Cocaine dependence

Overview
Cocaine dependence (or addiction) is physical and psychological dependency on the regular use of cocaine. It can result in physiological damage, lethargy, depression, or a potentially fatal overdose.

Presentation
The immediate craving of the addict for more soon after use is due the short-lived high that usually subsides within an hour, leading to prolonged, multi-dose binge use. When administration stops after binge use, it is followed by a "crash" (also known as a "come down"), the onset of severely dysphoric mood with escalating exhaustion until sleep is achieved, which is sometimes accomplished by taking sleeping medications, or sedatives, a popular one being Seroquel, or by combination use of alcohol and cannabis. Resumption of use may occur upon awakening or may not occur for several days, but the intense euphoria of such use can, as it has in many users, produce intense craving and develop rather quickly into addiction. The risk of becoming cocaine-dependent within 2 years of first use (recent-onset) is 5-6%; after 10 years, it's 15-16%. These are the aggregate rates for all types of use considered, i.e., smoking, snorting, injecting. Among recent-onset users, the relative rates are higher for smoking (3.4 times) and much higher for injecting. They also vary, based on other characteristics, such as gender: among recent-onset users, females are 3.3 times more likely to become addicted, compared to males; age: among recent-onset users, those who started using at ages 12 or 13 were 4 times as likely to become addicted, compared to those who started between ages 18 and 20; and race: among recent-onset users, non-Hispanic Blacks are 7 times as likely to become addicted, compared to non-Hispanic Whites. Many habitual abusers develop a transient manic-like condition similar to amphetamine psychosis and schizophrenia, whose symptoms include aggression, severe paranoia, and tactile hallucinations (including the feeling of insects under the skin, or "coke bugs") during binges.

Cocaine has positive reinforcement effects, which refers to the effect that certain stimuli have on behavior. Good feelings become associated with the drug, causing a frequent user to take the drug as a response to bad news or mild depression. This activation strengthens the response that was just made. If the drug was taken by a fast acting route such as injection or inhalation, the response will be the act of taking more cocaine, so the response will be reinforced. Powder cocaine, being a club drug is mostly consumed in the evening and night hours. Because cocaine is a stimulant, a user will often drink large amounts of alcohol during and after usage or smoke cannabis to dull "crash" or "come down" effects and hasten slumber. Benzodiazepines (e.g., Xanax®, Rohypnol®) are also used for this purpose. Other drugs such as heroin and various pharmaceuticals are often used to amplify reinforcement or to minimize such negative effects, further increasing addiction potential and harmfulness.

It has been shown in studies that rhesus monkeys, provided with a mechanism of cocaine self-administration, prefer the drug over food that is in the cage. This happens even when the monkeys are starving.

It is speculated that cocaine's addictive properties stem partially from its DAT-blocking effects (in particular, increasing the dopaminergic transmission from ventral tegmental area neurons). However, a study has shown that mice with no dopamine transporters still exhibit the rewarding effects of cocaine administration. Later work demonstrated that a combined DAT/SERT knockout eliminated the rewarding effects. The rewarding effects of cocaine are influenced by circadian rhythms, possibly by involving a set of genes termed "clock genes".

However, chronic cocaine addiction is not solely due to cocaine reward. Chronic repeated use is needed to produce cocaine-induced changes in brain reward centers and consequent chronic dysphoria (described above under "Effects and Health Issues - Chronic"). Dysphoria magnifies craving for cocaine because cocaine reward rapidly, albeit transiently, improves mood. This contributes to continued use and a self-perpetuating, worsening condition, since those addicted usually cannot appreciate that long-term effects are opposite those occurring immediately after use.

Mechanism of Dependence
It is speculated that cocaine's intense addictive properties stem partially from its DAT-blocking effects (in particular, increasing the dopaminergic transmission from ventral tegmental area neurons). However, a study has shown that mice with no dopamine transporters still exhibit the rewarding effects of cocaine administration. Later work demonstrated that a combined DAT/SERT knockout eliminated the rewarding effects. The rewarding effects of cocaine are influenced by circadian rhythms, possibly by involving a set of genes termed "clock genes".

However, chronic cocaine addiction is not solely due to cocaine reward. Chronic repeated use is needed to produce cocaine-induced changes in brain reward centers and consequent chronic dysphoria (described above under Effects and Health Issues - Chronic). Dysphoria magnifies craving for cocaine because cocaine reward rapidly, albeit transiently, improves mood. This contributes to continued use and a self-perpetuating, worsening condition, since those addicted usually cannot appreciate that long-term effects are opposite those occurring immediately after use.

Treatment
Cognitive Behavioral Therapy (CBT) combined with Motivational Therapy (MT) proven to be effective to treat drug and alcohol addictions. Cocaine vaccines are on trial that will stop desirable effects from the drug. The National Institutes of Health of US, particularly National Institute on Drug Abuse (NIDA) is researching modafinil, a narcolepsy drug and mild stimulant, as a potential cocaine treatment.

Twelve-step programs such as Cocaine Anonymous (modeled on Alcoholics Anonymous) are claimed by participants to be helpful in achieving long-term abstinence; however, the 12 step based programs have no statistically-measurable effect and does not release any quantifiable measure of its success rates.

Bupropion
Bupropion, an antidepressant, is U.S. FDA approved for the treatment of depression ("cocaine blues") associated with ending cocaine use.

GVG
Studies have shown that gamma vinyl-gamma-aminobutyric acid (gamma vinyl-GABA, or GVG), a drug normally used to treat epilepsy, blocks cocaine's action in the brains of primates. GVG increases the amount of the neurotransmitter GABA in the brain and reduces the level of dopamine in the region of the brain that is thought to be involved in addiction. In January 2005 the U.S. Food and Drug Administration gave permission for a Phase I clinical trial of GVG for the treatment of addiction.

GBR 12909
GBR 12909 (Vanoxerine) is a selective dopamine uptake inhibitor. Because of this, it reduces cocaine's effect on the brain, and may help to treat cocaine addiction. Studies have shown that GBR, when given to primates, suppresses cocaine self-administration.

Rimonabant
CB1 antagonist Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans, priming and cues. This shows that cocaine addiction is more complicated than simply the mesolimbic reward pathway, but also involves memory systems as well.

Venlafaxine
Venlafaxine (Effexor®), although not a dopamine re-uptake inhibitor, is a serotonin-norepinephrine reuptake inhibitor that has been successfully used to combat the depression caused by cocaine withdrawal and to a lesser extent, the addiction associated with the drug itself.

TA-CD
TA-CD is a vaccine in development which stops cocaine from crossing the blood-brain barrier, negating all psychostimulant effects. It also causes it to be attacked by endogenous antibodies, which destroy the molecule.