Jeffery N. Wilkins, MD, FASAM, DFAPA, Mark Hrymoc, MD, and David A. Gorelick, MD, PhD
CHAPTER OUTLINE
■ MARIJUANA
■ ANABOLIC STEROIDS
■ PHENCYCLIDINE
■ INHALANTS
■ NICOTINE WITH OTHER DRUGS
■ OPIOIDS WITH OTHER DRUGS
■ HALLUCINOGENS
■ CONCLUSIONS
Pharmacologic treatment of individuals with addiction can follow at least five different strategies (1). Patients can be given medications with pharmacologic actions similar to those of the target drug (e.g., cross-tolerant agonists), with the goal of substitution (as when methadone is employed for opioid dependence or nicotine for tobacco dependence). A second approach involves use of antagonists or receptor blockers, with the goal of preventing or blunting the action of the target drug (as when the opiate receptor antagonist naltrexone is used in the treatment of opioid dependence). A third approach uses medications that alter neural mechanisms mediating reinforcement or drug craving (other than by acting at the same drug receptor). A fourth approach is pharmacokinetic (i.e., to reduce drug concentration at its site of action by increasing drug metabolism or decreasing its crossing of the blood–brain barrier) (1). A fifth approach is to use medication to produce a conditioned aversion to the drug, with the goal of reducing or reversing the reinforcing qualities of the target drug (such as disulfiram in the treatment of alcohol use disorders).
This chapter focuses on pharmacologic therapies for single substances, such as marijuana, anabolic steroids, and phencyclidine (PCP), including limited discussion regarding ketamine, hallucinogens (such as lysergic acid diethylamide [LSD], 3,4-methylenedioxymethamphetamine [MDMA, “ecstasy”], N,N-dimethyltryptamine [DMT], and mescaline), and inhalants (volatile substances, including solvents), as well as the following mixed addictions—nicotine with other drugs (alcohol, opioids, cocaine), opioids with other drugs (alcohol, cocaine), and cocaine with PCP. Few of the potential treatment strategies listed here have been tried with these drugs. In almost all cases, the pharmacologic treatments described are experimental or unproven, in that they lack any rigorous clinical data (as from controlled clinical trials) to support their use. Therefore, in most cases, the mainstay of treatment is based on psychosocial modalities (see Section 8).
MARIJUANA
There is currently no recognized or proven role for pharmacotherapy in the short- or long-term treatment of marijuana abuse or dependence, and no medication is approved for this indication by any national regulatory body (2). However, two medications showed efficacy in recent controlled clinical trials. The anticonvulsant gabapentin (1,200 mg daily for 12 weeks) and the glutamate modulator N-acetylcysteine (1,200 mg bid for 8 weeks) significantly reduced marijuana use in marijuana-dependent adults (3) and adolescents (4), respectively. The anxiolytic buspirone (up to 60 mg daily for 12 weeks) showed some efficacy in the subgroup of marijuana-dependent adults who completed the controlled clinical trial (5). Several medications failed to show efficacy in controlled or open-label clinical trials (2). For example, synthetic Δ9-tetrahydrocannabinol (THC, chief psychoactive constituent of marijuana), at doses of 20 mg bid for 8 weeks, significantly reduced marijuana withdrawal symptoms but had no effect on marijuana use in a controlled clinical trial with marijuana-dependent adults (6).
Current research in cannabinoid pharmacology is opening new opportunities for pharmacologic treatment (7) (see also Section 2, Chapter 13). In particular, the development of specific antagonists for the cannabinoid CB1 receptor (which mediates the psychoactive effects of marijuana) could lead to a pharmacologic treatment for marijuana dependence, using the strategy of receptor blockade. The CB1 receptor antagonist/inverse agonist rimonabant (developed for the treatment of obesity and the metabolic syndrome, but no larger marketed because of adverse psychiatric effects) (8) blocks the physiologic and psychological effects of marijuana in animals and humans (9). CB1 receptor antagonists theoretically might be used to treat marijuana dependence in the way that naltrexone, a muopioid receptor antagonist, is used to treat opioid dependence. On a practical level, such clinical use awaits the development of compounds that minimize adverse psychiatric effects.
ANABOLIC STEROIDS
There is no established medication for the treatment of anabolic steroid misuse (10). Two pharmacologic treatment approaches have been suggested: hormonal treatments to reverse hypothalamic–pituitary–gonadal dysfunction caused by use of steroids and medications to relieve specific psychiatric symptoms associated with steroid withdrawal. Neither approach has been systematically evaluated for efficacy or safety.
The first approach could be implemented with tapering doses of a long-acting steroid such as testosterone enanthate (e.g., 200 to 400 mg intramuscularly initially, tapering by 50 to 100 mg every 1 to 2 weeks). This approach is analogous to treating heroin withdrawal with a long-acting opiate such as methadone. Other possible treatments include human chorionic gonadotropin or synthetic forms of luteinizing hormone–releasing hormone to stimulate testosterone production, or antiestrogenic agents such as clomiphene (e.g., 50 mg twice per day for 10 to 14 days) to reduce the elevated estradiol levels associated with anabolic steroid use.
The second approach uses standard psychotropic medications to target the depression, irritability, and aggression often associated with anabolic steroid use, although these symptoms often resolve without medication. The selective serotonin reuptake inhibitor (SSRI) antidepressants are most often used. The use of tricyclic antidepressants is discouraged by some on theoretical grounds because their cardiovascular and anticholinergic effects might exacerbate the cardiotoxicity and urinary retention (because of prostatic hypertrophy) associated with anabolic steroid use. Low-dose neuroleptics (chlorpromazine equivalent doses of about 200 mg daily) are reported effective for managing steroid-induced psychosis, hostility, and agitation.
PHENCYCLIDINE
PCP is a synthetic dissociative anesthetic that gained popularity as an abused drug in the 1960s and no longer is legally available in the United States (see Chapter 15). A synthetic analogue, ketamine, still is used clinically and marketed legally in the United States, although it also is subject to misuse (11). There is little systematic experience with pharmacologic treatment of PCP or ketamine misuse (12).
Almost all published studies that address PCP addiction involve psychosocial treatment approaches, which usually have poor long-term success rates (13–15). Both the tricyclic antidepressant desipramine and the anxiolytic buspirone have significantly improved psychological symptoms such as depression in small outpatient controlled clinical trials, but neither medication significantly reduced PCP use when compared with a double-blind placebo (16,17). A monoclonal anti-PCP antibody is in preclinical development (1).
PCP in Combination with Cocaine or Marijuana
PCP often is smoked with cocaine (“space basing”) or marijuana (“primos”). There is very little literature on the treatment of these dual addictions, and no clinical trial has shown any medication to be effective. The antidepressant desipramine has been used because of its possible effectiveness in the treatment of separate PCP or cocaine addiction. In a double-blind study of 20 chronic PCP/cocaine users, desipramine (200 mg/d) significantly reduced symptoms associated with withdrawal but had less effect on actual drug use (18).
INHALANTS
Inhalants are a heterogeneous group of volatile abused substances that includes adhesives, aerosols, solvents, anesthetics (including nitrous oxide), gasoline, cleaning agents, and nitrites (19) (see Section 2, Chapter 16). Because these agents usually are marketed legally for commercial purposes, they generally are inexpensive and readily available. Many inhalant abusers entering treatment have co-occurring psychiatric and addictive disorders, typically involving alcohol and marijuana, which can complicate treatment. The mainstay of treatment is psychosocial, including techniques such as cognitive–behavioral therapy, multisystem and family therapy, 12-step facilitation, and motivational enhancement, although treatment outcome tends to be poor (19,20). There is little published experience with pharmacologic treatment and few placebo-controlled clinical trials (19,20). Case reports suggest possible benefit from buspirone, lamotrigine, risperidone, haloperidol, or carbamazepine. Pharmacologic treatment of associated or comorbid psychiatric conditions may be effective (e.g., antipsychotics for psychosis).
NICOTINE WITH OTHER DRUGS
There is substantial comorbidity between nicotine dependence and other substance use disorders. Among US adults with current nicotine dependence, 8.2% have a current (nonalcohol) drug use disorder (21), an odds ratio of 3.2 for having a drug use disorder compared with those without nicotine dependence, after adjusting for sociodemographic characteristics and other psychiatric disorders (22). Conversely, 52.4% of those with a current drug use disorder are nicotine dependent. Comorbidity rates may exceed 70% among patients in treatment (23). Tobacco-related diseases are a substantial cause of morbidity and mortality among drug users, and many drug abuse treatment patients are interested in smoking cessation (24). Most studies find that smoking cessation treatment does not adversely influence the outcome of drug abuse treatment (25,26) and that patients with substance use disorders are interested in (27) and can respond well to smoking cessation treatment (28). Therefore, it makes good clinical sense to screen for and treat nicotine dependence in this population. Limited evidence suggests that polydrug abusers (e.g., alcohol + stimulants + cannabis) may respond better to the combination of nicotine replacement + bupropion than to either treatment alone (29).
Nicotine and Alcohol
Almost 3% of the US adult population has current nicotine dependence and an alcohol use disorder (30), a comorbidity rate that may be influenced by neurobiologic and neurocognitive effects of concurrent tobacco and alcohol use (31). Among adults with nicotine dependence, 22.8% have an alcohol use disorder (21). The odds ratio is 4.4 for an alcohol use disorder among those with nicotine dependence compared with those without nicotine dependence. Conversely, among adults with an alcohol use disorder, 34.5% have nicotine dependence (21), an odds ratio of 2.7 for having nicotine dependence compared with those without an alcohol use disorder, after controlling for sociodemographic characteristics and other psychiatric disorders (32). Thus, it is not surprising that individuals with alcohol dependence smoke more heavily than do persons who are not alcohol dependent (21,33).
Tobacco-related diseases are a greater cause of morbidity and mortality in patients with alcohol use disorders than are alcohol-related medical conditions (26,34), highlighting the importance of smoking cessation treatment for this population. Cigarette smokers with a current alcohol use disorder (but not those in remission) tend to have more severe nicotine dependence and so may need more intensive treatment, including higher doses of medication (33). Most, but not all, studies suggest that nicotine and alcohol dependence can be successfully treated at the same time without adversely affecting outcome (26,35).
Naltrexone is an FDA-approved treatment for both alcohol and opioid dependence, with some evidence for efficacy in treatment of nicotine dependence (36). When administered either alone or in combination with nicotine patches for smoking cessation, efficacy in individuals with concurrent heavy alcohol ingestion or alcohol dependence is inconsistent (37). In one recent controlled clinical trial, naltrexone (50 mg daily) reduced both heavy drinking and smoking in nondependent social drinkers (38).
There is limited evidence from controlled clinical trials that nicotine replacement therapy (e.g., nicotine patch) may be more effective than is naltrexone in reducing cigarette smoking by alcohol-dependent patients (35). Higher-than-usual doses of both medications may be needed to achieve efficacy. More research is needed to determine whether adding nicotine replacement therapy to a higher dose of naltrexone in alcohol-dependent smokers will significantly reduce smoking.
The anticonvulsant topiramate (up to 300 mg/d) reduced alcohol use and cigarette smoking in a controlled clinical trial (39). The nicotinic receptor partial agonist varenicline (1 mg bid), which is FDA approved for smoking cessation, significantly increased smoking abstinence in a controlled clinical trial with alcohol-dependent smokers (40).
Nicotine and Opioids
More than three-fourths of individuals with opioid dependence smoke cigarettes (23,25,41), and the prevalence of tobacco smoking in methadone maintenance treatment (MMT) patients ranges from 85% to 98% (42). The dose of methadone is positively associated with smoking rates in a dose-dependent manner (43); smoking satisfaction is also rated higher in those receiving a higher MMT dose (44). Opioid drugs themselves, including methadone, acutely increase cigarette smoking (23,41). Limited evidence suggests that nicotine replacement therapy, with or without bupropion, can be effective for smoking cessation in patients on methadone maintenance (45–47). Treatment outcomes are improved with concurrent psychosocial treatment (e.g., cognitive therapy or contingency management [CM]).
Nicotine and Cocaine
Cigarette smoking is associated with poorer short-term outcome of outpatient treatment for cocaine dependence but not of concurrent opioid dependence (48), suggesting the importance of offering smoking cessation treatment to cocaine-dependent patients.
OPIOIDS WITH OTHER DRUGS
Opioids and Alcohol
Heavy drinking or alcohol abuse/dependence occurs in one-third or more of individuals with opioid dependence, including those in MMT, and is associated with poor treatment outcome (49–52). Conversely, cessation of illicit opioid use and retention in MMT are positively correlated with a reduction in concurrent alcohol and/or cocaine misuse and the absence of the psychosocial complications associated with such misuse (53). Methadone dose and alcohol use are not strongly associated (50,54). Naltrexone, a muopioid receptor antagonist marketed for the treatment of both opioid and alcohol use disorders (55) and which is available in a long-acting depot formulation to improve treatment adherence, seems a plausible treatment option (37) for patients not on opioid agonist therapies but was associated with worsening depression in one case report (56). Buprenorphine, a partial muopioid receptor agonist marketed for the treatment of opioid use disorder, reduces alcohol intake in animal studies (57) but has not yet been evaluated for this in clinical trials. Disulfiram, at typical doses used to treat alcohol dependence, can be effective in reducing alcohol intake among patients in methadone maintenance (58). The careful medication monitoring and incentives for compliance that are possible in a methadone maintenance program make disulfiram treatment more effective than it is in other treatment settings. Other medications being studied for the treatment of dually dependent patients include acamprosate (marketed for the treatment of alcohol use disorder) and memantine (an N-methyl-D-Aspartate [NMDA] receptor antagonist marketed for the treatment of dementia) (37).
Opioids and Cocaine
Cocaine use is common among opioid-dependent individuals and is associated with greater opioid use, even among those in MMT (59–61). A popular pattern involves simultaneous use of the two drugs (“speed balling”) (61), which is said to provide a qualitatively better subjective experience (“high”) than does either drug alone (62). For patients already in methadone maintenance, increasing the methadone dose (usually to >60 mg/d) can reduce both opioid and cocaine use (37,63). A 2009 meta-analysis of 37 studies involving 3,029 patients on methadone maintenance demonstrated that high doses of methadone maintenance were more efficacious than were lower ones in the achievement of sustained heroin abstinence (RR = 2.24 [1.54, 3.24], p < 0.0001) but had no effect on cocaine abstinence (64). At equivalent doses, methadone was more efficacious than was buprenorphine in promoting cocaine abstinence (RR = 1.63 [1.20, 2.22], p = .002) and heroin abstinence (RR = 1.39 [1.00, 1.93], p = 0.05) (64). The meta-analysis did not demonstrate a direct relationship between high doses of methadone and decreased cocaine use. The apparent discrepancy between this result and that of studies demonstrating decreased cocaine use in patients receiving higher doses of methadone maintenance is likely due to a two-step process whereby high-dose methadone maintenance first reduces heroin use, as shown in the meta-analysis, and this subsequently leads to decreased cocaine use. This review also describes improvements in sustained cocaine abstinence when CM targeting cocaine abstinence is added (RR = 3.11 [1.80, 5.35], p < 0.0001); a similar potentiation occurs with supplementation with indirect dopaminergic agonists (RR = 1.44 [1.05, 1.98], p = 0.03) (64). Whereas CM targeting cocaine abstinence is effective across ethnic groups (65) and its time course defined (66), the literature for adjunctive medication to treat cocaine abuse in methadone-maintained patients is less clear and often negative.
The Consensus Panel for Substance Abuse and Mental Health Services Administration (SAMHSA)’s Center for Substance Abuse Treatment TIP 10 (Assessment and Treatment of Cocaine-Abusing Methadone-Maintained Patients) (67) identified ten promising adjunctive agents to potentially treat cocaine abuse in patients on methadone maintenance: dopamine (DA) agonists (amantadine and bromocriptine); antidepressants (bupropion, desipramine, and fluoxetine); mazindol, a catecholamine neuronal reuptake blocker; selegiline, a selective irreversible MAO-B inhibitor; and opioid agonists/antagonists (buprenorphine, naltrexone).
Including the medications listed above, at least 15 agents have been studied as adjunctive interventions to opioid maintenance treatment (OMT). Pharmacologic modulation of the DA system reduced cocaine use in some studies (64), including bupropion (68,69), dexamphetamine (70), disulfiram (71,72), mazindol (73), and DA antagonists such as risperidone (70). Two of five studies also demonstrated sustained cocaine abstinence from indirect noradrenergic agonism with desipramine (74). Recently, varenicline was administered to 31 methadone-maintained patients who were cocaine abusers and cigarette smokers: Smoking was significantly reduced, but there was no impact on cocaine use (75). In a second recent study, 145 methadone-maintained participants were randomized to receive either fluoxetine (60 mg/d, PO) or placebo alone or combined with a voucher incentive program contingent on abstinence from cocaine: The voucher program was effective on its own, but fluoxetine, either alone or added to the voucher program, did not reduce cocaine use (76). The results of this last study are consistent with a recent Cochrane Database Review that did not find sufficient power to support the use of DA agonists (amantadine, L-dopa/carbidopa, and bromocriptine) as treatments for cocaine abuse in patients not on OMT; the review results also did not support the combining of the DA agonist agents with established and more potent psychosocial interventions (77).
Buprenorphine is marketed as a parenteral and transdermal analgesic and for the treatment of opioid use disorder (as a sublingual tablet or film). High-dose buprenorphine (8 to 16 mg/d as sublingual liquid, equivalent to 16 to 32 mg/d as sublingual tablet) reduces both cocaine and opioid use in dually dependent patients (78), whereas lower doses do not (79,80). As noted above, methadone was superior to buprenorphine in reducing cocaine use when compared at equipotent doses (64).
Naltrexone has modest success in small pilot studies in reducing cocaine use in patients without opioid dependence (81,82) but has not been evaluated in patients addicted to both opioids and cocaine. A clinical trial (83) using injectable, sustained-release naltrexone preparation in heroin-dependent individuals found the percentage of urine samples negative for opioids, cocaine, and amphetamine varied significantly depending on the dose (84).
At this time, there are no Food and Drug Administration (FDA)–approved medications for the treatment of cocaine abuse in the presence or absence of OMT. Studies of cocaine abuse in OMT patients suggest the potential for dexamphetamine (70), disulfiram (71,72), and anticocaine vaccine (85) as adjunctive agents to OMT; buprenorphine (64,78) and naltrexone (81–84) are similarly under evaluation for the treatment of cocaine abuse in patients with opioid dependence.
HALLUCINOGENS
Hallucinogens are a varied group of plant-derived alkaloids and synthetic compounds that have in common the ability to produce sensory, perceptual, and cognitive changes without impairing attention or level of consciousness (i.e., with a clear sensorium) (86) (see Section 2, Chapter 14). They include compounds that influence serotonergic neurotransmission, such as LSD, psilocybin, and DMT and those that influence catecholaminergic neurotransmission (such as mescaline and amphetamine analogues like 3,4-methylenedioxy-N-methamphetamine [MDMA]).
At present, no pharmacologic treatment is available for the treatment of hallucinogen misuse (86–88). Several retrospective case reports suggest that long-term treatment with monoamine oxidase inhibitors (such as phenelzine) or SSRI antidepressants (fluoxetine, sertraline) can reduce the acute psychological effects of LSD, whereas treatment with tricyclic antidepressants (imipramine, desipramine) or lithium may enhance LSD effects (89).
Single doses of the SSRI antidepressant citalopram or the 5-HT2A/C receptor antagonist ketanserin attenuated many of the acute psychological effects of MDMA in human experimental studies (90,91), whereas a dose of the dopamine D2 receptor antagonist haloperidol attenuated only the mania-like mood effect (92). These findings suggest that medications affecting serotonergic neurotransmission are a promising area for development of pharmacologic treatments for hallucinogen abuse.
The mainstay of treatment remains psychosocial intervention, which can require residential treatment in patients with severe personality disorganization. Prolonged psychotic reactions occur chiefly in individuals who have preexisting psychiatric disorders; these can be difficult to distinguish from hallucinogen-induced precipitation or exacerbation of a preexisting psychotic disorder such as schizophrenia (93). Regardless of etiology, such psychotic reactions can require treatment with antipsychotic medication (87,92). Low doses of a high-potency neuroleptic have been recommended (such as 2 to 5 mg haloperidol) (92).
LSD use is associated with perceptual abnormalities, such as illusions, distortions, and hallucinations, persisting or recurring intermittently for long periods (up to years) after the last LSD use (hallucinogen persisting perception disorder in DSM-IV) (94–96). When these abnormalities occur after a period of normal perceptual functioning, they are termed flashbacks. Case reports suggest that sertraline, naltrexone, clonidine, or benzodiazepines can be helpful in the treatment of both persisting perceptual abnormalities and flashbacks, while antipsychotics (e.g., haloperidol, risperidone) and SSRIs have been reported to worsen the condition (92). These perceptual disorders can be associated with secondary depression or anxiety disorders such as panic and agoraphobia. In such cases, treatment with benzodiazepines or SSRI antidepressants may be helpful (87).
CONCLUSIONS
This chapter reviewed approaches to pharmacologic treatment of addiction to several individual drugs of abuse, including marijuana, anabolic steroids, PCP (and ketamine), inhalants, and hallucinogens, as well as to some common mixed addictions, including nicotine or opiates with each other, alcohol, and cocaine, and cocaine with PCP. In most cases, there is little or no published literature to guide the choice of pharmacologic treatment and no clinical trials to support the efficacy of any treatment.
Thus, the mainstay of treatment for marijuana, anabolic steroid, PCP, hallucinogen, or inhalant abuse is psychosocial interventions. The use of pharmacologic treatments remains a question for which the physician must rely almost exclusively on his or her own experience and judgment, with very little help from the medical or scientific literature. Future research may alter this situation and spur the development of effective new pharmacologic treatments.
ACKNOWLEDGMENTS
Dr. Wilkins is supported by the Lincy/Heyward-Moynihan Endowed Chair in Addiction Medicine, Cedars-Sinai Medical Center; Dr. Gorelick is supported by the Intramural Research Program, National Institutes of Health, and National Institute on Drug Abuse.
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