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Acute tolerance to cocaine in humans
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1988
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There is controversy over whether acute tolerance develops to the principal effects of cocaine in humans. The study demonstrates acute tolerance to cocaine’s chronotropic and subjective effects and quantifies the rate and extent of tolerance development. Stable plasma cocaine concentrations were achieved by an initial intravenous injection followed by an infusion compensating for clearance, and tolerance was modeled as an exponential process with a rate constant describing the progressive alteration of the concentration‑effect relationship. Euphoric effects peaked at about 1 h and returned to baseline by 4 h, while chronotropic effects peaked within 10 min and declined with a half‑life of ~31 min to a plateau at ~33 % of peak intensity, despite constant plasma cocaine levels. Clinical Pharmacology and Therapeutics 44:1–8 (1988), doi:10.1038/clpt.1988.104.
There is controversy as to whether acute tolerance develops to the principal effects of cocaine in humans. The studies described here demonstrate the phenomenon of acute tolerance to cocaine chronotropic and subjective effects and the rate and extent of tolerance development. Stable plasma cocaine concentrations were produced and then maintained in volunteer cocaine users by administering an intravenous cocaine injection followed by a cocaine infusion designed to compensate for the plasma clearance of cocaine. The euphoric effect (high) intensified to a peak at about 1 hour and then declined toward baseline at 4 hours despite the presence of constant plasma cocaine levels. The chronotropic effect reached a peak within 10 minutes and then declined, with a half-life of 31 ± 13 (mean ± SD) minutes toward a plateau at 33% ± 21% of its peak intensity. Tolerance development was quantified as an exponential process, with a rate constant (tolerance factor) accounting for the progressive alteration of the cocaine concentration-effect relationship. Clinical Pharmacology and Therapeutics (1988) 44, 1–8; doi:10.1038/clpt.1988.104