Sunday, November 29, 2009
Marijuana Withdrawal: A Survey of Symptoms (Part 1)
By Dirk Hanson
[Originally published in The Praeger International Collection on Addictions. Ed. by Angela Browne-Miller. Westport, Connecticut: Praeger, 2009. Vol. 2 Ch. 7 pp.111-124.]
(See also Marijuana Withdrawal Post)
More than 14 million Americans smoke marijuana regularly, making it the most commonly used illicit drug in America. In 2006, marijuana was the only drug used by 52.8 percent of illegal drug users (U.S. Department of Health and Human Services, 2006).
Over the past 15 years, as addiction researchers have been busily mapping out the chemical alterations in the human nervous system caused by alcohol, cocaine, nicotine, heroin, and tranquilizers, America’s most popular illegal drug has remained largely a scientific mystery. Marijuana, the drug millions of Americans have been using regularly for years, is the least studied drug of all.
Why has cannabis research lagged behind that of other drugs of abuse? For decades, the prevailing belief among users and clinical researchers alike was that marijuana did not produce dependency and therefore could not be responsible for major withdrawal symptoms. This thinking is based, quite understandably, on the widespread observation that most marijuana users do not have difficulty going without marijuana, either by choice or by necessity. However, marijuana withdrawal effects are frequently submerged in the welter of polyaddictions common to active addicts. The withdrawal rigors of, say, alcohol or heroin tend to drown out the subtler manifestations of cannabis withdrawal. As Barbara Mason, director of the Laboratory of Clinical Psychopharmacology at Scripps Research Institute, has explained: “People are deciding every day whether to use or not to use marijuana, for medical purposes or otherwise, and there is little scientific information to advise this decision” (2008).
Marijuana withdrawal, which typically affects only heavy smokers, has not been well characterized by the research community. Until recently, there was scant evidence in animal models for marijuana tolerance and withdrawal, the classic determinants of addiction. Now, however, several researchers have identified the existence of symptoms brought on by the abrupt discontinuation of regular marijuana use in both animal and human studies (de Fonseca et al., 1997, p. 2050). A growing body of evidence supports the existence of a clinically significant marijuana withdrawal syndrome in a subset of marijuana smokers. The syndrome is marked by irritability, restlessness, generalized anxiety, hostility, depression, difficulty sleeping, excessive sweating, loose stools, loss of appetite, a general “blah” feeling, and a mental state that has been described as “inner unrest.”
Recent clinical research, combined with anecdotal field reports collected by the author, demonstrate the existence of marijuana withdrawal and the consistency of the most common symptoms of withdrawal and detoxification.
In 1992, molecular biologists identified the elusive brain receptor where THC, the primary active ingredient in marijuana, did its work. Shortly after that discovery, researchers at Hebrew University in Jerusalem identified the body’s own form of THC, which uses the same CB1 receptors as THC. They christened the internally manufactured substance anandamide, after the Sanskrit ananda, or “bliss” (Fackelmann, 1993).
Anandamide has a streamlined three-dimensional structure that THC mimics. Both molecules slip easily through the blood brain barrier. Some of the mystery of marijuana’s effects was resolved after researchers demonstrated that marijuana definitely increased dopamine activity in the limbic area of the brain. Tanda, Pontieri, and Di Chiara demonstrated that dopamine levels in the nucleus accumbens doubled when rats received an infusion of THC (1997, p. 2048). It appears that marijuana raises dopamine and serotonin levels through the intermediary activation of opiate and GABA receptors (Wilson & Nicoll, 2001, p. 588). THC may perform a signaling function in neurons containing GABA and glutamate.
THC and its organic cousin, anandamide, make an impressive triple play in the brain: They effect movement through receptors in the basal ganglia, they alter sensory perception through receptors in the cerebral cortex, and they impact memory by means of receptors in the hippocampus. It is clear that some of the effects of cannabis are produced in much the same way as the effects of other addictive drugs—by means of neurotransmitter alterations along the limbic system’s reward pathway.
A great deal of the early research was marred by inconsistent findings and differing definitions of addiction and withdrawal. Most recreational marijuana users find that too much pot in one day makes them lethargic and uncomfortable. Self-proclaimed marijuana addicts, on the other hand, report that pot energizes them, calms them down when they are nervous, or otherwise allows them to function normally. Heavy marijuana users claim that tolerance does build. And when they withdraw from use, many report strong cravings.
Work by Jones, Benowitz, and Herning had helped establish certain baseline symptoms—irritability, insomnia, and lack of appetite—as early as 1981 (p. 143). Studies by Budney, Novy, and Hughes in 1999 further outlined the syndrome in heavy daily marijuana smokers (p. 1311). But the abstinence effects were often inconsistent, and frequently hard to measure. Moreover, their clinical relevance was not always evident.
For marijuana withdrawal to be considered a clinical fact, several criteria had to be met. First, the typically transient pattern of withdrawal effects must be distinguishable from rebound effects. (A rebound effect is defined as the reappearance of a preexisting symptom, and is thus not considered a true withdrawal effect.) In addition, the symptoms must occur reliably, as demonstrated by comprehensive prospective studies (Budney, Hughes, Moore, & Vandrey, 2004, p. 1970). The symptoms under consideration must also be considered clinically significant. Finally, there needs to be a clear and repeatable timeline in evidence for the withdrawal effects.
It has been suggested that the reported symptoms of abrupt marijuana cessation do not rise to the level of withdrawal typically associated with drug detox. It is now possible to lay out the neurochemical basis of marijuana withdrawal, and to demonstrate that marijuana acts on the brain in a fashion similar to other addictive drugs.
There is solid experimental evidence that chronic, heavy cannabis users develop tolerance to its subjective and cardiovascular effects. “In summary,” Budney et al. write, “cannabis withdrawal effects clearly occur in the majority of heavy, daily users” (2004, p. 1974). As a rough estimate, approximately 10 percent of marijuana users are at risk for dependence and withdrawal, the classic determinants of drug addiction (Joy, Watson, & Benson, 1999, p. 92). There is clinical and epidemiological evidence that some heavy cannabis users experience problems in controlling their cannabis use, and continue to use the drug despite experiencing adverse personal consequences of use (Hall, Solowij, & Lemon, 1999). Moreover, there is strong clinical evidence that some users experience a withdrawal syndrome upon the abrupt cessation of cannabis use. The timeline is similar to withdrawal from other addictive drugs.
In 2004, a group at the University of Vermont, funded by the National Institute of Drug Abuse (NIDA), undertook a critical review of all major relevant studies of the validity and clinical significance of marijuana withdrawal (Budney et al., p. 1967). The review of studies demonstrated with certainty that there are people with a propensity for heavy marijuana use who suffer a clearly delineated, verifiable, and frequently vivid set of withdrawal symptoms when they try to quit. One of the most striking pieces of evidence for this is the similarity of symptom sets emerging from the clinical studies to date. The most common “reliable and clinically significant” effects of abrupt withdrawal in heavy pot smokers, according to the University of Vermont research group, included “severity of craving and sleep difficulty, decreased appetite, and increased aggression, anger and irritability” (Budney, Hughes, Moore, & Novy, 2001, p. 917; Kouri, 2002, p. 30).
As another study author concluded: “Marijuana withdrawal doesn’t include dramatic physical symptoms such as the pain, nausea, heavy sweating, and cramps associated with opiate withdrawal. Nevertheless, the symptoms of marijuana withdrawal appear clinically significant” (Zickler, 2002).
A recent comprehensive outpatient study (Kouri & Pope, 2000, p. 483) with prewithdrawal baselines showed greater levels of anxiety, negative mood, physical discomfort, and decreased appetite during abstinence but not at baseline, compared with two control groups. Moreover, in a “home environment” study, researchers worked with marijuana users who provided self-ratings during marijuana withdrawal; these users smoked an average of 3.6 times daily, did not use other drugs or abuse alcohol, and were free of major psychiatric disorders. The same symptoms predominated, and onset of symptoms occurred reliably within 48 hours of cessation. Moreover, “telephone interviews with collateral observers living with the participants confirmed participants’ reports of increased irritability, aggression, and restlessness during abstinence. . . . [T]he validation of symptoms by home-based observers suggested that the effects were of a clinically significant magnitude” (Budney et al., 2004, p. 1971).
Other studies by Budney and colleagues expanded on the list of symptoms that changed significantly from baseline during withdrawal: “anger and aggression, decreased appetite, irritability, nervousness, restlessness, shakiness, sleep difficulty, stomach pain, strange dreams, sweating, and weight loss” (2003, p. 393; 2004, p. 1972). Although most effects were transient, generally lasting no more than two weeks, “strange dreams and sleep difficulties showed significant elevations throughout the study” (2003). Budney et al. conclude that, since most symptoms returned to baseline levels in the former users, “these findings were not rebound effects indicative of symptoms that existed before the use of cannabis” (2004, p. 1972).
More recent studies by Haney and others “controlled for potential confounders by using placebo conditions and excluding persons who abused other substances, had an active psychiatric disorder, or were taking psychoactive medication” ().
Overall, the research cited above confirms that the most common marijuana withdrawal symptom is low-grade anxiety and dysphoria. Anxiety of this sort has a firm biochemical substrate. A peptide known as corticotrophin-releasing factor (CRF) is primarily responsible. Neurologists at the Scripps Research Institute in La Jolla, California, found that CRF levels in the amygdalas of animals in marijuana withdrawal were as much as three times higher than the levels found in animal control groups (Wickelgren, 1997, p. 1967). Long-term marijuana use alters the function of CRF in the limbic system in a manner similar to other addictive drugs (de Fonseca et al., 1997, p. 2051). (CRF receptors in the amygdala also play a direct role in alcohol withdrawal.)
Personal observations and selected case histories of frequent marijuana users were gathered from anonymous, unedited comments posted on a blog site maintained by the author. Punctuation, capitalization, and spelling have been normalized in the excerpts included here. Most of the people who have posted comments thus far (more than 100) arrived at the site by means of the search term marijuana withdrawal. This may indicate that a large number of posters are heavy smokers seeking information about abstinence symptoms. The popularity of this search phrase on the Google search engine seems to suggest an interest in, and a need for, scientific information about marijuana withdrawal.
What has surprised many observers is that the idea of treatment for marijuana dependence seems to appeal to such a large and diverse group of people. NIDA has been able to find a cohort of withdrawal-prone smokers with relative ease. According to the principal investigator of one NIDA marijuana study, “We had no difficulty recruiting dozens of people between the ages of 30 and 55 who have smoked marijuana at least 5,000 times. A simple ad in the paper generated hundreds of phone calls from such people” (NIDA, 1999). This would be roughly equivalent to 14 years of daily pot smoking.
Comments gathered from anonymous users at an open Web forum created for the discussion of marijuana withdrawal symptoms cannot be controlled for confounding variables such as other addictions or psychological disorders. The comment section of the Web site is open to anyone. What such surveys can accomplish, however, is the demonstration of parallels, or lack of them, between findings in an experimental setting and anecdotal reports from the field. Survey studies cannot offer indisputable proof. Nonetheless, when combined with the results of formal clinical studies, such surveys offer a window into real-world experience, thus complementing the growing scientific data concerning marijuana withdrawal syndrome.
The comments were generated in large part by heavy, regular smokers who either recognized or have begun to recognize in themselves an addictive propensity toward marijuana. As a group, they have great difficulty—and suffer similar symptoms—whenever, and for whatever reason, they choose to abstain.
Perhaps, most important, the present survey adds to the growing documentation of the contention that withdrawal symptoms are a frequent cause of relapse in marijuana smokers attempting to achieve abstinence.
Cont. in Part 2.
Aharonovich, E., Liu, X., Samet, S., Nunes, E., Waxman, R., & Hasin, D. (2005). Postdischarge cannabis use and its relationship to cocaine, alcohol, and heroin use: A prospective study. American Journal of Psychiatry, 162(8), 1507–1514.
Budney, A. J., Hughes, J. R., Moore, B. A., & Novy, P. L. (2001). Marijuana abstinence effects in marijuana smokers maintained in their home environment. Archives of General Psychiatry, 58(10), 917–924. Retrieved February 27, 2008, from http://archpsyc.ama assn.org/cgi/content/full/58/10/917?cknck
Budney, A. J., Hughes, J. R., Moore, B. A., & Vandrey, R. (2004, November). Review of the validity and significance of cannabis withdrawal syndrome. American Journal of Psychiatry, 161, 1967–1977. Retrieved April 21, 2008, from http://ajp.psychiatryonline.org/cgi/content/full/161/11/1967
Budney, A. J., Moore, B. A., Vandrey, R., & Hughes, J. R. (2003). The time course and significance of cannabis withdrawal. Journal of Abnormal Psychology, 112, 393–402.
Budney, A. J., Novy, P. L., & Hughes, J. R. (1999, September 1). Marijuana withdrawal among adults seeking treatment for marijuana dependence. Addiction, 94, 1311–1322.
Copeland, J., Swift, W., & Rees, V. (2001, January). Clinical profile of participants in a brief intervention program for cannabis use disorder. Journal of Substance Abuse Treatment, 20(1), 45–52. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11239727
Cui, S. S., Gu, G. B., Hannesson, D. K., Yu, P. H., & Zhang, X. (2001, December 15). Prevention of cannabinoid withdrawal syndrome by lithium: Involvement of oxytocinergic neuronal activation. Journal of Neuroscience, 21(24), 9867–9876. Retrieved April 27, 2008, from http://www.jneurosci.org/cgi/content/abstract/21/24/9867
de Fonseca, F. R., Rocío, M., Carrera, A., Navarro, M., Koob, G. F., & Weiss, F. (1997, June 27). Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal. Science, 276, 2050–2054.
Fackelmann, K. A. (1993, February 6). Marijuana and the brain: Scientists discover the brain’s own THC-delta-9-tetrahydrocannabinol. Science News. Retrieved March 28, 2008, from http://findarticles.com/p/articles/mi_m1200/is_n6_v143/ai_13434805/pg_1
Hall, W., Solowij, N., & Lemon, J. (1999). The health and psychological consequences of cannabis use. (National Task Force on Cannabis Australia, Monograph Series No. 25). Sydney, NSW: University of New South Wales, National Drug and Alcohol Research Centre. Retrieved February 3, 2008, from http://www.druglibrary.org/schaffer/hemp/medical/home.htm
Haney, M., Hart, C. L., Vosburg, S. K., Nasser, J., Bennetti, A., Zubaran, C., et. al. (2004). Marijuana withdrawal in humans: Effects of oral THC or divalproex. Neuropsychopharmacology, 29, 158–170.
Haney, M., Hart, C. L., Ward, A. S., & Foltin, R. W. (2003, January). Nefazodone decreases anxiety during marijuana withdrawal in humans. Psychopharmacology, 165(2), 157–165.
Haney, M., Ward, A. S., Comer, S. D., Foltin, R. W., & Fischman, M. W. (1999, February). Abstinence symptoms following smoked marijuana in humans. Psychopharmacology, 141(4), 395–404.
Hanson, D. (2007, October 17). Addiction inbox: Marijuana withdrawal. Retrieved May 3, 2008, from http://addiction-dirkh.blogspot.com/2007/10/marijuana-withdrawal.html
Jones, R. T., Benowitz, N. L., & Herning, R. I. (1981, August–September). Clinical relevance of cannabis tolerance and dependence. Journal of Clinical Pharmacology, 8–9(Suppl.), 143–152. Retrieved April 14, 2008, from http://www.ncbi.nlm.nih.gov/sites/entrez
Joy, J. E., Watson, S. J., & Benson, J. A. (1999). Marijuana and medicine: Assessing the science base. Institute of Medicine, Division of Neuroscience and Behavioral Health. Washington, DC: National Academy Press. Retrieved March 5, 2008, from http://www.nap.edu/html/marimed/
Kouri, E. M. (2002, February 1). Does marijuana withdrawal syndrome exist? Psychiatric Times, 19(2). Retrieved March 17, 2008, from http://www.psychiatrictimes.com/display/article/10168/54701?pageNumber3
Kouri, E. M., & Pope, H. G., Jr. (2000, November). Abstinence symptoms during withdrawal from chronic marijuana use. Experimental and Clinical Psychopharmacology, 8(4), 483–492. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/
Lichtman, A. H., & Martin, B. R. (2002). Marijuana withdrawal syndrome in the animal model. Journal of Clinical Pharmacology, 42, 20s–27s.
Mason, B. (2008, March 15). North County Times.
National Institute on Drug Abuse. (1999, April 20). Chronic marijuana users become aggressive during withdrawal. (NIDA News Release). Rockville, MD: Author. Retrieved April 9, 2008, from http://www.nida.nih.gov/MedAdv/99/NR-420.html
Schuckit, M. A., Daeppen, J.-B., Danko, G. P., Tripp, M. L., Li, T.-K., Hesselbrock, V. M., et. al. (1999). Clinical implications for four drugs of the DSM–IV distinction between substance dependence with and without a physiological component. American Journal of Psychiatry, 156, 41–49.
“Scripps Given $4M Grant to Study Effects of Marijuana.” (2008, March 15). North County Times. Retrieved March 16, 2008, from http://www.nctimes.com/articles/2008/03/15/news/sandiego/16_02_343_14_08.txt
Somers, T. (2008, March 14). Study aims to clear haze surrounding pot addiction. San Diego Union-Tribune. Retrieved March 16, 2008, from http://www.signonsandiego.com/news/science/20080314–9999–1n14dope.html
Tanda, G., Pontieri, F. E., & Di Chiara, G. (1997, June 27). Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common 1 opioid receptor mechanism. Science, 276, 2048–2050.
U.S. Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. (2006). Results from the 2006 National Survey on Drug Use and Health: National Findings. Rockville, MD: Office of Applied Studies. Retrieved March 12, 2008, from http://www.oas.samhsa.gov/NSDUH/2k6NSDUH/2k6results.cfm#Ch2
Vandrey, R. G., Budney, A. J., Hughes, J. R., & Liguori, A. (2008, January 1). A within-subject comparison of withdrawal symptoms during abstinence from cannabis, tobacco, and both substances. Drug and Alcohol Dependence, 92, 48–54.
Wickelgren, I. (1997, June 27). Marijuana: Harder than thought? Science, 76, 1967–1968.
Photo Credit: http://hubpages.com/