effects. Addiction 92:409–417

    Article  CAS  PubMed  Google Scholar 

  • Martin CS, Earleywine M, Musty RE, Perrine MW, Swift RM (1993) Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17:140–146

    Article  CAS  PubMed  Google Scholar 

  • Mascia MS, Obinu MC, Ledent C, Parmentier M, Bohme GA, Imperato A et al (1999) Lack of morphine-induced dopamine release in the nucleus accumbens of cannabinoid CB1 receptor knockout mice. Eur J Pharmacol 383:R1–R2

    Article  CAS  PubMed  Google Scholar 

  • McNair DM, Lorr M, Droppleman LF (1971) Profile of Mood States (Manual). Educational and Industrial Testing Service, San Diego, CA

    Google Scholar 

  • Morita Y, Ujike H, Tanaka Y, Uchida N, Nomura A, Ohtani K et al (2005) A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia. Neurosci Lett 376:182–187

    Article  CAS  PubMed  Google Scholar 

  • Payne TJ, Schare ML, Levis DJ, Colletti G (1991) Exposure to smoking relevant cues: effects on desire to smoke and topographical components of smoking behavior. Addict Behav 16:467–479

    Article  CAS  PubMed  Google Scholar 

  • Rhee SH, Hewitt JK, Young SE, Corley RP, Crowley TJ, Stallings MC (2003) Genetic and environmental influences on substance initiation, use, and problem use in adolescents. Arch Gen Psychiatry 60:1256–1264

    Article  PubMed  Google Scholar 

  • Robinson TE, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18:247–291

    Article  CAS  PubMed  Google Scholar 

  • Rohsenow DJ, Niaura RS, Childress AR, Abrams DB, Monti PM (1990) Cue reactivity in addictive behaviors: theoretical and treatment implications. Int J Addict 25:957–993

    PubMed  Google Scholar 

  • Singleton EG, Trotman AJ, Zavahir M, Taylor RC, Heishman SJ (2002) Determination of the reliability and validity of the Marijuana Craving Questionnaire using imagery scripts. Exp Clin Psychopharmacol 10:47–53

    Article  PubMed  Google Scholar 

  • Sipe JC, Chiang K, Gerber AL, Beutler E, Cravatt BF (2002) A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci USA 99:8394–8399

    Article  CAS  PubMed  Google Scholar 

  • Sobell LC, Sobell MB (1992) Timeline follow-back: A technique for assessing self-reported alcohol consumption. In: Allen JP, Litten RZ (eds) Measuring alcohol consumption: Psychosocial and biochemical methods. Humana, Totowa, NJ, pp 41–72

    Google Scholar 

  • Sobell MB, Sobell LC, VanderSpek R (1979) Relationships between clinical judgment, self-report, and breath analysis measures of intoxication in alcoholics. J Consult Clin Psychol 47:204–206

    Article  CAS  PubMed  Google Scholar 

  • Substance Abuse and Mental Health Services Administration (SAMHSA) (2007) Summary of findings from the 2006 National Survey on Drug Use and Health. SAMHSA, Rockville, MD

    Google Scholar 

  • Tyndale RF, Payne JI, Gerber AL, Sipe JC (2007) The fatty acid amide hydrolase C385A (P129T) missense variant in cannabis users: studies of drug use and dependence in Caucasians. Am J Med Genet B Neuropsychiatr Genet 144:660–666

    Google Scholar 

  • van den Bree MB, Johnson EO, Neale MC, Pickens RW (1998) Genetic and environmental influences on drug use and abuse/dependence in male and female twins. Drug Alcohol Depend 52:231–241

    Article  PubMed  Google Scholar 

  • Wiskerke J, Pattij T, Schoffelmeer AN, Vries TJD (2008) The role of CB1 receptors in psychostimulant addiction. Addict Biol 13:225–238

    Article  CAS  PubMed  Google Scholar 

  • Wölfling K, Flor H, Grüsser M (2008) Psychophysiological responses to drug-associated stimuli in chronic heavy cannabis use. Eur J Neurosci 27:976–983

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by a NIDA-funded Ruth L. Kirchstein National Research Service Award Predoctoral Fellowship (F31 DA021496) to Joseph P. Schacht.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joseph P. Schacht.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schacht, J.P., Selling, R.E. & Hutchison, K.E. Intermediate cannabis dependence phenotypes and the FAAH C385A variant: an exploratory analysis. Psychopharmacology 203, 511–517 (2009). https://doi.org/10.1007/s00213-008-1397-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-008-1397-z

Keywords

Navigation