A Collaborative Initiative for Patients and Clinical Professionals

 

The Cocaine Conundrum & MMT

Stewart B. Leavitt, PhD, editor, Addiction Treatment Forum

"How does one deal with a patient, stabilized on 70 mg/day of methadone, who continues to use cocaine on a regular basis? Should we medically detox the person for failure to abstain from coke per clinic policy, or increase the methadone dose due to the depleting effects cocaine has on methadone? Can an increase in methadone dose automatically curtail cocaine use?" ­ A counselor at a New York methadone clinic.

 

 

Multifaceted Problem

Concurrent dependence on opioids and other substances of abuse (polysubstance abuse) is a frequent problem for MMT programs, as the counselor's questions above suggest. Unfortunately, according to the State Methadone Maintenance Treatment Guidelines from the Center for Substance Abuse Treatment, research in this area seems deficient and initial hopes that MMT would in itself reduce cocaine use have been abandoned.[1]

Of course, methadone treatment was a modality designed to only control the use of heroin and other opioids. So, developing effective interventions for opioid-dependent cocaine users ­ who might also have multiple psychological disabilities and social problems ­ has been difficult.

Also, research to date has been unclear as to which specific behavior interventions might be most effective for MMT patients who use cocaine.

In 1991, Condelli and associates presented a review of the significance and scope of cocaine use by patients in methadone programs.[2] Methadone patients using cocaine were largely grouped into the category of "polydrug users," and some MMT programs found that as few as 18 percent of patients initially presented with just heroin in their urine screens at intake.

Today as well, addicts coming into MMT may include persons using pharmacologically diverse substances: other opioids besides heroin, cocaine, alcohol, amphetamines, barbiturates, marijuana, and other psychotropic substances of abuse. Some use such substances to get "high" while others use them for quasi-legitimate or clinically relevant reasons (pain, insomnia, concurrent psychiatric disorder, etc.)

To say the least, heroin addicts are often not "purists" in their choices and uses of drugs.

 

 

Heroin/Cocaine Differences

Heroin is a narcotic, while cocaine is a stimulant. Hence, the cravings and effects are quite distinct for each drug.

A heroin addict takes his drug, gets calm, waits a few hours, then takes it again. With cocaine itís different, as comedian George Carlin once said: "What does cocaine make you feel like? It makes you feel like more cocaine!"

There seems to be some science behind Carlin's jest. Researchers have found that cocaine's half-life is merely about 20 minutes and such rapid clearance encourages its prompt readministration and behavioral reinforcement. The pleasurable response experienced after taking cocaine is linked to the release of dopamine in the brain ­ it "primes" the brain's reward system ­ and the continuous activation of neural pathways leads to intensified cravings for more of the drug.[3,4]

In short, heroin is like a tall, cold drink which satisfies thirst for a time; whereas cocaine is like salty snacks ó take one and you'll immediately be grabbing for more... and more.

The drugs themselves differ in their ability to induce dependence based on their unique effects on brain cell chemoreceptors, their routes of administration, rates of effect onset, and rates of elimination from the body. Heroin and cocaine counteract each others' side effects.

Heroin "mellows out" cocaine-induced agitation, while cocaine allows the addict to experience opioid euphoria without the "nod." Addicts in whom cocaine is the drug of choice will use that first and then take heroin to amend adverse effects of the withdrawal or "crash."[1]

Cocaine withdrawal may also produce severe depression. By using heroin to self-medicate such effects, cocaine addicts also develop physiologic dependence on heroin and can greatly benefit from MMT. Experts believe, it is inappropriate to deny opioid addicts methadone treatment simply due to the presence of other addictions.[1] Indeed, one survey of MMT programs in the U.S. found that about 70 percent of them also attempt to treat drug problems other than heroin.[5]

Ubiquitous Cocaine

Evaluations of MMT programs in the U.S. have discovered a range of 16 percent to 75 percent of patients using cocaine while in methadone treatment.[1,2,6] Cocaine use is also a common problem among opioid-dependent patients treated with LAAM (a long-acting opioid agonist), naltrexone (a strong opioid antagonist),[7] or buprenorphine (an opioid agonist).[8]

For many MMT patients, cocaine use represents a continuation of drug abuse that began prior to admission to the program. Reportedly, methadone, with its longer half-life than heroin, lengthens and mellows the effects of cocaine, and this may adversely impact the ability of MMT patients to abstain from cocaine use. Unfortunately, in the case of those injecting cocaine, the demonstrated benefit of MMT programs for slowing the spread of AIDS are greatly diminished. Furthermore, remediations of criminal activities otherwise engendered by MMT are lost among those who continue to use cocaine.[2]

The link between heroin and crack cocaine (a smokable form) leading to IV drug injection and possible exposure to AIDS is of great concern. A survey of over 1200 addicts revealed that crack smokers may turn to heroin injection to ease crack withdrawal. In a significant number of cases the addicts began by snorting high quality heroin before moving on to injecting the drug.[9]

Although crack can be traced to the 1970s, it wasn't until the late '80s that it became an important part of the American drug scene.[10] By 1986, it was estimated that one million persons had tried crack for its "incredible high" that could create addicts in weeks. By 1990, there were reportedly up to three million cocaine users, including 600,000 youngsters between age 12 and 17 hooked on crack.[11] Its popularity has continued to the present day and, as noted above, is often accompanied by other drugs of abuse.

MMT Dilemma

Cocaine use has increased the number of MMT patients who have failed to comply with clinic rules and, therefore, have been discharged. This circumstance, of course, makes it impossible for methadone programs to treat, let alone rehabilitate their clients.

Some believe that MMT programs may actually "unwittingly promote cocaine use among treated addicts" by not providing comprehensive treatments specifically targeting cocaine abuse. And since methadone blocks euphoric effects of heroin, but does not prevent patients from getting a cocaine "high," cocaine becomes all the more appealing for its effects.[6]

Since methadone's long half life stabilizes mood swings in most persons, and tolerance for its side effects is achieved in a matter of weeks, the very success of methadone can leave some addicts with a desire to achieve a mood shift using other substances. For this reason, it has been estimated that "as many as half of those entering [methadone] treatment without a significant history of other substance use will initiate or accelerate such use during the first year of treatment."[1]

Further, it has been suggested that some addicts may use cocaine as a stimulant to self-medicate any sedating effects of methadone, perhaps due to inappropriate methadone dosing. And, patients no longer needing to support an expensive heroin habit, may simply have more money to spend on cocaine.[6]

The above seems to pose quite a dilemma. The good news, according to some experts, is that by the end of the second year of retention in MMT (if that is achieved) about half of those who developed a secondary drug problem after entering treatment may experience a spontaneous remission of that behavior.[1]

Program Reactions

Insufficient resources, inadequate staff training, and high staff turnover have plagued clinics in their efforts to deal with the cocaine problem among patients. However, while many believe the effectiveness of MMT is proportional to drug abuse counseling and rehabilitative services in addition to the methadone itself, others claim the levels and types of those services appear "unlikely to have much of an impact on cocaine use by methadone clients."[2]

It has been recommended that cocaine-using MMT patients be referred to specialized programs for this and other forms of stimulant abuse. However, cost and accessibility concerns have limited such an approach.

Few MMT programs have treatment protocols targeted specifically at patients who abuse both cocaine and opioids, although different behavioral interventions have been reported in this regard:[1,2]

  • contingencies for testing urine more frequently;
  • stopping methadone take-home privileges;
  • lowering methadone doses;
  • increasing individual and/or group counseling;
  • methadone detox after continued cocaine abuse.

Yet, there is still the question of how effective such measures, some quite draconian in nature, might be for these polyaddicted patients. Condelli's survey [2] of available research covering a 20 year span up to 1991 found only three specific studies evaluating the effectiveness of specific behavioral interventions for cocaine use among MMT patients (the numbers in bracket represent percent reduction in cocaine use, and only the first two studies achieved statistical significance; at p<0.05):

1. Confronting patients and staff about urine tests positive for cocaine [-16%];

2. Withdrawing patients from methadone for continued cocaine use [-36%];

3. Rewarding patients with methadone take-homes for not using cocaine [-21%].

While the studies did show reductions in cocaine use, those investigations have not been replicated under more rigorous experimental conditions. Furthermore, the sample sizes were small and it is unclear whether the limited successful outcomes were due more to the interventions or to continuously relapsing patients selectively dropping out of the respective programs (and not being included in the statistical analyses).

Although contingency withdrawal from methadone showed the sharpest declines in cocaine abuse, this most severe action uses an all or nothing penalty, rather than graduated costs, and it overlooks possible positive rewards that might more productively induce patients to abstain from cocaine.

Current belief is that contingency contracts and other forms of setting limits on substance abuse behavior should not involve methadone dose levels in a negative sense (e.g., reduction or withdrawal of dose).[1]

Other suggested interventions have included:

  • cognitive-behavioral therapies focusing on reducing depressive symptoms associated with chronic cocaine use;
  • cue extinction approaches targeting the deconditioning of physiological and psychological cravings for cocaine;
  • skills training that enhances patients' abilities to manage stress and anxiety and resolve problems of everyday life to better manage triggers for cocaine relapse.

Condelli conceded that the behavioral interventions mentioned may not work for patients in whom the perceived psychological and physiological rewards of cocaine overshadow the rewards or punishments of the interventions. In particular, he briefly mentioned the powerful attraction of crack cocaine, which was just becoming an issue of great concern at the time of his study's publication.

It has been strongly noted that, in this era of HIV-spectrum disease and multidrug-resistant TB, there are few, if any, compelling reasons to abruptly discharge patients from addiction treatment. Detoxification and dismissal should not be considered as options.[1] Plus, any other severe interventions or punitive policies that might induce the patient to resume illicit activities and/or IV drug abuse, or to leave treatment prematurely, could be detrimental to the patient and ultimately pose a public health threat.

Recent Studies

More recent studies within MMT programs have assessed various remedies for the cocaine dilemma. Here are a few:

1. A six-month enhanced treatment program for cocaine-dependent MMT patients at the Narcotic Rehabilitation Center of the Mount Sinai Medical Center [12] enrolled 77 subjects between 1991 and 1993. The special program included individual and group sessions focusing on cognitive-behavioral and relapse prevention therapies. Of the 61 percent who completed the six month course, frequency of cocaine use decreased by a third overall, and 21 percent achieved abstinence during a 30 day period when interviews were conducted. Patients attending the most therapy sessions also showed the greatest improvement.

2. A recently reported pilot study at Beth Israel Hospital in New York [13] introduced a three-phase high-intensity MMT program geared toward unemployed "low bottom" opiate/cocaine addicts. Two-thirds of the subjects completed a six month protocol that included intensive group and individual therapy sessions supported by monetary reward reinforcements for expected performance (such as, attending all sessions). Preliminary results, based on cocaine positive urines, suggested that those patients using the most cocaine also benefited the most from high-intensity treatment approaches.

3. A program at the Montefiore Substance Abuse Treatment Program, Bronx, NY, [14] implemented three week courses of daily acupuncture treatments for its cocaine-dependent methadone patients, followed by a maintenance period of less frequent acupuncture treatments. As with the two programs mentioned above, only about two-thirds of patients completed the initial phase of the study, although reasons for the drop-outs were unclear in all studies. There was roughly an average 41 percent decrease in cocaine positive urines among patients completing the daily acupuncture portion of this program.

While the above studies do not entirely resolve the problem of cocaine-dependence among MMT patients, the results might offer some directions for further and more rigorous clinical investigations.

Methadone/MMT Efficacy

The studies mentioned above, being of limited focus, looked at treatment modalities for cocaine within the context of MMT programs, but did not elucidate the possible potential of methadone itself as a factor in reducing cocaine use. Nor did they comment on the efficacy of various methadone doses or program effects on continued drug abuse.

One analysis [15] using rather dated information examined drug abuse patterns among 513 MMT patients between 1979 and 1981 gathered via a nationwide Treatment Outcome Prospective Study (TOPS). The authors concluded that methadone programs indirectly reduce patients' uses of illicit substances insofar as MMT is successful in eliminating or decreasing opiate use. However, they also noted that their findings did not support the commonly held belief that heroin addicts substitute other drugs for heroin. These findings, first reported in 1993, used data that predated the surge in cocaine use during the 1980s and the advent of popular and powerful crack cocaine.

There has also been commentary regarding methadone dose level and cocaine use in MMTs:

A. One small study [16] of 16 subjects suggested that improvements in cocaine abuse observed in methadone patients were not related to a blocking of the subjective effects of cocaine, and that higher methadone doses could have a negative impact leading to increased cocaine abuse. In this case, however, a high dose of methadone was described as about 60 mg/day, which many practitioners today would not consider a high (or even adequate) dose for patients using cocaine.

B. Another study [8] found that methadone dose increases were effective in suppressing opioid but not cocaine use. At an average 54 mg/day dose of methadone, opiate-positive urines were 47 percent and cocaine-positive urines were 58 percent. Also of note, only 56 percent of subjects remained in treatment for the 16-week dosing period.

The above studies are worthy of mention here only because they are among the very few discovered that report the efficacy of methadone in association with controlling cocaine use. In general, the methadone doses under evaluation were hardly what might be considered in a high range, or even optimal for many patients according to many experts.[1,5]

Research in California [17] included 74 cocaine-using MMT patients who were initially maintained on methadone dosages between 30 and 80 mg/d. Slightly over 28 percent ceased cocaine use when their methadone dose was progressively raised to a maximum of 160 mg/d. The authors noted also that cocaine appeared to accelerate elimination of methadone, since "inadequate methadone serum concentrations" of below 100 ng/ml were found in over 70 percent of subjects. (Concentrations below 200 ng/ml might be expected to produce objective signs of abstinence syndrome.)

It is interesting to observe that the authors concluded from their study that alternative treatments for cocaine abuse in MMT patients must be identified; rather than suggesting a raising of methadone doses to overcome the serum concentration lowering effect of cocaine.

Other researchers, such as Shinderman and Maxwell of the Center for Addictive Problems in Chicago have observed that clinically determined "high doses" of methadone (ranging up to 580 mg/day depending on individual patient needs) not only greatly increased retention in treatment and opiate cessation, but decreased cocaine use as a side benefit.[18]

Protocols for treating polydrug addiction using higher methadone dose levels than previously examined would seem worthy of further clinical research.

Antidepressants & Cocaine

There have been limited reports of the impact other pharmacologic agents might have in controlling cocaine use, with or without concurrent methadone administration. Antidepressant medications seem to offer some promise.

Early studies using fluoxetine (Prozac®) showed some dramatic decreases in cocaine use ­ from over 14 times per week down to slight over once weekly ­ by small test groups of cocaine addicts. One explanation for the link between cocaine and depression was that patients were trying to modulate (via self-medication) their depression through the stimulant properties of cocaine. However, more current thinking holds that fluoxetine may decrease cravings in general, whether or not there is depression, and it has been shown to also reduce alcohol, nicotine, and even food consumption. It should be noted, however, that group therapy was also used as an adjunct to the medication therapy in those studies.[19]

Researchers from Yale University discovered that certain antidepressants (desipramine and imipramine) and dopaminergic agents (amantadine, bromocriptine, and mazindol) showed promising results in treating cocaine addiction. Some of those medications reduced post-cocaine dysphoria and further cocaine craving, while others increased negative effects of cocaine making further administration aversive.[6]

Regarding use of fluoxetine in MMT, one study found that polyaddicted methadone patients treated with 45 mg/day of fluoxetine significantly reduced cocaine use by the end of a nine week treatment period, although most did not achieve abstinence.[20] However, a more extensive study, albeit using lower doses of fluoxetine, found no improvements in cocaine use or craving. A higher frequency of required clinic attendance in this study decreased patient retention in treatment but reduced cocaine use.[21]

Of further interest, Shinderman has anecdotally observed that high ranges of methadone dose, providing optimum blood levels, seem to allow antidepressant medications to work more efficaciously in MMT patients.[18]

"Magic Bullets"

Alan Leshner, Director of the National Institute on Drug Abuse, has observed the need for a treatment to counter cocaine overdose and addiction. Recent discoveries in animal research indicate that an anti-cocaine medication might be within reach:

A. Scientists have demonstrated that cocaine, which binds strongly to the dopamine-reuptake transporters in the brain, blocks the normal "mopping up" of the pleasure-sensation-producing chemical after neuronal activity. Due to this blocking effect, dopamine remains at high concentrations within the synapses and continues to affect adjacent neurons, producing the characteristic cocaine "high." Agents which prevent cocaine from attaching to the transporters may inhibit the characteristic response to cocaine and short-circuit addiction.[22]

Only recently it has been reported that at least 47 percent of the transporters must be blocked (via cocaine attached to them) before addicts perceive cocaine's effects, and intravenous doses commonly abused block between 60 and 77 percent of transporter sites. This has implications for developing medications that would sufficiently replace cocaine on the dopamine transporters to negate it's effects.[23]

B. Another advance reported that there are multiple dopamine receptors in the brain that respond selectively to different chemical compounds. An agonist for one type of receptor can diminish cocaine cravings, whereas it will have just the opposite effect on another type of receptor, triggering cravings.[22]

This research also helps explain why just a little cocaine can be a big threat due to its "priming" of the brain's reward system and intensifying a craving for more cocaine. Therapeutic agents attacking the correct receptors may prevent relapses by eliminating cravings in people who've stopped using the drug.[4]

C. A third discovery showed that it might be possible to immunize addicts against the stimulant effects of cocaine by reducing concentrations of the drug in the brain. Other researchers are exploring the use of antibodies and other external agents affecting cocaine metabolism.[22]

Along those lines, Scientists at the Scripps Research Institute have developed a cocaine vaccine that effectively binds the active drug metabolite in an antibody complex to block the drug's psychoactive effects. However, there is some question as to whether this approach would be potent once cocaine addiction, with its associated neuromechanism changes, has already occurred.[24]

It should be noted that ongoing research has also sought to describe the brain centers and neuronal pathways associated with cocaine addiction and craving. Several brain regions ­ such as the forebrain, striatum and thalamus ­ have been implicated as playing important roles.[25,26] It is hoped that such basic research investigations may one day allow scientists to better target pharmacologic (and/or other) interventions for cocaine addiction to the brain areas most affected.

Genetic research is also a strong area of interest these days, and scientists in Israel have identified a gene that seems to raise a person's risk of addiction, especially to opiates.[27] This gene is the same one researchers have linked to "novelty-seeking," which includes impulsiveness, excitability, and extravagance. The gene has been further implicated in the brain's production of one type of dopamine receptor that might foster cocaine addiction.

No Easy Answers

As one examines the literature to date concerning polydrug abuse among MMT patients it appears the field is still very much in its infancy. Even the results of positive studies are sometimes unimpressive and the dosages of methadone involved are often below what many practitioners today would consider optimal.

A particular difficulty with the above mentioned reward or punishment approaches toward changing patients' behaviors is that such interventions assume to an extent that the addict has control over the cocaine addiction and can turn off the behavior at will, like turning off a water spigot. This is normally not the case with addiction.

Another challenge is not only developing interventions that reduce cocaine use among methadone patients, but also addressing the social, psychological, and physiological problems that elicit the addictive behavior in the first place, reinforce it once it has begun, and can lead to relapse long after the person has seemingly recovered.

Even if a "methadone" for cocaine ­ or some magic bullet anti-cocaine medicament ­ were discovered, it is doubtful that it would constitute effective therapy without some range of psychosocial services.[6] And, at best, recovery might take place over an extended period of time.

CSAT guidelines seem to offer a most reasonable perspective:

"Because chemical dependency is a chronic disease, there are two principles of treatment. The first principle is that a chronic disease requires long-term care and that treatment is a process that occurs over a long period. The second principle is that few chronic diseases respond to a single model of care, and, therefore, a variety of techniques may be appropriate for a patient. Abstinence from other substance use should be long-term or at least for increasing periods, and the patient should experience improved life functioning and well-being."[1]

The simple truth seems to be that there is very little sound science at present to guide the rehabilitation of cocaine addicts within the context of methadone maintenance treatment for opioid dependence. This is a field wide open for further research and hopefully future discoveries providing more therapeutically efficacious and cost effective treatments.

In response to this report's opening query from the MMT counselor: Given the current state of research, medically withdrawing the patient from methadone as punishment for not abstaining from cocaine would seem to serve no purpose other than returning an active addict to the streets and the potential ravages of HIV-TB-Hepatitis, criminality, and socioeconomic impoverishment. Increasing methadone dose could be advantageous if the amount was indeed sufficient to be optimal for that individual patient. And, while a dose adjustment may resolve the opioid problem, cessation of cocaine use may also depend on adjunctive psychosocial services and/or other interventions within the context of an enlightened MMT program.

It would certainly be much easier and economical if, as was once widely promulgated, addicts could be simply admonished: "Just say no to drugs!"

 

References...

1. Barthwell A, Gastfriend DR, eds. Treating Multiple Substance Abuse. In: Parrino MW, ed. State Methadone Maintenance Treatment Guidelines. Rockville, MD: U.S. Department of Health and Human Services, Center for Substance Abuse Treatment; 1992:151-171.

2. Condelli WS, Fairbank JA, Dennis ML, Rachal JV. Cocaine use by clients in methadone programs: significance, scope, and behavioral interventions. J Subs Abuse Treatment. 1991;8:203-212.

3. Volkow N. Cocaineís rapid clearance leads to bingeing, then compulsive use. J Addict Dis. 1996;15:55-71.

4. Self DW, et al. Dopamine receptor agonist inhibits craving for cocaine. Science. 1996;271:1586-1589,1499.

5. D'Aunno T, Vaughn TE. Variations in methadone treatment practices: Results from a national study. JAMA. 1992;267:253-258.

6. Avants SK, Margolin A, Kosten TR. Cocaine abuse in methadone maintenance programs: Integrating pharmacotherapy with psychosocial interventions. J Psychoactive Drugs. 1994;26:137-146.

7. Kreek MJ. Multiple drug abuse patterns and medical consequences. In: Meltzer HY, ed. Psychopharmacology:The third generation of progress. New York: Raven Press; 1987:1597-1604.

8. Strain EC, Stitzer ML, Liebson IA, Bigelow GE. Comparison of buprenorphine and methadone in the treatment of opioid dependence. Am J Psychiatry. 1994;151:1025-1030.

9. Irwin KL, et al. Crack cocaine smokers who turn to drug injection: characterisitcs, factors associated with injection, and implications for HIV transmission. Drug Alcohol Depend. 1996;42:85-92.l

10. The men who created crack. US News & World Report. August 19, 1991:44-53.

11. Gelman D, et al. Some things work; it's never easy, but crack addicts can now be successfully treated. Newsweek. 1990; September 24:78-80.

12. Magura S, et al. Enhanced positive reinforcement in cognitive-behavioral treatment of cocaine dependent methadone patients. In: Proceedings from the Symposia on Cocaine Addiction: Trends, Laboratory Research, Critical Issues and Treatment. New York, NY: The Chemical Dependency Research Working Group; The New York State Office of Alcoholism and Substance Abuse; 1994(Monograph Series Number 1):25-27.

13. Freidman E, Rosenbloom A, Joseph H. Integrating cocaine treatment into MMTPs. Presented at the American Methadone Treatment Association annual conference; April 16, 1997; Chicago, IL. Workshop session W-27.

14. Merrill H. Acupuncture and the treatment of cocaine/crack abuse in a methadone maintenance program. In: Proceedings from the Symposia on Cocaine Addiction: Trends, Laboratory Research, Critical Issues and Treatment. New York, NY: The Chemical Dependency Research Working Group; The New York State Office of Alcoholism and Substance Abuse; 1994(Monograph Series Number 1):32-33.

15. Fairbank JA, Dunteman GH, Condelli WS. Do methadone patients substitute other drugs for heroin? Predicting substance use at 1-year follow-up. Amer J Drug and Alcohol Abuse. 1993:19;465.

16. Foltin RW, Christiansen I, Levin FR, Fischman MW. Effects of single and multiple intravenous cocaine injections in humans maintained on methadone. J Pharmacol Exp Ther. 1995;275:38-47.

17. Tennant F, Shannon J. Cocaine abuse in methadone maintenance patients is associated with low serum methadone concentrations. J Addic Dis. 1995;14(1):67-74.

18. "High dose" methadone best for many. Addiction Treatment Forum. 1997:IV(3, Summer):1.

19. Miller C. Anti-depressant shows promise in decreasing cocaine use. C/CRWG Newsletter (New York State Division of Substance Abuse Services). 1991;1(March):10.

20. Batki SL, Manfredi LB, Jacob P, Jones RT. Fluoxetine for cocaine dependence in methadone maintenance. J Clin Psychopharmacol. 1993;13:243-250.

21. Grabowski J, et al. Fluoxetine is ineffective for treatment of cocaine dependence or concurrent opiate and cocaine dependence: two placebo-controlled double-blind trials. J Clin Psychopharmacol. 1995;15:163-174.

22. Leshner AI. Molecular mechanisms of cocaine addiction. NEJM. 1996;335(2). Letter.

23. Volkow ND, et al. Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature. 1997;386:824. Letter.

24. Cocaine vaccine blocks drug passage across the blood-brain barrier. Nature. 1995;378:666-667,725-728.

25. Volkow ND, et al. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature. 1997;386:827. Letter.

26. Koob G. Neurobiological mechanisms in cocaine and opiate dependence. In: O'Brien CP, Jaffe JH, eds. Addictive States. New York: Raven Press, Ltd; 1992:79-92.

27. Ritter M, Study: gene may raise heroin risk. Associated Press. May 1, 1997. News wire report.

 

The author thanks Marc Shinderman, MD, Center for Addictive Problems, Chicago, IL, for his technical review of this report.