Dr. Sussman is the editor of Primary Psychiatry and clinical professor of psychiatry in the Department of Psychiatry at the New York University School of Medicine in New York City.
Dr. Westreich is clinical associate professor in the Division of Alcoholism and Drug Abuse in the Department of Psychiatry at New York University School of Medicine.
Disclosure: Dr Westreich is on the speaker’s bureau for Odyssey, and Pfizer.
Please direct all correspondence to: Norman Sussman, MD, DFAPA, Department of Psychiatry, New York University School of Medicine, 150 East 58th St., 27th Floor, New York, NY 10155; Tel: 212-588-9722; Fax: 212-588-9721; E-mail: firstname.lastname@example.org.
• In the United States, marijuana is perceived as innocuous and commonly used, which presents problems for the clinician encouraging abstinence in an addicted patient.
• Signs and symptoms of marijuana withdrawal include irritability, restlessness, depression, anxiety, impaired sleep, nausea, aggression, sweating, and rhinorhea.
• Treatment of marijuana withdrawal should include acknowledgment of the difficulty in stopping marijuana use, referral to support and counseling, aggressive pharmacologic treatment of withdrawal effects, and aggressive pharmacologic treatment of any underlying psychopathology.
Knowledge that a patient with a psychiatric disorder is a chronic marijuana smoker presents the clinician with a dilemma: should the patient be treated even with ongoing use of marijuana or should the patient be advised to stop smoking? Although these decisions are made on a case-by-case basis, it would be helpful if some basic guidelines could be developed for treatment decisions in these cases. This article reviews some of the findings from recent research and combines it with the clinical experience of the authors in order to provide some help in understanding the difficulties patients have in discontinuing marijuana and of the ways in which continued use may complicate efforts to treat the underlying psychiatric disorder.
Marijuana is the most commonly used illicit drug in the United States.1 Thus, it is likely that many patients who visit their physicians for routine physical examinations or for treatment of medical problems are smokers of marijuana. It is not known how often patients spontaneously report information about the use of marijuana or how often physicians specifically elicit information about it from their patients. What happens if a marijuana user is diagnosed with depression, anxiety, or another psychiatric disorder? What should the physician recommend about continuing or discontinuing the use of marijuana?
There is a remarkable lack of research literature and clinical guidelines about how to use psychotropic agents in patients who are regular users of marijuana. Indeed, considering the pervasive use of marijuana and the widespread perception of many users, remarkably little has been written about the potential impact of regular use on the course of psychiatric disorders. Physicians may feel challenged about how to advise daily marijuana smokers when treating them with psychotropic drugs, and what the nature and impact of marijuana discontinuation may be in the context of psychiatric treatment.
Marijuana is typically regarded as a relatively innocuous substance. There is even considerable popular sentiment that marijuana and hashish should be legalized. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text-Revision2 does not include chronic use of cannabis as a disorder. Thus, suggestions by a psychiatrist that chronic marijuana use may interfere with treatment, or that use may be contributing to mood, anxiety, or cognitive symptoms are often dismissed as being judgmental.
Daily marijuana use often results in dependence. In the US, 7.4% of adults and 14.4% of adolescents who used cannabis met diagnostic criteria for dependence within the year.3 A common dilemma is distinguishing between a causal and coincidental relationship. Thus, if there is an association between marijuana use and psychiatric disorder or a specific syndrome, it is not always obvious whether or not the use of marijuana is the cause of the problem. For example, according to data from the National Longitudinal Study of Adolescent Health, marijuana use by adolescents is among the six risk factors for suicide attempts.4
Given the pervasiveness of cannabis use, and its status as a recreational drug, as opposed to a “hard” drug, physicians may encounter patients who are both depressed and regular marijuana users. In this clinical context, a number of questions arise:
• How should treating clinicians address the ongoing use of marijuana if treatment for depression is started?
• Should patients be told to stop smoking?
• If patients are told to stop smoking, is it reasonable to expect that they will be compliant?
• Does use of marijuana while being treated with antidepressant interfere with the effectiveness of the medication?
• What is known about marijuana withdrawal syndrome?
• How can withdrawal be managed?
• Does marijuana increase the risk of mental disorders?
• Does chronic marijuana use represent self-medication?
• Can mental disorders be treated effectively in the face of chronic marijuana use?
This review offers guidance to clinicians who may encounter the dilemma of treating depression in marijuana smokers.
Relationship Between Marijuana and Mental Health
Studies have shown that substance abuse, primarily involving alcohol, marijuana, and cocaine, is common among persons with mental disorders.5 While some studies have found little or no association between marijuana use and poor mental health, others have shown that marijuana users are at increased risk for symptoms of poor mental health.6 It has been argued that marijuana use causes mental disorder and that it represents an attempt to self-medicate.
Epidemiological evidence of a possible causal role of marijuana use in the development of major depressive disorder (MDD) suggests that the risk of a first MDD episode is moderately associated with the frequency of marijuana use and with more advanced stages of marijuana use.7 Compared to those who never use marijuana, even nondependent marijuana users have a 1.6 times greater risk of MDD.7 In addition, one study8 found that continuous heavy use of marijuana can induce psychotic disorder that can be distinguished from cannabis intoxication.
Prenatal Marijuana Exposure
Marijuana is the illicit drug most commonly used by pregnant women. The human placenta is a target for cannabinoids. Marijuana use during pregnancy has been found to affect placental clearance of serotonin through the serotonin transporter.9 There are data suggesting that prenatal exposure is associated with behavior problems beginning at 10 years of age.10
Impact of Marijuana Use at an Early Age
Use is more prevalent among adolescents and younger adults.11 Perhaps the most consistent and most robust finding across the board was the relationship between age of first marijuana and later depression and schizophrenia. A study of the association of marijuana use and adult symptomatology6 found that use of marijuana at an early age appeared to be an important determinant of later mental health outcomes. Use of marijuana at ≤16 years of age was found to have an effect on later depression.6 This effect negatively impacted educational attainment, employment, marital status, use of alcohol and tobacco, and likelihood of marijuana use as an adult. Depressed adolescents report more frequent use of marijuana, tobacco, and cocaine than nondepressed peers.12
Some findings point to differences in the causal direction of mental disorders based on age. For example, McGee and colleagues13 found that marijuana use among adolescents was the result of a primary mental disorder, while among young adults the use of cannabis seemed to lead to mental disorder. If correct, these findings would suggest that marijuana abuse among adolescents might signal the presence of a primary psychiatric disorder.
Chronic marijuana use has consistently been linked with an amotivational syndrome. Symptoms include apathy, loss of productivity, difficulty in carrying out long-term plans, lethargy, depression, inability to concentrate, and inability to sustain attention.14 These amotivational effects are often additive to the effects of another, freestanding, mental illness. For example, the lethargy and passivity associated with depression can be exacerbated by the misguided use of marijuana as an attempt to self-medicate dysphoria. In addition, subtle effects of marijuana are often missed in the relatively high-functioning individual. For the student or professional with a very high intellectual capacity, steady marijuana use may degrade performance by 20% to 30%, a loss of potential undetectable to the outside world. In this circumstance, only confrontation by a skilled clinician can elicit an attempt at abstinence and a real examination of the benefits of not smoking marijuana.
Marijuana Use for Coping
Marijuana appears to be ineffective when used as a method of coping, the so-called avoidance coping. Indeed, marijuana users who smoke in order to cope are more depressed than others despite their use of the drug. Green and Ritter6 found that current marijuana use does not appear to have a positive association with depression unless a person uses it to cope with problems.
The neuropharmacology of marijuana is relatively poorly understood.15 Does marijuana actually produce physiological effects that underlie the development of psychiatric disorders?
The cannabinoid receptor type 1 (CB1) is highly concentrated in dopamine modulate areas of the brain associated with schizophrenia, and some evidence points to a link between specific genetic polymorphisms in these areas and schizophrenia.16 In an editorial, Rey and Tennant17 point out that marijuana use among young people has become as common, or more common, than smoking cigarettes in some countries. Despite the best efforts of agencies like the Office of National Drug Control Policy (ONDCP), marijuana use is considered relatively benign and socially acceptable in the US, and in many jurisdictions has minor or nonexistent legal consequences. However, there has been little research into the best treatment for those who use marijuana. As with other addictions, moral issues associated with a recommendation for abstinence should be put aside in favor of more practical problems with marijuana use in the psychiatric patient. Although the anxious individual may not identify marijuana as contributing cause for the anxiety, and may even perceive marijuana as a treatment for anxiety, the adept clinician can point out that marijuana functions as a central nervous system depressant and hallucinogenic agent. Like alcohol, marijuana may initially relieve anxiety, but as time passes both substances worsen anxiety and pose risks for addiction and further maladaptive use. This empathic teaching approach is more likely to yield good results from the marijuana-using individual than a punitive or angry approach.
Marijuana is more socially acceptable than other recreational drugs and there is considerable pressure to legalize it. Thus, a better understanding of how chronic marijuana use affects the development and management of mental disorders is warranted.
There are few references to marijuana withdrawal in the literature. The lifetime prevalence of marijuana dependence is the highest of all illicit drugs in the US.18 Some chronic users experience extreme difficulty in discontinuing use. Most discussions characterize discontinuation symptoms as being mildly distressing.
Symptoms of Withdrawal
Only in the past few years have studies begun to appear that define a marijuana withdrawal syndrome. Evidence suggests that while marijuana may lack many of the intense physiological symptoms and life-threatening reactions that accompany discontinuation of other drugs of abuse, the manifestations of its cessation after long-term use may be sufficiently distressing to cause difficulty with discontinuing the drug. Users may find that the rapid emergence of withdrawal symptoms leads them to start smoking again. Regular heavy use of marijuana is associated with the development of tolerance to some psychoactive and some cardiovascular effects, such as tachycardia and hypotension.19
Rat studies20at Virginia Commonwealth University in Richmond found that the administration of a marijuana (cannabinoid) receptor antagonist (SR 141716A) following the administration of chronic tetrahydrocannabinolproduces ptosis, “wet dog shakes,” facial rubbing (interpreted as signs of withdrawal), retropulsion, ear twitching, chewing, licking, and arching of the back. Overall, the animals appeared hyperactive and disorganized.
A summary of symptoms of withdrawal after daily use based on studies from several research centers are listed in the accompanying Table.3,21,22
It has generally been thought that the duration of withdrawal symptoms last only a few days. However, a Harvard University study22 found that symptoms often last for at least 4 weeks. Withdrawal symptoms were more pronounced during the first 10 days after marijuana cessation.
Acknowledgment of Difficulty in Stopping Marijuana Use
As with cocaine withdrawal, the absence of a definitive treatment modality should not lead to ignoring the syndrome itself. By understanding the patient’s reluctance to stop marijuana use as real and mostly biologically based, the clinician can encourage abstinence by using available psychopharmacologic remedies and encouraging emotional support from therapists, family, friends, and peer-led self-help groups, such as Alcoholics Anonymous.
Aggressive Psychopharmacologic Treatment of Withdrawal Effects
There is no clearly established pharmacologic treatment for cannabis dependence and no agent proven to mitigate withdrawal symptoms. Naltrexone, an opioid antagonist, failed to show evidence for efficacy in the treatment of compulsive marijuana use.15 A small study at the New York State Psychiatric Institute in New York City found that the antidepressant nefazodone attenuated some symptoms of marijuana withdrawal.23 The drug reduced ratings of anxiety and muscle pain, but not irritability. In a separate study, the investigators found that the antidepressant bupropion increased the severity of withdrawal symptoms compared to the placebo maintenance group,3 but that it worsened mood.
Insomnia associated with marijuana withdrawal can be treated with soporifics such as zolpidem or the antidepressant trazodone. The patient should be told that these drugs will be only partial remedies, but will likely “take the edge off” the withdrawal syndrome. Often, these sorts of therapeutic maneuvers by the clinician foster a strong therapeutic alliance because the withdrawing patient is reassured that his or her discomfort is being recognized, understood, and treated as well as possible.
Among patients with schizophrenic and schizoaffective disorders, clozapine has been shown to facilitate abstinence from marijuana, but has not been studied for any antiwithdrawal properties.5 Remarkably, a search found no citations of benzodiazepines, such as alprazolam or clonazepam, in the use of withdrawal reduction.
Cui and colleagues18 reported that systemic infusion of lithium suppressed the cannabinoid withdrawal syndrome in rats. The animals were treated chronically with the cannabinoid agonist HU210 and then injected with the cannabinoid antagonist AM281 to provoke withdrawal symptoms. Lithium blocked all the withdrawal symptoms. Caution is recommended in giving too much clinical significance to these results as they were derived from an animal study, but they do suggest a possible avenue of further research. It is of interest that the researchers found evidence that lithium may have protected against withdrawal effects through release of oxytocin from the pituitary gland. To test whether the observed effects were in fact mediated through an oxytocinergic mechanism, they administered high-dose oxytocin. It was found that the exogenous oxytocin, like lithium, blocked the cannabinoid withdrawal syndrome. As mentioned by Uvnas-Moberg and colleagues,24 “There is both clinical and laboratory evidence to suggest a role for oxytocin as an endogenous antidepressant/anxiolytic hormone.” Several classes of drugs that increase plasma oxytocin levels are also effective anxiolytics.
Aggressive Psychopharmacologic Treatment of Underlying Psychopathology
An early and forceful attempt to treat underlying psychopathology reassures the patient that his or her discomfort is understood and will be treated. For example, a depressed patient may complain that only marijuana relieves persistent dysphoria. In this case, prescription of an antidepressant during the time that marijuana withdrawal is being attempted will elicit the earliest possible therapeutic response, while reinforcing the idea that the beneficial effects of marijuana will be replaced by the effects of a medication, without the side effects of marijuana. The clinician should specifically inform the patient that psychotropic medication is less likely to work under the condition of continued marijuana use. That is, ideally, no medication can allow the addict to continue using marijuana without a potentially negative impact on efficacy. At some point, after therapeutic trials of different medications have failed, the need for cessation of marijuana use becomes the foremost issue in ongoing treatment.
The consequences of occasional marijuana use are not known. Marijuana use is not necessarily impairing to its users. Many patients occasionally smoke marijuana recreationally without discernable adverse impact on their emotional state and cognitive performance. Many successful musicians, artists, and writers report that marijuana increases their creativity. Cancer patients undergoing chemotherapy use marijuana to suppress treatment-associated nausea.
Despite the benefits of marijuana use in some patients, the continued use of the drug may be problematic in adolescents and chronic adult users for whom marijuana is associated with a mental disorder. In terms of evidence-based medicine, the clinical implications of regular marijuana use by patients who are being treated for psychiatric disorders has not been systematically studied. Yet, based on clinical experience, it is clear that marijuana use interferes with performance in many areas of life, such as work, school, and family relationships. There is also sufficient evidence to suggest that regular use of marijuana can induce or exacerbate symptoms in the mentally ill person, regardless of the acuteness or chronicity of use. Because of this, continued use of cannabis may constitute a causal or perpetuating factor in the disorder, and should be discontinued if only to ascertain if the symptoms remit. It is analogous to a patient who is unsuccessfully treated for panic attacks, yet who drinks several cups of coffee a day. Eliminating the coffee often alleviates the anxiety symptoms, or permits medications to work. However, cessation of caffeine use may result in a withdrawal syndrome that can be anticipated.
Because discontinuation of chronic cannabis use can result not only in craving, but also in clinically significant psychiatric and physiological withdrawal symptoms, continued abstinence is problematic for many patients. Even though treatment should be attempted while marijuana smoking continues, it should be clearly stated that successful treatment may not be possible in these circumstances. If several trials of medications fail and smoking cannot be stopped, hospitalization for detoxification may be necessary. Since most medical insurance companies do not cover cannabis addiction, hospitalization should be based on the severity of the disorder and its resistance to treatment. PP
1. Johnston D. National Survey Results on Drug Use From the Monitoring the Future Study, 1975-1998, Vol I: Secondary School Students (DHHS Publication No. NIH 99-4660). Rockville, MD: US Department of Health and Human Services; 1999.
2. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text-rev. Washington, DC: American Psychiatric Association; 2000.
3. Haney M, Ward AS, Comer SD, Hart CL, Foltin RW, Fischman MW. Bupropion worsens mood during marijuana withdrawal. Psychopharmacology (Berl). 2001;155:171-179.
4. Borowsky IW, Ireland M, Resnick MD. Adolescent suicide attempts: risks and protectors. Pediatrics. 2001;107:485-493.
5. Zimmet SH, Strous RD, Burgess ES, Kohnstam AB, Green AI. Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: a retrospective survey. J Clin Psychopharmacol. 2000;20:94-98.
6. Green BE, Ritter C. Marijuana use and depression. J Health Soc Behav. 2000;41:40-49.
7. Chen CY, Wagner FA, Anthony JC. Marijuana use and the risk of major depressive episode. Epidemiological evidence from the United States National Comorbidity Study. Soc Psychiatr Epidemiol. 2002;37:199-206.
8. Nunez LA, Gurpegui M. Cannabis-induced psychosis: a cross-sectional comparison with acute schizophrenia. Acta Psychiatr Scand. 2002:105:173-178.
9. Kenney SP, Kekuda R, Prasad PD, Leibach FH, Devoe LD, Ganapathy V. Cannabinoid receptors and their role in the regulation of the serotonin transporter in human placenta. Am J Obstet Gynecol. 1999;181:491-497.
10. Goldschmidt L, Day NL, Richardson GA. Effects of prenatal marijuana exposure on child behavior problems at age 10. Neurotoxicol Teratol. 2000;22:325-336.
11. National Household Survey. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2000.
12. Field T, Diego M, Sanders C. Adolescent depression and risk factors. Adolescence. 2001;36:491-498.
13. McGee R, Williams S, Poulton R, Moffitt T.
A longitudinal study of caanabis use and mental health from adolescence to early adulthood. Addiction. 2000;95:491-503.
14. Cherek DR, Lane SD, Dougherty DM. Possible amotivational effects following marijuana smoking under laboratory conditions. Exp Clin Psychopharmacol. 2002;10:26-38.
15. Wachtel SR, de Wit H. Naltrexone does not block the subjective effects of oral Delta(9)-tetrahydrocannabinol in humans. Drugs Alcohol Deprend. 2000;59:251-260.
16. Leroy S, Griffon N, Bourdel MC, Olie JP, Poirier MF, Krebs MO. Schizophrenia and the cannabinoid receptor type 1 (CB1): association study using a single-base polymorphism in coding exon 1. Am J Med Genet. 2001;105:749-752.
17. Rey JM, Tennant CC. Cannabis and mental health: More evidence establishes clear link between use of cannabis and psychiatric illness [editorial]. BMJ. 2002;325:1183-1184.
18. Cui SS, Bowen RC, Gu GB, Hannesson DK, Yu PH, Zhang X. Prevention of cannabinoid withdrawal syndrome by lithium: involvement of oxytocinergic neuronal activation. J Neurosci. 2001;21:9867-9876.
19. Cohen S. The 94-day cannabis study. Ann N Y Acad Sci. 1976;282:211-215.
20. Aceto MD, Scates SM, Lowe JA, Martin BR. Dependence on delta 9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal. J Pharmacol Exp Ther. 1996;3:1290-1295.
21. 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.
22. Kouri EM, Pope HG Jr. Abstinence symptoms during withdrawal from chronic marijuana use. Exp Clin Psychopharmacol. 2000;8:483-492.
23. Haney M, Hart CL, Ward AS, Foltin RW. Nefazodone decreases anxiety during marijuana withdrawal in humans. Psychopharmacology (Berl). 2003;2:157-165.
24. Uvnas-Moberg K, Bjokstrand E, Hillgaart V, Ahlenius S. Oxytocin as a possible mediator of SSRI-induced antidepressant effects. Psychopharmacol (Berl). 1999;142:95-101.