Does Marijuana Withdrawal Matter?

What happens to some smokers when they cut out the cannabis.

People who say they are addicted to marijuana tend to exhibit a characteristic withdrawal profile. But is cannabis withdrawal, if it actually exists, significant enough to merit clinical attention? Does it lead to relapse, or continued use despite adverse circumstances? Should it be added to the list of addictive disorders in the rewrite of the Diagnostic and Statistical Manual of Mental Disorders (DSM) currently in progress?

Marijuana fits in fairly well with the existing criteria for clinical addiction—except for one common diagnostic marker. Among the identifying criteria currently used in the DSM, we find: “The presence of characteristic withdrawal symptoms or use of substance to alleviate withdrawal.” Opponents of marijuana’s inclusion as an addictive drug have long insisted that cannabis has no characteristic withdrawal symptoms, but this position has been severely eroded of late, as new research has consistently identified a withdrawal syndrome for marijuana, which includes drug cravings, despite decades of controversy over this basic medical question.

A group of researchers at the University of New South Wales, Australia, along with Dr. Alan J. Budney of the Geisel School of Medicine at Dartmouth, New Hampshire, writing in PLOS ONE, presented evidence that the characteristic withdrawal symptoms displayed by addiction pot smokers are in fact strong enough to be considered clinically significant.
(For more on the marijuana withdrawal profile, see HERE, and HERE. For a bibliography of relevant journal articles, go HERE).

But how does one go about determining if withdrawal reactions rise to the level of clinical significance? The researchers wanted to know whether functional impairment reported during abstinence was clinically significant, whether it correlated with severity of addiction, and whether it was predictive of relapse. 46 survey volunteers who were not seeking any formal treatment for marijuana addiction were recruited in Sydney, Australia. Users ranged in age from 18 to 57, with an average age of 30. After a one-week baseline phase, the participants underwent two weeks of monitored abstinence. Using a “Severity of Dependence Scale” (SDS) to measure variability in functional impairment, the researchers compared a high SDS subgroup to a low SDS subgroup in an effort to tease out whether functional impairments in high SDS participants were predictive of relapse. The researchers noted that earlier work had established that the symptoms most likely to cause impairment to normal daily functioning were: Trouble getting to sleep, angry outbursts, cravings, loss of appetite, feeling easily irritated, and nightmares or strange dreams.” The investigators broke these symptoms into two groups: “somatic” and “negative affect” variables.

The researchers then examined self-reports about the impact of cannabis withdrawal on normal daily activities.  While the common yardstick for withdrawal is typically taken to be intensity of cravings, the authors argue that this reliance on craving “may mask the extent to which symptoms led to functional impairment, as those who maintained abstinence may still have experienced clinically significant negative consequences from cannabis withdrawal (e.g. relationship or work problems resulting from the withdrawal syndrome.”)

As might have been expected, higher levels of cannabis dependence were associated with greater functional impairment. And while the average level of functional impairment caused by cannabis is “mild for most users, it appears comparable with tobacco withdrawal which is of well established clinical significance.”

And certain symptoms were, in fact, correlative: “Increased somatic withdrawal symptoms are predictive of relapse, and…. increased physical tension is a significant predictor of relapse.”

 Physical distress, a “somatic” variable, mattered more, in terms of relapse, than the amount of marijuana smoked, or any other symptom on the roster of functional impairments—including mood and other negative affect variables.

“In conclusion,” the investigators write, “cannabis withdrawal is clinically significant because it is associated with elevated functional impairment to normal daily activities, and the more severe the withdrawal is, the more severe the functional impairment is. Elevated functional impairment from a cluster of cannabis withdrawal symptoms is associated with relapse in more severely dependent users.”

Furthermore: “Targeting the withdrawal symptoms that contribute most to functional impairment during a quit attempt might be a useful treatment approach (e.g. stress management techniques to relieve physical tension and possible pharmacological interventions for alleviating the physical aspects of withdrawal such as loss of appetite and sleep dysregulation.)”

As with most studies, there are limitations. As noted, the participants were not in a formal cessation program. And while urine tests were used, there was no external corroboration of the self reports.

Allsop, D., Copeland, J., Norberg, M., Fu, S., Molnar, A., Lewis, J., & Budney, A. (2012). Quantifying the Clinical Significance of Cannabis Withdrawal PLoS ONE, 7 (9) DOI: 10.1371/journal.pone.0044864

Graphics Credit: http://www.addictionsearch.com/

A Drug For Marijuana Withdrawal?

Researchers get good results with gabapentin.

Marijuana, as researchers and pundits never tire of pointing out, is the most widely used illegal drug in the world, by a serious margin. And while the argument still rages, for some years now drug researchers have been migrating to the camp that sees marijuana as an addictive drug for a minority of people who exhibit a propensity for addiction. The scientific literature supporting the contention of marijuana as addictive for some users is robust and growing, as is the body of anecdotal evidence.  It’s also clear that in many countries, cultures, and subcultures, combining cannabis with tobacco is a common practice that increases health risks all around.

Ongoing work at the Scripps Research Institute’s Pearson Center for Alcoholism and Addiction Research in La Jolla, California, has focused in part on the lack of FDA-approved medical therapies for treating marijuana addiction. Barbara J. Mason and coworkers at Scripps have reported preliminary success in a 12-week, double-blind, placebo-controlled pilot study with 50 treatment-seeking volunteers, using the anti-seizure drug gabapentin. Gabapentin, sold as Neurontin, pops up as a possible treatment for various forms of pain and anxiety, and sharp-eyed readers will recall that gabapentin was one of the ingredients in the now-defunct addiction drug Prometa.

Marijuana addiction numbers are hard to come by, and often inflated, since many small-time pot offenders end up in mandatory treatment programs, where they tend to be classified as marijuana addicts, whether or not that is objectively the case. Nonetheless, there are plenty of people seeking treatment on their own for cannabis dependence. For people strongly addicted to pot, the problems are very real, and withdrawal and abstinence pose serious challenges. People for whom marijuana poses no addictive threat should bear this in mind, the way casual drinkers bear in mind the existence of alcoholism in others.

The study, published recently in Neuropsychopharmacology, says that “activation of brain stress circuitry caused by chronic heavy marijuana use” can lead to withdrawal symptoms that persist “for weeks or even months, as in the case of marijuana craving and sleep disturbances.” A variety of existing medications have been tested in recent years, including buspirone, an anti-anxiety medication; Serzone, an antidepressant; and Wellbutrin, an antidepressant commonly used for smoking cessation. None of these treatments has shown any effect on cannabis use or withdrawal, according to Mason.

Gabapentin, as the name suggests, was modeled after the neurotransmitter GABA, and works via a transporter protein to raise GABA levels. Effective only for partial-onset seizures, common side effects include drowsiness, dizziness, and possible weight gain. It is a popular anti-epileptic drug, because it is relatively safe, with a low side-effect profile, compared to many of the medications in its class. For the same reasons, it is a common treatment for neuropathic pain. In addition to neuralgia, it has found some use as a migraine preventative.

Gabapentin normalizes GABA activation caused by corticotrophin-releasing factor, or CRF. CRF is a major player in the brain’s stress responses. As it turns out, withdrawal from both cannabis and alcohol ramp up anxiety levels by increasing CRF release in the amygdala, animal studies have shown. “Gabapentin had a significant effect in decreasing marijuana use over the course of treatment, relative to placebo,” the authors report. In addition, gabapentin produced “significant reductions in both the acute symptoms of withdrawal as well as in the more commonly persistent symptoms involving mood, craving, and sleep.”

As a bonus, the researchers discovered that “overall improvement in performance across cognitive measures was significantly greater for gabapentin-treated subjects compared with those receiving placebo.” Gabapentin was associated with improvement in “tasks related to neurocognitive executive functioning”—things like attention, concentration, visual-motor functioning, and inhibition. Counseling alone, represented by the placebo group, “resulted in less effective treatment of cannabis use and withdrawal, and no improvement in executive function.”

As in the case of Chantix for cigarette cessation, a treatment, which now requires additional caveats about possible suicidal ideation, researchers looking for a treatment for drug withdrawal, must weigh the benefits of pharmacological treatment against the possible side effects of the treatment itself. Does gabapentin for marijuana withdrawal pass the “Do No Harm” test? According to Mason, it does. “Gabapentin was well tolerated and without significant side effects” in the admittedly small trial study. The two groups did not differ in the number of adverse medical events reported in the first two weeks, when dropout rates due to side effects are highest in these kinds of studies. The investigators were not relying solely on self-reporting, either. They used urine drug screens, and verified that only 3% of the study sample tested positive for other drugs.

In short, the authors report that gabapentin reduced cannabis use and eased withdrawal with an acceptable safety profile and no signs of dependence. Gabapentin, the authors conclude, “may offer the most promising treatment for cannabis withdrawal and dependence studied to date.” Further clinical research is needed, of course, but the positive results of this proof-of-concept study should make funding a bit easier.

Mason, B., Crean, R., Goodell, V., Light, J., Quello, S., Shadan, F., Buffkins, K., Kyle, M., Adusumalli, M., Begovic, A., & Rao, S. (2012). A Proof-of-Concept Randomized Controlled Study of Gabapentin: Effects on Cannabis Use, Withdrawal and Executive Function Deficits in Cannabis-Dependent Adults Neuropsychopharmacology DOI: 10.1038/npp.2012.14

Photo Credit: http://pep3799.hubpages.com/