Seeking a Patch or a Pill for Pot

Drug treatments for marijuana withdrawal.

Sometimes it’s easy to forget that marijuana is the most widely used illegal drug of all. We demonize it, yet we take it for granted. We punish citizens for its possession, but we call it a “soft” drug.

The idea of marijuana as an addictive drug--for some but by no means all users—still seems preposterous to a large number of recreational pot smokers. Yet these same people have far less trouble dealing with the existence of raging alcoholics surrounded by a majority of controlled, recreational drinkers or non-drinkers.

 For purposes of this post, we are going to stipulate that sufficient scientific evidence now exists to include marijuana in the category of addictive psychoactive drugs. Heavy, daily users of marijuana sometimes find themselves in an unexpected bind if they decide to quit cold. Perhaps as many as one or two in every ten heavy pot smokers will find themselves suffering from flu-like symptoms, loss of appetite, insomnia, vivid dreams, irritability, generalized anxiety, and other side effects that can be at least as unpleasant as quitting cold turkey after a long cigarette habit.

 Why didn’t we know this earlier? Perhaps for the same reasons that we didn’t know until the 1980s, as a general piece of knowledge, that cocaine was highly addictive. (Marijuana Anonymous didn’t start up until 1989). Doesn’t that sound absurd now, the state of our understanding of cocaine’s effects only 30 years ago? For people who suffer strong and repeatable withdrawal symptoms when they try to quit smoking weed, it is equally absurd to proclaim that what they are wrestling with does not resemble a genuine drug addiction (See the Addiction Inbox thread on marijuana withdrawal, which is now approaching 1,000 comments, and which constitutes a major database of self-reported data on marijuana withdrawal).

Having identified marijuana as classically addictive for a small slice of the user population, the focus has lately turned toward human laboratory studies, although most of the human studies thus far have been open-label trials rather than controlled double-blind studies. A group of researchers at Columbia University has been testing a variety of medications in search of a compound with demonstrated effects on marijuana abstinence and withdrawal. A study published online last year examines the effectiveness of a variety of medications on the course of marijuana craving and withdrawal in users classified as marijuana dependent. In other words, they are looking for the equivalent of a nicotine patch for marijuana.

In an article for CNS Drugs, Ryan Vandrey of Johns Hopkins University School of Medicine and Margaret Haney of the New York State Psychiatric Institute, surveyed such studies as presently exist on the subject of pharmacotherapy for cannabis dependence. There are presently no clinically validated treatments for marijuana withdrawal. And, unlike the hundreds of controlled, double blind trials of pharmaceuticals for addiction to alcohol, cigarettes, cocaine, and heroin, recent research on medications for marijuana dependence has been sparse and scattershot.

 Nonetheless, the marijuana withdrawal syndrome is now well established in the scientific literature, as well as anecdotally.  Among heavy dope smokers, the authors write, cold-turkey cessation from marijuana “produces cellular changes in the brain reward pathway (increased corticotrophin-releasing factor, decreased dopamine) that have been linked to the dysphoric effects associated with withdrawal from drugs such as alcohol, opiates, and cocaine, and are thought to contribute to relapse.”

What have they discovered so far?

One obvious starting point was dronabinol, a.k.a. Marinol, the government-approved synthetic THC often prescribed for nausea, vomiting, and appetite loss due to chemotherapy. Marinol is a direct approach to the nicotine patch strategy: A substance that stimulates cannabis receptors in a manner similar to, but by no means identical with, the high produced by natural marijuana. Perhaps a regular low dose of Marinol would keep the cannabis cravings at bay among problem users trying to quit. As it turns out, not really. Some studies showed that you could reduce a pot addict’s withdrawal symptoms somewhat in a home environment with Marinol, but the dose required to accomplish this was high enough to represent potential problems of its own.

Another obvious candidate for investigation was rimonabant, a.k.a. Accomplia—but for the opposite reason. Rimonabant, which started out life as an anti-obesity medication, blocks the cannabinoid receptor CB1, so in that sense it should function roughly like Antabuse for alcoholics. It is the “anti-weed,” but as it turned out, rimonabant’s effect on cannabis receptors didn’t do the trick, either. Rimonabant “reduced the effects of smoked cannabis in two studies,” Vandrey and Haney write, “but a reduction of subjective drug effects was not consistently observed.” Furthermore, rimonabant is under suspicion for causing “adverse psychiatric effects” and is not much in favor at present.

Next up, naltrexone—an opiod receptor antagonist, which blocks the effects of heroin and is used in alcohol and heroin detox and withdrawal. Naltrexone has been shown in some studies to “reduce the subjective effects of cannabinoids in humans,” the authors note. But no dice: “In cannabis users, pretreatment with high doses of naltrexone (50-200 mg) failed to attenuate, and in some cases enhanced, the subjective effects of dronabinol and smoked cannabis.” To make matters worse, “the effect of naltrexone can be overcome with higher doses of cannabis.”

Other possible anti-craving drugs for marijuana have not been as rigorously studied. An open-label investigation of buspirone, which works on serotonin and dopamine systems, caused a decline in self-reported cannabis use, and pot smokers showed marked decreases in craving and irritability—but, as these things often go, buspirone was not well-tolerated by the participants, with too many dropouts due to adverse side effects.

Lithium, a mood stabilizer commonly prescribed for bipolar disorder, has shown promise in several small studies. An open-label lithium trial by the National Drug and Alcohol Research Centre in New South Wales resulted in “significant reductions in symptoms of depression and anxiety and cannabis-related problems.” More studies are needed.

Fluoxetine, better known to the world as Prozac, has been anecdotally associated with reduced marijuana use in depressed alcohol-dependent patients, but has never been the subject of any large clinical studies with a population of users whose primary drug is marijuana.

And finally, there is a dark-horse candidate, a treatment drug sometimes employed to prevent relapse

 in cases of heroin addiction. Lofexidine is an alpha-2-adrenergic agonist that has been in use for years in the U.K. under the name BritLofex to treat the common symptoms of heroin withdrawal, such as cramps, chills, sweating, loss of appetite, and diarrhea. Similar but less intense withdrawal symptoms also afflict heavily addicted marijuana users. In a 2008 paper published in Psychopharmacology, “lofexidene was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse.” Lofexidine combined with THC yielded even better results.

It appears that immediate research might be most profitably focused on lofexidine and lithium. And indeed, additional studies of the two drugs for cannabis dependency are planned by NIDA.  Also, the combination of dronabinol and lofexidine appears to be worth pursuing in future clinical investigations of anti-craving drugs for marijuana.

Vandrey, R., & Haney, M. (2009). Pharmacotherapy for Cannabis Dependence CNS Drugs, 23 (7), 543-553 DOI: 10.2165/00023210-200923070-00001

Graphics Credit: http://archives.drugabuse.gov

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.

Background

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.)

Method

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.

References

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?cknck

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?pageNumber3

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

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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.

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Photo Credit: http://hubpages.com/

Marijuana Withdrawal Revisited

Is cannabis addictive?

See also Marijuana Withdrawal


Until recently, there was very little evidence in animal models for marijuana tolerance and withdrawal, the classic symptoms of addiction. For at least four decades, million of Americans have used marijuana without clear evidence of a withdrawal syndrome. 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. They feel lethargic and uncomfortable without it. Heavy marijuana users claim that tolerance does build. And when they withdraw from use, they report strong cravings.

While the scientific evidence weighed in against the contention that marijuana is addictive, there were a few researchers who were willing to concede the possibility. “Probably not, for most people,” a researcher at the University of Minnesota’s Chemical Dependency Program told me in the late 1990s. “But there may be some small percentage of people who are on the same wavelength with it chemically, and who end up in some way hooked to it physically. It’s a complicated molecule.”

The difference between animal models and humans may be the difference between pure THC and naturally grown marijuana. Despite the fact that rats and monkeys find whopping doses of synthesized THC aversive in the lab, psychopharmacologist Ronald Siegel, in his book Intoxication, has documented numerous instances of rodents feeding happily on wild marijuana plants in the field. There are apparently other components in the psychoactive mix that makes marijuana what it is. When the lab version of THC is hundreds of times more potent that the genuine article, it is hard to know exactly what the research is telling us.

Some of the mystery of cannabis was resolved after researchers demonstrated that marijuana definitely increased dopamine activity in the ventral tegmental area of the brain. Some of the effects of pot are produced the old-fashioned way—by means of neurotransmitter alterations along the limbic system’s reward pathway.

A report prepared for Australia’s National Task Force on Cannabis put the matter straightforwardly:

There is good experimental evidence that chronic heavy cannabis users can develop tolerance to its subjective and cardiovascular effects, and there is suggestive evidence that some users may experience a withdrawal syndrome on the abrupt cessation of cannabis use. 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.

The U.S. government’s essentially unchanged opposition to marijuana research has meant that, until quite recently, precious few dollars were available for pot research. This official recalcitrance is one of the reasons for the belated recognition and characterization of marijuana’s distinct withdrawal syndrome.

To pluck one statistic out of many, representing estimates made in the late 1990s, more than 11 million Americans smoked marijuana regularly in the NIDA-sponsored “National Household Survey on Drug Abuse.” What NIDA has learned about cannabis addiction, according to the principal investigator of a recent NIDA study, was that “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” (This would be roughly equivalent to 14 years of daily pot smoking).

There now exists a nice body of clinical trials showing that mice and dogs show evidence of cannabis withdrawal. (For THC-addicted dogs, it is the abnormal number of wet-dog shakes that give them away.) Today, scientists have a much better picture of the jobs performed by anandamide, the body’s own form of THC. This knowledge helps explain a wide range of THC withdrawal symptoms. Among the endogenous tasks performed by anandamide are pain control, memory blocking, appetite enhancement, the suckling reflex, lowering of blood pressure during shock, and the regulation of certain immune responses.

These functions shed light on common hallmarks of cannabis withdrawal, such as anxiety, chills, sweats, flu-like physical symptoms, and decreased appetite. At Columbia University’s National Center on Addiction and Substance Abuse, where a great deal of NIDA-funded research takes place, researchers have found that abrupt marijuana withdrawal leads to symptoms similar to depression and nicotine withdrawal.

In a 2003 research report entitled “Nefazodone Decreases Anxiety During Marijuana Withdrawal in Humans,” published in Psychopharmacology, researchers at the New York State Psychiatric Institute used Serzone (nefazodone) to decrease some symptoms of marijuana withdrawal in human subjects who had been regularly smoking six joints of pot per day. Anxiety and muscular discomfort were reduced, but Serzone had no effect on other symptoms, like irritability and sleep problems. The drug did not alter the perceived effects of marijuana intoxication (the SSRIs didn’t, either). Serzone is another antidepressant, a modest inhibitor of serotonin and norepinephrine, but its mechanism of action is ill defined. It is not in the SSRI or tricyclic families.

To date, there is no effective anti-craving medication approved for use against the marijuana withdrawal syndrome, for addiction-prone individuals unlucky enough to suffer from it.

For more, see earlier posts:

Marijuana Withdrawal

Is Marijuana Addictive?

Photo credit: 2nd International Cannabis and Mental Health Conference Programme