Human Laboratory Studies

Binge/Intoxication Stage

For the binge/intoxication stage of the addiction cycle, self-administration procedures for cocaine, heroin, and marijuana in humans have been established largely using operant responding, in which participants who are dependent on the drug make a behavioral response, such as pressing a key on a computer, to receive a drug. Similar to animal models, heroin self-administration is reduced by all three medications currently approved by the FDA to treat opioid dependence – methadone, naltrexone, and buprenorphine – providing some predictive validity. However, for cocaine, the validity is much less robust. A range of medications has been shown to reduce the subjective effects and craving associated with cocaine but do not decrease cocaine self-administration itself. These results are consistent with data from clinical trials. Of the more than 60 medications tested, none have proven to be reliably effective in clinical trials. To date, little or no work has been done on specific treatments for marijuana self-administration.

Other measures, such as impulsivity, could be considered endophenotypes of the binge/intoxication stage and have some potential for predicting drugs with possible efficacy for addiction treatment. Impulsivity likely contributes to increasing the probability of engaging in initial drug taking, and the subsequent drug effects on impulsivity may increase impulsive behaviors that in turn facilitate further drug use, prolonging the binge or even provoking relapse (see below). Various tasks have been used to assess impulsivity, including tasks of delayed discounting (i.e., relative preference for smaller, more immediate rewards over larger, more delayed rewards), tasks of behavioral inhibition (e.g., Stop Task), and attentional measures (i.e., subjects show increased variability in reaction times on a simple reaction time task, reflecting lapses in attention).

Withdrawal/Negative Affect Stage

In the withdrawal/negative affect stage, negative reinforcement mechanisms are engaged, rather than positive reinforcement mechanisms. Numerous human laboratory measures of acute withdrawal are available and sensitive to drug substitution. In the laboratory, marijuana withdrawal is alleviated by marijuana smoking or by the administration of oral Δ9-THC. Cognitive measures could be envisioned as sensitive to the withdrawal effects of drug dependence during acute and protracted abstinence and could be considered another endophenotype of the addiction process that is sensitive to medication screening. Nicotine can improve cognitive processing and reduce negative affect in smokers. The cascade of stress hormone interactions with drugs of abuse, from facilitation of the binge/intoxication stage to exaggeration of the withdrawal/negative affect stage, and sensitization to stress-induced relapse may all be amenable to human laboratory studies.

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