Marijuana Use, Withdrawal, and Craving in Adolescents

Marijuana is the most commonly used illicit drug in the United States and worldwide. Initiation of use typically occurs during adolescence. The most recent epidemiological data indicate that in the United States, 42% of high school seniors have tried marijuana, 18% have used it in the past 30 days, and 5% use it daily.¹ Among adolescents aged 12 to 17, 3.6% met criteria for cannabis use disorder (abuse or dependence) and 2% met criteria for cannabis dependence.²

More than half (51%) of adolescents reported that marijuana is fairly or very easy to obtain.² This ease of availability may have contributed to a recently reported "reverse gateway" from marijuana use to cigarette use to nicotine dependence.^3,4 The initial age of first marijuana use has been declining,^5,6 and there is evidence to indicate that earlier initiation is associated with problem- related marijuana use, "hard" drug use, polydrug use, and academic failure.⁷ Positive subjective response to marijuana during early adolescence, independent of potentially confounding factors, is a strong risk factor for the development of cannabis dependence in young adulthood.⁸ Adolescent marijuana use is also associated with impaired driving^9,10 and delinquent behavior.^11,12 Using marijuana once per week or more during adolescence is associated with a 7-fold increase in the rate of daily marijuana use in young adulthood.¹³

Chronic use is associated with impaired immune function,¹⁴ respiratory illnesses,¹⁵ cognitive problems,^16,17 and motivational impairment.^18-20 Association does not necessarily imply causation; however, there is a confluence of evidence suggesting that heavier use and earlier initiation of use are associated with generally poorer outcomes.

Marijuana use and comorbidity

It has become increasingly clear that frequent marijuana use during adolescence is often associated with psychiatric disorders, although the directionality and nature of these associations has long been debated. Some argue that marijuana use can begin as "self-medication" for psychiatric disorders, while others say that habitual marijuana use can predispose some individuals to psychiatric symptoms. It is also argued that shared risk factors may predispose some adolescents to both marijuana use and psychopathology.

Social anxiety disorder in adolescence is associated with 6.5-times great- er odds of subsequent cannabis dependence developing.²¹ Other anxiety and major depressive disorders, however, do not appear to predispose adolescents to development of cannabis use disorders. Instead, frequent marijuana use during adolescence appears to increase the risk of subsequent development of anxiety and depressive disorders.^22,23 The prevalence of cannabis use disorders is 2 to 3 times greater among adolescents who have major depression.²

Conduct disorder possesses a bidirectional relationship with marijuana use in adolescence. Conduct disorder predicts marijuana and other substance use, while early-onset marijuana use predicts conduct disorder, even when controlling for potential confounds.^24-26 Marijuana use has long been known to precipitate acute psychotic symptoms in some people, and rates of marijuana use are relatively high among persons with psychotic disorders. Of significant interest, there is emerging literature supporting a causal association between adolescent marijuana use and subsequent onset of psychotic illness in those who are vulnerable.^27-33 Further work is needed in this area to clarify the directionality, causality, and specificity of relationships between adolescent marijuana use and psychopathology.

Treatment

Marijuana is the primary substance of abuse in most adolescent treatment admissions.³⁴ The evidence base for treatment of adolescent marijuana use disorders is generally limited to psychosocial interventions. The most comprehensive investigation is the Cannabis Youth Treatment Study, which evaluated the effectiveness of 5 treatment arms.³⁵ This included a combination motivational enhancement/cognitive-behavioral therapy (MET/CBT) treatment (in both 5- and 12-session formats), a family education and therapy intervention, a community reinforcement approach, and multidimensional family therapy. All modalities ex- hibited similarly modest effect sizes, with the MET/CBT and community reinforcement treatments being most cost-effective.

Contingency management, which includes rewards for marijuana abstinence, is a modality with emerging evidence in this population as well.³⁶ Multisystemic therapy, an intensive multimodal treatment approach that incorporates individual, family, and community components, has demonstrated effectiveness among delinquent adolescents with substance use dis- orders, including cannabis abuse and dependence.³⁷

Despite evidence that adolescent marijuana users are more likely than adults to exhibit symptoms of dependence and difficulty in quitting,³⁸ factors contributing to continued use and relapse are not well understood in this population and may differ from those in adults.^39,40 Given that the current evidence base includes only modestly effective interventions, it is important to closely investigate barriers to treatment response to develop more successful treatments.

It is commonly posited that among substances of abuse in general, craving and withdrawal symptoms are factors that commonly interfere with successful cessation of use and sustained abstinence. Indeed, multiple FDA-approved medications for substance use disorders specifically target craving, such as sustained-release bupropion for nicotine dependence and naltrexone for alcohol dependence.

In addition, medications are often used to target withdrawal from substances, such as benzodiazepines for alcohol dependence and clonidine and buprenorphine for opioid dependence. These medications have been prescribed as adjunctive interventions to be used with psychosocial interventions. It may be that treatments targeting withdrawal and craving in adolescent marijuana users could be developed to complement concurrent psychosocial treatments.

Withdrawal

Withdrawal is a core feature of substance dependence, with the most severe withdrawal phenomena generally associated with alcohol, benzodiazepine, and opioid use. Withdrawal from marijuana is not recognized in DSM-IV, purportedly because at the time of publication it was not felt that this was a clinically significant phenomenon. Since then, however, substantial evidence has developed that supports the existence and clinical relevance of marijuana withdrawal.^41-44 Marijuana withdrawal syndrome is most frequently characterized by a constellation of emotional, behavioral, and physical symptoms that include anger and aggression, anxiety, decreased appetite and weight loss, irritability, restlessness, and sleep difficulty.⁴⁵ Less frequent but sometimes present are depressed mood, stomach pain and physical discomfort, shakiness, and sweating.

Onset of withdrawal symptoms typically occurs within 24 hours of cessation. Symptoms may last days to approximately 1 to 2 weeks.^43,44 The specificity of these withdrawal symptoms to marijuana's active ingredient-Δ-9-tetrahydrocannabinol-is supported by pharmacological studies. In nonhuman species, cannabis withdrawal has been reliably precipitated after the administration of a cannabinoid 1-receptor antagonist.⁴⁶ In humans, oral Δ-9-tetrahydrocannabinol has been demonstrated to suppress marijuana withdrawal symptoms.^47,48

Adolescents have been the focus of recent investigations of marijuana withdrawal. Initial reports noted the above symptoms among cannabis-dependent adolescents with comorbid conduct problems in residential treatment^49,50 and in adolescents with cannabis use disorders in a community sample.⁵¹ More recent literature reveals that adolescents who seek treatment may experience clinically significant withdrawal symptoms.⁵² A brief report also described withdrawal symptoms in adolescents presenting for nontreatment research.⁵³ Further work is needed to elucidate similarities and differences between adolescent and adult presentations of marijuana withdrawal.

Craving

Craving is typically thought of as a subjective desire to use a substance and is often associated with drug dependence, including cannabis dependence.⁵⁴ Cravings and urges are considered to reflect the fundamental motivational processes that maintain continued drug use.^55-57

A well-established laboratory method for evaluating craving is the cue reactivity paradigm, in which the researcher attempts to induce craving of a substance in patients by presenting them with cues associated with their respective substance of use and/or abuse (eg, sight or smell of a substance, films of drug-taking locations, and drug-related paraphernalia). This paradigm is designed to approximate levels of craving that an individual experiences in his or her substance use environment, rather than the comparatively lower levels of craving experienced in an ordinary clinical setting. In general, this approach leads to robust increases in craving, along with modest increases in objective physiological measures, such as skin conductance (reflecting perspiration) and heart rate.⁵⁸ Several studies have demonstrated that cue reactivity can be predictive of drug relapse.^59-66 Investigation of cue reactivity in adolescents is a relatively recent development. Initial reports suggest that adolescents with nicotine and alcohol use disorders react to cues in a manner similar to their adult counterparts.^67-71

Marijuana cue reactivity research is also in its early stages and has yielded promising results. Small-scale studies have demonstrated reliable reactivity to marijuana-related cues in adults^72,73 and adolescents^74,75 with cannabis use disorders.

Conclusion

Marijuana use in adolescence remains a significant problem. Frequent use and early initiation of use during adolescence are associated with poor outcome. Existing treatments have demonstrated generally modest results. Research is needed to further elucidate factors involved in relapse among adolescents attempting to abstain.

Marijuana withdrawal and craving are 2 potential targets of focused investigation, from both experimental and treatment standpoints. These phenomena are increasingly recognized in adults with cannabis use disorders, and recent preliminary investigation is yielding compelling data pointing toward their validity in adolescents.

Treatments being developed for adolescent cannabis use disorders, both psychosocial and pharmacological, should consider craving and withdrawal symptoms as potential targets to reduce relapse. Similarly, clinicians treating adolescents with cannabis use disorders should not disregard marijuana craving and withdrawal symptoms as potential factors complicating treatment.

References:

References

1.

Johnston LD, O'Malley PM, Bachman JG, Schulenberg JE. Teen drug use continues down in 2006, particularly among older teens; but use of prescription-type drugs remains high. Ann Arbor, Mich: University of Michigan News and Information Services. December 21, 2006. Available at: www.monitoringthefuture.org/dada/06data.html# 2006data-drugs. Accessed March 21, 2007.

2.

Substance Abuse and Mental Health Services Administration.

Results from the 2005 National Survey on Drug Use and Health: National Findings.

Rockville, Md: Office of Applied Studies; 2006. NSDUH Series H-30, DHHS publication SMA 06-4194.

3.

Patton GC, Coffey C, Carlin JB, et al. Reverse gateways? Frequent cannabis use as a predictor of tobacco initiation and nicotine dependence.

Addiction

. 2005;100: 1518-1525.

4.

Timberlake DS, Haberstick BC, Hopfer CJ, et al. Progression from marijuana use to daily smoking and nicotine dependence in a national sample of US adolescents.

Drug Alcohol Depend

. 2006;[Epub ahead of print].

5.

Hall WD, Pacula RL.

Cannabis Use and Dependence: Public Health and Public Policy

. Cambridge, UK: Cambridge University Press; 2003.

6.

Hall WD. Cannabis use and the mental health of young people.

Aust N Z J Psychiatry

. 2006;40:105-113.

7.

Ellickson PL, Tucker JS, Klein DJ, Saner H. Antecedents and outcomes of marijuana use initiation during adolescence.

Prev Med

. 2004;39:976-984.

8.

Fergusson DM, Horwood LJ, Lynskey MT, Madden PA. Early reactions to cannabis predict later dependence.

Arch Gen Psychiatry

. 2003;60:1033-1039.

9.

Khiabani HZ, Bramness JG, Bjorneboe A, Morland J. Relationship between THC concentration in blood and impairment in apprehended drivers.

Traffic Inj Prev

. 2006;7:111-116.

10.

Ramaekers JG, Moeller MR, van Ruitenbeek P, et al. Cognition and motor control as a function of ?198-157?-9-THC concentration in serum and oral fluid: limits of impairment.

Drug Alcohol Depend

. 2004;85:114-122.

11.

Jessor R, Jessor S.

Problem Behavior and Psychosocial Development: A Longitudinal Study of Youth

. New York: Academic Press; 1977.

12.

Rob M, Reynolds I, Finlayson PF. Adolescent marijuana use: risk factors and implications.

Aust N Z J Psychiatry

. 1990;24:45-56.

13.

Patton GC, Coffey C, Lynskey MT, et al. Trajectories of adolescent alcohol and cannabis use into young adulthood.

Addiction.

2007;102:607-615.

14.

Tashkin DP, Baldwin GC, Sarafian T, et al. Respiratory and immunologic consequences of marijuana smoking.

J Clin Pharmacol

. 2002;42(suppl 11):71S-81S.

15.

Taylor D, Poulton R, Moffitt TE, et al. The respiratory effects of cannabis dependence in young adults.

Addiction

. 2000;95:1669-1677.

16.

Bolla KI, Brown K, Eldreth D, et al. Dose-related neurocognitive effects of marijuana use.

Neurology

. 2002;59: 1337-1343.

17.

Messinis L, Kyprianidou A, Malefaki S, Papathanasopoulos P. Neuropsychological deficits in long-term frequent cannabis users.

Neurology

. 2006;66:737-739.

18.

Cohen S. Cannabis: impact on motivation, part I.

Drug Abuse and Alcoholism Newsletter

. 1980;9.

19.

Cohen S. Cannabis: impact on motivation, part II.

Drug Abuse and Alcoholism Newsletter

. 1981;10.

20.

Schwartz RH. Marijuana: an overview.

Pediatr Clin North Am

. 1987;34:305-317.

21.

Buckner JD, Schmidt NB, Lang AR, et al. Specificity of social anxiety disorder as a risk factor for alcohol and cannabis dependence.

J Psychiatr Res

. 2007; [Epub ahead of print].

22.

Fergusson DM, Horwood LJ, Swain-Campbell N. Cannabis use and psychosocial adjustment in adolescence and young adulthood.

Addiction

. 2002;97:1123-1135.

23.

Patton CG, Coffey C, Carlin JB, et al. Cannabis use and mental health in young people: cohort study.

BMJ

. 2002; 325:1195-1198.

24.

Brook JS, Balka EB, Whiteman M. The risks for late adolescence of early adolescent marijuana use.

Am J Public Health

. 1999;89:1549-1554.

25.

Brook JS, Brook DW, Rosen Z, Rabbitt CR. Earlier marijuana use and later problem behavior in Colombian youths.

J Am Acad Child Adolesc Psychiatry

. 2003;42: 485-492.

26.

McGee R, Williams S, Poulton R, Moffitt T. A longitudinal study of cannabis use and mental health from adolescence to early adulthood.

Addiction

. 2000;95:491-503.

27.

Arseneault L, Cannon M, Poulton R, et al. Cannabis use in adolescence and risk for adult psychosis: longitudinal prospective study.

BMJ

. 2002;325:1212-1213.

28.

Ferdinand RF, Sondeijker F, van der Ende J, et al. Cannabis use predicts future psychotic symptoms, and vice versa.

Addiction

. 2005;100:612-618.

29.

Fergusson DM, Horwood LJ, Swain-Campbell NR. Cannabis dependence and psychotic symptoms in young people.

Psychol Med

. 2003;33:15-21.

30.

Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people.

BMJ

. 2005;330:11.

31.

Stefanis NC, Delespaul P, Henquet C, et al. Early adolescent cannabis exposure and positive and negative dimensions of psychosis.

Addiction

. 2004;99:1333-1341.

32.

van Os J, Bak M, Hanssen M, et al. Cannabis use and psychosis: a longitudinal population-based study.

Am J Epidemiol

. 2002;156:319-327.

33.

Zammit S, Allebeck P, Andreasson S, et al. Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study.

BMJ

. 2002;325:1199.

34.

Substance Abuse and Mental Health Services Administration.

Treatment Episode Data Set (TEDS). Highlights--2004. National Admissions to Substance Abuse Treatment Services

. Rockville, Md: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2006. DASIS Series: S-31, DHHS publication (SMA) 06-4140.

35.

Dennis M, Godley SH, Diamond G, et al. The Cannabis Youth Treatment (CYT) Study: main findings from two randomized trials.

J Subst Abuse Treat

. 2004;27:197-213.

36.

Kamon J, Budney A, Stanger C. A contingency management intervention for adolescent marijuana abuse and conduct problems.

J Am Acad Child Adolesc Psychiatry

. 2005;44:513-521.

37.

Randall J, Cunningham PB. Multisystemic therapy: a treatment for violent substance-abusing and substance-dependent juvenile offenders.

Addict Behav

. 2003;28: 1731-1739.

38.

Chen CY, Anthony JC. Possible age-associated bias in reporting of clinical features of drug dependence: epidemiological evidence on adolescent-onset marijuana use.

Addiction

. 2003;98:71-82.

39.

Latimer WW, Newcomb M, Winters KC, Stinchfield RD. Adolescent substance abuse treatment outcome: the role of substance abuse problem severity, psychosocial, and treatment factors.

J Consult Clin Psychol

. 2000;68: 684-696.

40.

Ramo DE, Anderson KG, Tate SR, Brown SA. Characteristics of relapse to substance use in comorbid adolescents.

Addict Behav

. 2005;30:1811-1823.

41.

Budney AJ, Hughes JR, Moore BA, Novy PL. Marijuana abstinence effects in marijuana smokers maintained in their home environment.

Arch Gen Psychiatry

. 2001; 58:917-924.

42.

Budney AJ, Moore BA, Vandrey RG, Hughes JR. The time course and significance of cannabis withdrawal.

J Abnorm Psychol

. 2003;112:393-402.

43.

Haney M, Ward AS, Comer SD, et al. Abstinence symptoms following smoked marijuana in humans.

Psychopharmacology (Berl)

. 1999;141:395-404.

44.

Kouri EM, Pope HG Jr. Abstinence symptoms during withdrawal from chronic marijuana use.

Exp Clin Psychopharmacol

. 2000;8:483-492.

45.

Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity and significance of cannabis withdrawal syndrome.

Am J Psychiatry

. 2004;161:1967-1977.

46.

Lichtman AH, Martin BR. Marijuana withdrawal syndrome in the animal model.

J Clin Pharmacol

. 2002;42 (suppl 11):20S-27S.

47.

Budney AJ, Vandrey RG, Hughes JR, et al. Oral delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symptoms.

Drug Alcohol Depend

. 2007;86:22-29.

48.

Haney M, Hart CL, Vosburg SK, et al. Marijuana withdrawal in humans: effects of oral THC or divalproex.

Neuropsychopharmacology

. 2004;29:158-170.

49.

Crowley TJ, Macdonald MJ, Whitmore EA, Mikulich SK. Cannabis dependence, withdrawal, and reinforcing effects among adolescents with conduct symptoms and substance use disorders.

Drug Alcohol Depend

. 1998;50: 27-37.

50.

Mikulich SK, Hall SK, Whitmore TJ, Crowley TJ. Concordance between

DSM-III-R

and

DSM-IV

diagnoses of substance use disorders in adolescents.

Drug Alcohol Depend

. 2001;61:237-248.

51.

Young SE, Corley RP, Stallings MC, et al. Substance use, abuse and dependence in adolescence: prevalence, symptom profiles and correlates.

Drug Alcohol Depend

. 2002;68:309-322.

52.

Vandrey R, Budney AJ, Kamon JL, Stanger C. Cannabis withdrawal in adolescent treatment seekers.

Drug Alcohol Depend

. 2005;78:205-210.

53.

Dawes MA, Liguori A, Dougherty DM. Cannabis withdrawal among adolescent cannabis users in an outpatient research setting.

Am J Addict

. 2006;15:485-486.

54.

Anton RF, Drobes DJ. Clinical measurement of craving in addiction

. Psychiatr Ann

. 1998;28:553-560.

55.

Baker TB, Morse E, Sherman JE. The motivation to use drugs: a psychobiological analysis of urges. In: Rivers P, ed.

The Nebraska Symposium on Motivation: Alcohol Use and Abuse

. Lincoln, Neb: University of Nebraska Press; 1987.

56.

Shiffman S. The tobacco withdrawal syndrome. In: Krasnegor NW, ed.

Cigarette Smoking as a Dependence Process

. Washington, DC: National Institute on Drug Abuse; 1979.

57.

United States Department of Health and Human Services.

The Health Consequences of Smoking: Nicotine Addiction. A Report of the Surgeon General

. Washington, DC: US Department of Health and Human Services, Office on Smoking and Health; 1988. DHHS publication (CDC) 89-8406.

58.

Carter BL, Tiffany ST. Meta-analysis of cue-reactivity in addiction research.

Addiction

. 1999;94:327-340.

59.

Abrams DB, Monti PM, Carey KB, et al. Reactivity to smoking cues and relapse: two studies of discriminant validity.

Behav Res Ther

. 1988;26:225-233.

60.

Cooney NL, Litt MD, Morse PA, et al. Alcohol cue reactivity, negative-mood reactivity, and relapse in treated alcoholic men.

J Abnorm Psychol

. 1997;106:243-250.

61.

Drummond DC, Glautier S. A controlled trial of cue exposure treatment in alcohol dependence.

J Consult Clin Psychol

. 1994;62:809-817.

62.

Junghanns K, Tietz U, Dibbelt L, et al. Attenuated salivary cortisol secretion under cue exposure is associated with early relapse.

Alcohol Alcohol

. 2005;40:80-85.

63.

Monti PM, Rohsenow DJ, Hutchison KE. Toward bridging the gap between biological, psychobiological and psychosocial models of alcohol craving.

Addiction

. 2000;95(suppl 2):S229-S236.

64.

Niaura R, Abrams D, Demuth B, et al. Responses to smoking-related stimuli and early relapse to smoking.

Addict Behav

. 1989;14:419-428.

65.

Rohsenow DJ, Monti PM, Rubonis AV, et al. Cue reactivity as a predictor of drinking among male alcoholics.

J Consult Clin Psychol

. 1994;62:620-626.

66.

Waters AJ, Shiffman S, Sayette MA, et al. Cue- provoked craving and nicotine replacement therapy in smoking cessation.

J Consult Clin Psychol

. 2004;72: 1136-1143.

67.

Tapert SF, Cheung EH, Brown GG, et al. Neural response to alcohol stimuli in adolescents with alcohol use disorder.

Arch Gen Psychiatry

. 2003;60:727-735.

68.

Thomas SE, Drobes DJ, Deas D. Alcohol cue reactivity in alcohol-dependent adolescents.

J Stud Alcohol

. 2005;66:354-360.

69.

Curtin JJ, Barnett NP, Colby SM, et al. Cue reactivity in adolescents: measurement of separate approach and avoidance reactions.

J Stud Alcohol

. 2005;66:332-343.

70.

Upadhyaya HP, Drobes DJ, Thomas SE. Reactivity to smoking cues in adolescent cigarette smokers.

Addict Behav

. 2004;29:849-856.

71.

Upadhyaya HP, Drobes DJ, Wang W. Reactivity to in vivo smoking cues in older adolescent cigarette smokers.

Nicotine Tob Res

. 2006;8:135-140.

72.

Singleton EG, Trotman AJ, Zavahir M, et al. Determination of the reliability and validity of the marijuana craving questionnaire using imagery scripts.

Exp Clin Psychopharmacol

. 2002;10:47-53.

73.

Lundahl LH, Cederlind LA, Johanson CE. Cue-induced marijuana craving in medication development: specificity of the model. Presented at: College on Problems of Drug Dependence Annual Meeting; Scottsdale, Ariz; June 2006.

74.

Lundahl LH, Borden KN, Lukas SE. Marihuana cue-induced craving in cannabis dependent adolescents in psychiatric treatment. Presented at: College on Problems of Drug Dependence Annual Meeting; Scottsdale, Ariz; June 2001.

75.

Gray KM, LaRowe SD, Upadhyaya HP. Marijuana cue reactivity in adolescents: a pilot investigation. Presented at: College on Problems of Drug Dependence Annual Meeting; Scottsdale, Ariz; June 2006.