Abuse of SSRIs

Despite the moderate value of SSRIs in the treatment of drug addiction, there is increasing evidence that these drugs, like other antidepressants, may themselves be abused. In view of the two-edged, stimulant and suppressant, actions of 5-HT on reward systems, this observation is perhaps not as paradoxical as it may at first seem.

It has been long known that addiction to MAOIs, especially those with amphetamine-like structures, can occur with some patients taking large doses to maintain stimulant and euphoric effects.93 There were also reports of abuse of amitriptyline in opiate users on methadone maintenance programs. Cohen et al94 reported that 25% of 346 methadone maintenance patients in New York admitted to taking amitriptyline for the purpose of achieving euphoria. Evidence of dependency was deduced from the persistent efforts of many patients to have their dosage increased, attempts to forge prescriptions, the presence of an illicit market for amitriptyline and the confirmation by urinalysis that patients who had not been prescribed it were taking the drug. Cantor95 confirmed that the practice was not uncommon among opiate-dependent patients and that an active street market for amitriptyline had existed in New York for many years. The effect of amitriptyline taken in doses of 50 mg to over 150 mg (sometimes up to 20 pills at once) was described as a sedative euphoria and potentiation of methadone effects.

Somewhat later Dorman et al96 reported misuse of dothiepin among intravenous drug abusers in Dublin: 46% of 83 addicts at a methadone maintenance clinic admitting to misuse of dothiepin in the previous 6 months. Patients described obtaining euphoria and sedation with complex auditory and visual hallucinations which were regarded as pleasant. Dothiepin was taken orally in doses of 150-600 mg/day.

The abuse potential of MAOIs and TCAs may not be related to their effects on 5-HT since they also increase synaptic levels of noradrenaline and to some extent dopamine. They may thus have some actions in common with amphetamine which increases central dopaminergic, noradrenergic and serotonergic activity and releases dopamine from the nucleus accumbens.41 However there is now evidence that SSRIs are also occasionally abused and that they are entering the teenage 'rave scene'. Singh97 and Singh and Catalan98 reported the use of fluoxetine and sertraline amongst people taking 3,4 methylenedioxy-methamphetamine (MDMA, "Ecstasy") at clubs. Users stated that fluoxetine (20 mg) or sertraline (50 mg) taken with or before Ecstasy prolonged the 'high' from 2 to 4 hours and made it easier to 'come down' with no hangover. Singh (personal communication) points out that MDMA is largely metabolized by the cytochrome P450, CYP2D6, which is inhibited by fluoxetine and sertraline, and suggests that SSRIs enhance and prolong the effects of MDMA by decreasing its rate of metabolism. However, CYP2D6 inhibition by these SSRIs occurs at high plasma concentrations which take time and regular usage to build up14 while recreational users take single, and not very high doses, of SSRIs irregularly. The 'high' obtained from Ecstasy is thought to be due to release of 5-HT from neurons arising in the raphe nuclei,99,100 an effect which in animals and possibly humans101 leads eventually to 5-HT depletion. Ironically, SSRIs appear to block this effect in laboratory animals97 and may protect against MDMA-induced neurotoxicity. It is not clear whether SSRIs have similar protective effects in humans since they clearly do not inhibit the Ecstasy 'high'.

Abuse of SSRIs is not confined to Ecstasy users. The Alcohol and Drugs Unit in Newcastle-upon-Tyne (personal communication) confirms the not uncommon use of fluoxetine and paroxetine among young people, usually in combination with amphetamines. Users anecdotally say that these drugs (usually 1-3 tablets) enhance and prolong the amphetamine 'high' and that fluoxetine is better than paroxetine for this purpose. Some users also take amitriptyline, using it mainly as a hypnotic. In this connection, it is interesting to note that fluoxetine has been shown to potentiate the stimulant effects of cocaine in rats, suggesting that it could amplify the subjective effects of cocaine in humans.102

These observations suggest that misuse of SSRIs may be a hazard for abusers of Ecstasy, lysergic acid diethylamide (LSD), amphetamine and cocaine. To date there appear to have been no reports of SSRI misuse in opiate abusers. It is difficult to calculate the risks, but Zawertailo et al103 compared the abuse liability of sertraline, alprazolam and d-amphetamine in 20 volunteers who were experienced but non-dependent users of CNS depressants and concluded that sertraline had a very low abuse potential compared with the other two drugs. Yet it may be salutary to remember that benzodiazepines were once thought to have a low dependence potential but illicit use of these drugs make them (especially oral and intravenous temazepam) the single most abused category of drug in Scotland.104

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