Numerous medications have been investigated for use in cocaine dependence, but , none of them were considered to be effective. Anticonvulsants, such as carbamazepine, gabapentin, lamotrigine, and topiramate, do not appear to be effective as treatment. Limited evidence suggests that antipsychotics are also ineffective for treatment of cocaine dependence. Few studies have examined bupropion (a novel antidepressant) for cocaine dependence; however, trials performed thus far have not shown it to be an effective form of treatment for this purpose.

The National Institute on Drug Abuse (NIDA) of the U.S. National Institutes of Health is researching modafinil, a narcolepsy drug and mild stimulant, as a potential cocaine treatment. Ibogaine has been under investigation as a treatment for cocaine dependency and is used in clinics in Mexico, the Netherlands and Canada, but cannot be used legally in the United States. Other medications that have been investigated for this purpose include acetylcysteine, baclofen, and vanoxerine. Medications, such as phenelzine, have been used to cause an "aversion reaction" when administered with cocaine.

Twelve-step programs such as Cocaine Anonymous (modeled on Alcoholics Anonymous) have been widely used to help those with cocaine addiction. Cognitive behavioral therapy (CBT) combined with motivational therapy (MT) have proven to be more helpful than 12 step programs in treating cocaine dependency. However, both these approaches have a fairly low success rate. Other non-pharmacological treatments such as acupuncture and hypnosis have been explored, but without conclusive results.

Comedown or crashing is the deterioration in mood that happens as a psychoactive drug, typically a stimulant, is either decreasing or is cleared from the blood and thus the cerebral circulation. The improvement and deterioration of mood (euphoria and dysphoria) are represented in the cognitive as high and low elevations; thus, after the drug has "elevated" the mood (a state known as a high), there follows a period of "coming back down," which often has a distinct character from withdrawal in stimulants. Generally, a comedown ("down", "low", sometimes "crash") can happen to anyone as a transient symptom, but in people who are dependent on the drug (especially those addicted to it), it is an early symptom of withdrawal and thus can be followed by others. Various drug classes, most especially stimulants and to a lesser degree opioids and sedatives, are subject to comedowns. A milder analogous mood cycle can happen even with blood sugar levels (thus sugar highs and sugar lows), which is especially relevant to people with diabetes mellitus and to parents and teachers managing children's behavior, as well as in adults with ADHD. Stimulant comedowns are unique in that they often appear very abruptly after a period of focus or high, and are typically the more intensely dysphoric phase of withdrawal than that following complete elimination from the bloodstream. Besides general dysphoria, this phase can be marked by frustration, anger, anhedonia, social withdrawal, and other symptoms characteristic to a milder mixed episode in bipolar disorder. Alertness and other general stimulant effects are still present.