Potential Pharmacotherapies for Cannabis Dependence

Introduction

Cannabis, which comprises Δ ⁹ -tetrahydrocannabinol-containing products including marijuana and hashish, is the most widely used illicit drug in the world, with 183 million people reporting annual use in 2015. During 2015, in the United States alone, an estimated 22.2 million (8.3%) individuals report current marijuana use, defined as use within the past 30 days. Most users of cannabis consume the drug infrequently and without apparent negative consequences. There is, however, a small proportion of users who experience problems related to frequent cannabis use. It has been estimated that the cumulative probability of transitioning from use to dependence is 8.9% for cannabis users. Although this number is low compared with dependence rates for nicotine users (67.5% of tobacco users will become dependent), rates of cannabis dependence in several countries have increased substantially over the past decade as well as the number of individuals seeking treatment for cannabis-related problems ^{. ,} The terms “dependence” and “dependent” encompass the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) and the 10th revision of the International Statistical Classification of Diseases and Related Health Problems .

Although the total number of cannabis-dependent individuals who seek treatment is higher than the number of individuals who seek treatment for other illicit drugs, the relative proportion of those seeking treatment for cannabis dependence is low. For example, in the United States, the percentage of regular drug users who received treatment for a cannabis use disorder (includes cannabis abuse and dependence) in 2015 was around 5%, whereas this number was nearly 20% for cocaine users. Several possible explanations for the relatively low percentage of cannabis treatment seekers include the fact that many individuals perceive cannabis as a relatively innocuous drug. However, several investigators have reported that heavy, daily cannabis use is associated with an abstinence syndrome upon cessation of the drug (for review, see Budney ). Although cannabis withdrawal is not life-threatening, the accompanying symptoms such as irritability, anxiety, sleep disruptions, aches, and pains can be quite unpleasant. In addition, many individuals seeking treatment for cannabis dependence reported that these symptoms made it more difficult to maintain abstinence.

In addition, heavy cannabis use has been reported to be associated with poor cognitive performance. For example, Bolla and colleagues reported that heavy use of cannabis was associated with poorer cognitive performance on a wide range of tasks (e.g., memory and executive functioning) and that decreased performance persisted as long as 28 days of abstinence. Lifetime exposure to cannabis alone higher than 7 joint-years is also possibly associated with pulmonary dysfunction. The concept of joint-years indicates the cumulative dose of cannabis ingested in lifetime, being, for example, in the case of 7 joint-years either one joint every day during 7 years or seven joints every day during 1 year. Regarding the controverted relationship between cannabis and psychosis, Ksir and colleagues published a recent review. In their study, they concluded that both early use of cannabis and heavy use of cannabis were more likely in individuals with a vulnerability to a variety of problems, such as early or heavy use of cigarettes or alcohol, use of other illicit drugs, and poor school performance. In some individuals, the same vulnerability also resulted in increased risk for psychosis or some other mental disorder.

Some investigators have speculated that the low percentage of individuals seeking treatment for cannabis dependence may be related to the fact that there are relatively few specific treatments for cannabis dependence, although this issue does not appear to deter treatment-seeking cocaine abusers. Regular cannabis users may also be reluctant to participate in treatment programs dominated by alcohol-, cocaine-, and opioid-dependent individuals. Preference to quit without treatment and fear of stigma seem to be among the main barriers to seeking treatment. There are data indicating that some cannabis dependence–specific therapies are successful in decreasing drug use and many associated negative consequences. Other data, however, show that cannabis-dependent individuals exhibit high rates of relapse, similar to those found with other substances of abuse. To date, the majority of treatment studies have investigated behavioral/psychosocial therapies. The development of pharmacotherapy presents another option that would be available to cannabis-dependent individuals who have a high relapse rate. Pharmacotherapies may be used alone, in combination with behavioral/psychosocial therapies, or in a staged manner following inadequate response to behavioral/psychosocial therapies. In general, the problem in treating substance-dependent individuals has been less that of treating withdrawal and more of preventing relapse. However, treating withdrawal symptoms continues to be an important first step in eventual success and one that clinicians often need to begin this therapeutic endeavor. The treatment of cannabis dependence in this regard is similar to efforts underway for decades for opioids, cocaine, and alcohol dependence.

Since the original review in 2005, there have been several reviews addressing pharmacotherapies for cannabis dependence. This chapter incorporates most recent reviews and extends them by including the most recent studies. The chapter reviews findings from recent research on cannabinoids (a group of compounds related to Δ ⁹ -tetrahydrocannabinol, the primary psychopharmacologically active constituent of marijuana smoke) that may be relevant for the development of pharmacotherapies for cannabis dependence. Data from studies that assessed the ability of medications to attenuate cannabinoid-related abstinence symptoms in laboratory animals and in humans will be reviewed. In addition, results from studies that have investigated the effects of pharmacological agents on response to cannabinoids are reviewed because these data may prove useful in informing the development of cannabis relapse prevention medications. The review begins with a brief overview of the different phases of the dependence cycle that cannabis pharmacotherapies might target as well as cannabinoid relevant neuropharmacology.

Detoxification and Relapse Prevention or Maintenance Phase

Medications are typically initiated at two different phases of the dependence cycle: during detoxification and prevention of relapse. Detoxification is usually an initial and immediate goal during which medications are administered to assuage unpleasant abstinence symptoms that may appear following abrupt cessation of drug use, for example, the administration of a benzodiazepine during alcohol withdrawal. Medications used in the detoxification phase are also sometimes used in the relapse prevention or maintenance phase, for example, nicotine replacement medications. Thus the distinction between a detoxification medication and a relapse prevention medication is sometimes less clear. It is also important for us to note that although we recognize that the goal of this chapter is to review pharmacotherapies that may have some utility in decreasing cannabis withdrawal symptoms, we want to be careful not to overstate the problem of cannabis withdrawal because such symptoms may play a limited role in the addictive process when compared with other important psychosocial factors.

Maintenance medications can be viewed as a longer-term strategy used to help the dependent individual avoid relapsing to the abused drug. There are at least three major maintenance strategies. First, agonist or substitution therapy is used to induce cross-tolerance to the abused drug. For example, methadone (a long-acting μ-opioid agonist) and nicotine replacement medications have been used for opioid dependence and tobacco dependence, respectively, as agonist maintenance treatments to prevent relapse and cravings in individuals attempting to maintain abstinence. Agonist maintenance agents typically have safer routes of administration and diminished psychoactive effects relative to the abused drug. Second, antagonist therapy is used to produce extinction by preventing the user from experiencing the reinforcing effects of the abused drug. For example, the naltrexone blocks opioid mu receptors and agonists’ associated effects and is therefore used as an antagonist therapy for opioid dependence. Finally, punishment therapy produces an aversive reaction following ingestion of the abused drug. For example, disulfiram (Antabuse) is used in the treatment of alcohol dependence. Disulfiram inhibits aldehyde dehydrogenase, a major enzyme involved in alcohol metabolism, thereby preventing the complete breakdown of alcohol, and the resultant accumulation of aldehyde produces unpleasant symptoms including headache, vomiting, and breathing difficulties.