Cocaine is an alkaloid that can be found in the leaf of the Erythroxylum coca (coca plant). For the past 4000 years, the use of coca has been greatly entrenched in the social and religious culture of many ancient civilizations in the territory that is now known as Chile and Peru. It had a wide range of uses, the most notorious of which were as a stimulant, a hunger suppressant, and a remedy to relieve pain. In 1860, Albert Niemann isolated cocaine for the first time, a method which he published as his PhD dissertation, titled On a New Organic Base in the Coca Leaves.
Following, its use for many purposes became widespread in all stratums of Western society, reaching the point where it became the stimulant additive in the ubiquitously known beverage Coca-Cola®; nonetheless, it was eventually replaced by caffeine. This phenomenon, although anecdotal, is a good reflection of the social impact it caused.
In 1914, cocaine became a controlled substance in the United States, due to its high abuse potential, and it is not until the mid XX century when its use increased substantially. Nonetheless, obtaining it was relatively expensive, which served as a significant limiting factor for its use. This restriction disappeared in the 1980s, with the rise of crack cocaine. Crack is the freebase form of cocaine; it has the distinct property of being stable when vaporized, generating inhalable smoke. The pulmonary route of administration allows users to obtain a more intense high with less amount of cocaine, despite the duration of the effect being substantially shorter. These properties make crack a notably cheaper and more addictive substance than its chlorhydrate homologue; this circumstance caused cocaine use and the number of cocaine addicts to rise dramatically, unleashing a full-blown epidemic, especially in the United States.
Mechanism of action
Currently, cocaine is used almost uniquely as a stimulant. Users report increased alertness, energy and well-being. This effect is mediated by a strong increase in extracellular monoamines, which cannot be pumped back into the terminal due to the blockade of their transporter protein, thus accumulating in the synaptic cleft.
This phenomenon holds true for DAT, SERT and NET, although the psychostimulant effect of cocaine is mostly attributed to an increase in dopamine.
Furthermore, cocaine causes the blockade of sodium channels, thus interfering with the transmission of action potentials; although this has little relevance as regards to the psychostimulant properties of cocaine, it does mediate its anesthetic effects, as well as some of its undesired effects, such as cardiac arrhythmia.
The half-life of cocaine is subject to the administered dose, with values averaging 60 minutes. Furthermore, cocaine fits into a first order pharmacokinetic model.
It is metabolized in the liver, mostly through hydrolytic ester cleavage, generating benzoylecgonine, ecgonine methyl-ester and ecgonine. Additional metabolites include norcocaine, p-hydroxycocaine, m-hydroxycocaine, p- hydroxybenzoylecgonine (pOHBE), and m-hydroxybenzoylecgonine (Kolbrich et al., 2006). Interestingly, when used concomitantly with alcohol, cocaine conjugates with ethanol molecules, forming the unique metabolite cocaethylene, which has been reported to possess higher cardiotoxicity than cocaine (Wilson et al., 2001).
Although cocaine is known to exert strong cardiovascular toxic effects, the matter of its neurotoxic potential is controversial. There are many discrepancies in the extensive literature on this issue, which contrast significantly with the good agreement there is on the strong neurotoxic potential of amphetamines. Thus, cocaine is generally believed to have little to no neurotoxic effects (Benmansour et al., 1992); nonetheless, some studies have found that continuous cocaine exposure can cause persistent changes in acetylcholine (ACh) and GABA receptors, as well as in markers for dopaminergic function, pointing to the existence of damage in the structures of dopaminergic neurons (reviewed by Ellison et al., 1996).