Cocaine abuse treatment strategies


Strategies devised to treat cocaine abuse have existed since its intractable lure for some first became obvious almost a century ago. During this period no generally accepted or successful treatment has emerged. Chronic cocaine abuse has been assumed to cause no physiologic withdrawal state on discontinuation because of insufficient evidence for an abstinence syndrome of major physiological changes like the classic sort characterizing sedative or opiate withdrawal (). Cocaine abuse has thus been assumed to be a “psychological dependence” rather than one involving neurophysiological adaptations, and currently used treatments consist of psychological strategies aimed at modifying addictive behaviors. Issues related to current psychological strategies will be discussed first, followed by a summary of evidence indicating cocaine abuse may cause neuroadaptation. The latter includes a review of pharmacological strategies, aimed at reversal of such adaptation, which may hold future potential as adjuncts in cocaine abuse treatment.

Cocaine abuse treatment strategies: Current treatments

Potential New Directions in Treatment

Despite the past assumption that cocaine abuse is a “psychological addiction,” it is plausible that chronic cocaine abuse could lead to neurophysiologic adaptations which require more than psychological intervention. Cocaine exerts its effects neurochemically. The nervous system’s usual response to persistent neurochemicat perturbation is compensatory adaptation. It is illogical to assume that this does not occur or is unimportant in cocaine abuse. This does not rnean a classic abstinence syndrome and tolerance uniformly occur; rather chronic high dose use may generate sustained neurophysiological modification whose clinical expression is psychological.

Neuroadaptation following extensive chronic cocaine use is suggested by presence of persistent post-cocaine symptomatology () evidence that enduring neurophysiologic changes occur in animals following chronic cocaine administration () preliminary data indicating neuroendocrine abnormalities may be associated with cocaine ”withdrawal”() and reports that pharmacologic interventions () may facilitate cocaine abstinence. Pharmacologic interventions in cocaine abuse could thus be useful, but pharmacotherapy aimed at correcting presumably cocaine-altered neurophysiologic states has not been systematically examined.

The following review outlines evidence indicating that desipramine, lithium and methylphenidate could each facilitate cocaine abstinence, by different mechanisms. Although these are the same treatments discussed earlier in relationship to diagnosis, we wish to make clear that the following discussion pertains to the possible use of these agents as general treatments, irrespective of distinctions in symptomatology. Some points at which “diagnosis” may interact with general treatments will however, be noted.

Tricyclic Antidepressants (TCAs)

Animal research on neurotransmitter and receptor changes following chronic cocaine suggests long-term effects possibly reversible by treatment with TCAs. Studies of receptor changes in animals, measured by radioligand binding, report increased beta-adrenergic (), alpha-adrenergic (), and dopaminergic () receptor binding. Receptor supersensitivity (beta-adrenergic or dopaminergic) could be a neurochemical substrate for post-cocaine dysphoria or craving.

One study () also shows some human cocaine abusers have elevated plasma growth hormone and decreased plasma prolactin, findings that are consistent with the adrenergic and dopaminergic receptor changes in animals. Beta-adrenergic supersensitivity has been hypothesized to be a cause of depressive illness, and beta-adrenergic subsensitivity, which can be induced by different types of antidepressant treatments may explain antidepressant effectiveness (). Dopaminergic receptor changes following antidepressant treatment () also are in the opposite direction from those occurring following chronic cocaine use, and could be even more important, since dopamine may mediate acute cocaine euphoria (), and craving or dysphoria after chronic cocaine could be based on adaptations within dopaminergic systems ().

Additional support comes from studies done on amphetamine. Evidence from acute experiments in humans (), observations of the post-use state () as well as animal behavioral (), electrophysiological (), and neurochemical studies () indicate that generalization to cocaine from amphetamine data is appropriate. Reports indicate that treatment with TCAs reverses chronic amphetamine-induced decreases in self-stimulation (), a possible model for stimulant craving and its treatment. TCAs also appear to have effects opposite to those of cocaine on urinary MHPG ().

These data lend neurochemical plausibility to the clinical observation that TCA therapy can be helpful in treating the cocaine abuser (). However, little systematic evaluation of TCA treatment of cocaine abusers has been done. Tennant and Rawson () reported anecdotal data that desipramine facilitated abstinence in 14 cocaine abusers, but their study was based on a rationale involving acute desipramine-induced decreases in noradrenalin reuptake rather than receptor changes, and consequently 11 of their subjects received desipramine less than 7 days. The other 3 subjects were not described. Also several methodologic shortcomings () and limited followup make the meaning of this report unclear. Gawin and Kleber () report prolonged desipramine treatment in 6 subjects, systematically evaluating cocaine use, craving, and psychosocial function. All 6 demonstrated prolonged abstinence (> 12 weeks) and craving decrease followed a delayed time course consistent with desipramine’s time course for neuroreceptor changes and its known clinical characteristics in depression. Unlike Tennant and Rawson’s () results, half of the patients continued cocaine use throughout the first week and until the third week of treatment. Two of the subjects had diagnoses of major depressive disorder, but the remainder did not, and displayed desipramine-associated craving decreases and abstinence-facilitating effects despite lack of neurovgetative symptoms and prior treatment failures. Although the above results are encouraging, the reports cited were both non-blind and uncontrolled. Further more rigorous studies with larger sample size are needed before any conclusions arc drawn regarding desipramine use in cocaine abuse treatment.

Lithium Carbonate

Lithium carbonate treatment has been advocated for stimulant abuse () based on lithium’s antagonism of multiple acute stimulant effects including euphoria. Lithium blocks behavioral (), electrophysiologic () and neurochemical () effects of acute cocaine and amphetamine. Case studies report blockade of amphetamine euphoria by lithium (), as does one doubleblind placebo-controlled study of 11 depressed patients (). Lithium had more variable results on amphetamine euphoria in 8 patients with personality disorders (). In several case studies () lithium attenuated cocaine-induced euphoria. Decreasing cocaine usage during the lithium treatment was also reported. Lithium did not block i.v. cocaine euphoria in an experiment done on 6 methadone-treated opiate addicts with significant cocaine abuse (). In the latter study (not a direct treatment evaluation) lithium administration was associated with decreases in cocaine abuse despite lack of euphoria-attenuating effects. Studies of other stimulants () report similar results. In both studies of stimulants reporting no lithium blockade () the agents were administered intravenously in relatively large boluses. Studies using other routes of administration do report blockade. Lithium effects may thus be competitively antagonized by large abrupt increases in stimulant blood levels. Since much street cocaine use is intranasal, the practical impact of this possibility on treatment is unclear and merits examination.

Overall, neurochemical evidence clearly indicates lithium has multiple acute effects which counteract those of cocaine. Clinical evidence further indicates that such properties may be useful in the treatment of stimulant abusers; however placebo-controlled studies do not exist. In the study by Gawin and Kleber () cited in the discussion of diagnosis, the responding cyclothymic subjects did not use cocaine to test euphoria-blocking effects, but the nonresponding patients reported cocaine euphoria was unchanged in intensity. Some suggestion of decreased duration of euphoria was noted, but this did not appear to be therapeutically useful.

Although the theoretical focus in lithium treatment of cocaine abuse has been on blockade, another potential mechanism of action exists. Lithium is reported to modulate fluctuations in functional receptor activity (). Lithium’s effectiveness in bipolar patients could be due to damping of abnormal oscillations of select neuroreceptor populations (). Lithium might reverse cocaine-induced neurophysiologic changes in a manner similar to that postulated for desipramine. Further, if cocaine causes receptor changes, bipolar or cyclothymic patients might be more sensitive to both such cocaine effects and to opposite lithium effects. This could explain any diagnostic specificity found in lithium treatment of cocaine abuse. In all, lithium’s efficacy, diagnostic specificity, and possible mechanisms of action in cocaine abuse treatment all require further study.

Methylphenidate (MPH)

There is experimental evidence logically supporting possible clinical usefulness of MPH as a general treatment for severe cocaine abuse. Stimulant “high” in humans appears to be related to both plasma stimulant level prior to an additive increment and to the characteristics of plasma level changes, rather than to simple absolute plasma level (). Increases of plasma stimulant level in subjects with preexistent stimulant concentrations may correspond to less euphoric effect than identical increases in plasma level in subjects with a stimulant-free baseline. Similarly, increases occurring slowly may correspond to less subjective euphoria than increases occurring more rapidly. Self-administration data in animals also support this phenomenon () which has been called “acute tolerance.”

Since methylphenidate produces euphoria indistinguishable from amphetamine () and, presumably, cocaine, MPH could produce consistent tolerance-sustaining effects. Through such an acute “cross tolerance,” a given dose of cocaine might be less euphorigenic and have less abuse liability.

This is similar to high dose methadone maintenance causing Longer term tolerance to opiates, thereby reducing heroin euphoria and abuse. Unlike methadone, however, MPH tolerance would end sooner, requiring more frequent administration, due to its shorter half life.

Although MPH is an abusable euphorigen, it has advantages parallel to methadone administration. The advantages of medical dispensation include controlled dosage, decreased legal risk, economic stabilization, and a breaking of “street” associations and secondary abuse reinforcers. In preliminary use, cocaine abusers considered MPH far less desirable than cocaine, decreasing compliance. Attenuated cocaine effects and decreased abuse were reported when compliance occurred () in three pilot non-ADD patients treated by the authors; but abstinence from cocaine was not sustained, and it is unclear whether methylphenidate has practical utility as a general treatment. In all, methylphenidate may be similar to lithium, with treatment response in the few reports available occurring only in one diagnostic subgroup (ADD-residual type) and not in other cocaine abusers.

The potential pharmacotherapies described simply represent the treatment rationales available given the state of current theory and research. Much is unknown, and other possibilities also exist.


Single focus approaches are generally ineffective in drug abuse treatment. A number of approaches to cocaine abuse are in current use and a number of issues require resolution. Preliminary data on pharmacologic treatments are beginning to appear and pharmacologic adjuncts may show promise in the future. However, it currently appears no more likely that any unimodal approach to cocaine abuse treatment will arise than it has for opiate abusers. Integration of various approaches based on the needs of the patients seems indicated instead. A possible schema illustrating this and utilizing the impressions and preliminary studies reviewed here is presented in figure I. Before any such schema is used in clinical practice, however, detailed comprehensive research will be needed.


Selections from the book: “Cocaine: Pharmacology, Effects, and Treatment of Abuse”. John Grabowski, Ph.D., ed. Content ranges from an introductory overview through neuropharmacology, pharmacology, animal and human behavioral pharmacology, patterns of use in the natural environment of cocaine users, treatment, through commentary on societal perceptions of use. National Institute on Drug Abuse Research Monograph 50, 1984.