Rationale
Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable.

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Controversies in translational research: drug self-administration

To investigate sex and menstrual cycle effects in response to cocaine administration, data from existing studies were analyzed. First, responses to a single delivery of 0.4 mg/kg smoked cocaine were investigated. Women reported lower ratings for measures of paranoid/suspicious and heart racing/pounding than did men. In addition, women in the luteal phase reported diminished ratings for a measure of feel high than did both women in the follicular phase of the menstrual cycle and men. Second, responses to up to 6 deliveries of 0.4 mg/kg smoked cocaine were investigated. Women, compared with men, had lower ratings on feel high, heart racing/pounding, and feel stimulated. Results suggest that there are significant sex and menstrual phase differences in the subjective effects of cocaine.

Sex and menstrual cycle differences in the subjective effects from smoked cocaine in humans.

The effects of female sex hormones on responses to cocaine have not been systematically investigated in women. In this study, the safety and efficacy of acute progesterone treatment on smoked cocaine response was examined in female cocaine users. Five women had two experimental sessions during the early follicular phase, within 3–9 days after the beginning of their menses. In each experimental session, subjects received a single 200-mg dose of progesterone or placebo orally. Starting 2 h after the medication treatment, subjects received three deliveries of 0.4-mg/kg smoked cocaine 30 min apart. Progesterone treatment, compared to placebo, did not affect the blood pressure and heart rate changes in response to cocaine deliveries. For subjective responses to cocaine, the average of five-item Cocaine Effects Questionnaire (CEQ) was attenuated under progesterone treatment compared to placebo. For individual items of CEQ, progesterone treatment was associated with diminished rating of “feel the effect of last dose” in response to cocaine. These preliminary results suggest that acute progesterone treatment, given during the early follicular phase, may attenuate some of the subjective effects of cocaine. Further studies are warranted to examine the effects of progesterone treatment on cocaine dependence.

Effects of progesterone treatment on smoked cocaine response in women.

We recently reported that progesterone treatment attenuated some of the subjective effects of smoked cocaine in female cocaine users. In this study, we further examined the interaction between progesterone and cocaine in both male and female cocaine users using subjective, physiological and behavioral outcomes. A total of 10 subjects, 6 male and 4 female cocaine users, had two experimental sessions. Before each session, participants received either two oral doses of 200 mg of progesterone or placebo. Two hours after the second dose of medication treatment, the participants received a 0.3 mg/kg dose of cocaine intravenously and started the self-administration period, in which five optional doses of cocaine were available. Progesterone treatment attenuated the cocaine-induced diastolic blood pressure increases without affecting the systolic blood pressure and heart rate increases. Progesterone treatment also attenuated the subjective ratings of high and feel the effect of last dose in response to cocaine but did not affect cocaine self-administration behavior. These results suggest that progesterone attenuates some of the physiological and subjective effects of cocaine in both male and female participants. The effects of progesterone treatment on cocaine dependence need to be further studied in controlled trials.

Effects of progesterone treatment on cocaine responses in male and female cocaine users.

Aims There are no studies directly comparing self-administration of methamphetamine and d-amphetamine by humans. This study compared intranasal methamphetamine- and d-amphetamine self-administration and characterized the mood, performance and physiological effects produced by the drugs.



Design  A randomized, double-blind, placebo-controlled, cross-over study.



Setting  An out-patient research unit at the New York State Psychiatric Institute.



Participants  Male recreational methamphetamine users (n = 13).



Measurements  Five 2-day blocks of sessions were conducted. On the first day of each block, participants ‘sampled’ a single methamphetamine or d-amphetamine dose (0, 12, 50 mg/70 kg) and a monetary reinforcer ($5 or $20). Amphetamine plasma levels, cardiovascular, mood, and psychomotor performance effects were assessed before drug administration and repeatedly thereafter. On the second day of each block, participants chose between the sampled reinforcers (drug or money).



Findings  There were no significant differences between the drugs on the majority of measures. Under the $5 condition, both amphetamines increased self-administration dose-dependently, with 41% drug choices overall. Under the $20 condition, only 17% drug options were selected. Both drugs increased cardiovascular activity and ‘positive’ mood, although methamphetamine produced more prominent effects on some measures (e.g. heart rate and ratings of ‘high’).



Conclusions  Methamphetamine and d-amphetamines appear to produce a similar dose-related profile of effects in humans, which supports their equivalence for abuse potential.

/pdf/comparison-of-intranasal-methamphetamine-and-d-amphetamine-1doyo7ltf2.pdf

Comparison of intranasal methamphetamine and d-amphetamine self-administration by humans.

Many methodological issues exist in human laboratory research with smoked cocaine-base that include safety, precision of dose delivery of smoked cocaine, and the lack of an adequate placebo. All of these issues are particularly apparent with studies involving multiple doses of cocaine. Addressing these concerns is important in conducting parametric studies that require examining dose-response effects. The purposes of this study were to determine: 1) the safest interval between doses to deliver smoked cocaine; 2) the accuracy or reproducibility of administering precise and multiple doses of cocaine; 3) the potential for using a control dose of cocaine; and 4) the influence of multiple doses on these parameters. Six black males were given 10 doses of either 5 or 35 mg of cocaine-base at 15-, 30-, and 45-min intervals. The dependent measures included physiological, subjective, and performance responses. These measures were taken prior to dosing and at specific time intervals after each dose of smoked cocaine. The results showed: 1) dosing at 30-min intervals allowed sufficient time for recovery of blood pressure and heart rate to permit up to 10 doses to be safely administered; 2) reproducible blood cocaine levels were obtained with repeated dosing using a heated wire-coil device; 3) significant differences were observed between the 5- and 35-mg dose with 5 mg being a low enough dose to produce minimal effects; 4) acute tolerance was evidenced with multiple doses of cocaine for most of the measures; and 5) considerable between- and within-subject variability was observed in the pattern of responses to cocaine.

Methodological issues in the administration of multiple doses of smoked cocaine-base in humans

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Methodological issues in the administration of multiple doses of smoked cocaine-base in humans