The abuse potential of designer drugs

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The term ''designer drug'' was first used in the US to describe a synthetic opioid analogue that was sold to heroin addicts in California in 1980 as a very potent form of heroin (called ''China white'', and reputed to be 200 times more potent than morphine). Subsequently the compound was identified as alpha-methyl fentanyl, an analogue of the dissociative analgesic fentanyl. It has been estimated that this compound has caused several hundred deaths through overdose in California alone, the main danger being the narrow margin between the dose producing euphoria and that leading to respiratory depression. People using these fentanyl derivatives show all the features of opiate abuse.

Another synthetic heroin-like compound was sold to heroin-dependent individuals in California in 1982 as ''new heroin'', which was soon recognized to cause severe Parkinsonian symptoms in young people. Eventually it was discovered that ''new heroin'' contained pethidine together with an N-methyl-phenyl-tetrahydropyridine (MPTP) contaminant. It is now established that MPTP is converted to a neurotoxic metabolite, MPP+, by the action of MAO-B in the substantia nigra, where it acts as a neurotoxin and destroys the dopamine cell bodies. MPTP thus acts as a pro-toxin. Its neurotoxicity can be prevented by inhibiting the action of MAO-B by deprenyl, for example, or by the administration of mazindol, which inhibits the dopamine carrier mechanism whereby MPP+ is transported into the dopaminergic neurons. Should MPP+ enter the dopaminergic neurons, irreversible parkinsonism occurs which is amenable to treatment with L-dopa. Treatment of rodents and monkeys with MPTP is now used to produce a model of the disease.

The Health Authorities in many countries are concerned over the widespread use of methylenedioxymethamphetamine, MDMA (''Ecstasy'') as a recreational drug. This has been a reflection of the increase in reports in both the medical and popular press of MDMA related fatalities and severe adverse effects. MDMA is structurally related to methylenedioxyampheta-mine (MDA), known amongst recreational drug users as ''Eve''. Both drugs cause euphoria and are drugs of abuse which are similar to methamphe-tamine. The acute effects of these drugs in volunteers who have had previous experience of MDMA include symptoms commonly seen after use of stimulants, for example, tachycardia, hypertension, dry mouth, mood elevation and a subjective sense of increased energy. Impaired judgement has also been frequently noticed. Other psychiatric symptoms which have been reported in weekend users of MDMA include a significantly reduced mood during the week following the use of the drug and an impairment of memory which may reflect the temporary depletion of brain serotonin. Reduced non-REM sleep and a disturbed sleep pattern have also been described in these users. In a study of individuals with a history of MDMA abuse, a PET imaging study showed that there was a decreased global and regional binding of a specific ligand for the serotonin transporter which suggests that, in man as in primates and rodents, regular use of MDMA is neurotoxic to serotonergic neurons. The mechanism of this neurotoxicity is unclear but there is experimental evidence to suggest that free radicals, produced by the oxidation of metabolites of MDMA, are implicated. In contrast to these chronic effects of MDMA, the acute effects include both the sympathomimetic effects and those symptoms such as hyperthermia, hyperreflexia and myoclonus which are attributed to the enhanced release of serotonin. Both the acute and chronic effects of MDMA seen in rodents and primates occur at doses commonly taken by recreational drug users (75-150 mg).

MDMA and MDA abuse has been associated with panic disorder, depression and chronic paranoid psychosis. As these conditions may also occur independently of these drugs, it is difficult to prove causality but it seems reasonable to conclude that some individuals are more vulnerable to such psychiatric disorders which are exacerbated by these drugs. In

Figure 15.5. Structures of some ''designer drugs'' of abuse. Compare the structure of alpha-methyl fentanyl with that of fentanyl, MMP+ with that of pethidine, and ecstasy with that of methamphetamine.

addition to the neurological and psychiatric effects that are elicited by these amphetamines, recent evidence suggests that some aspects of cellular immunity are suppressed for several hours even after a single dose of MDMA. It is currently unclear what impact this might have, particularly after regular recreational use, on the resistance of the immune system to infections but clearly these drugs have effects which far exceed those anticipated from the pharmacology of amphetamine.

In conclusion, recent evidence suggests that MDMA and related compounds do not deserve the widespread belief that they are harmless substances which should be legally available. They constituted a potentially serious risk for acute toxic reactions that cannot be predicted by the dose taken. The acute reactions carry with them significant mortality and morbidity while the neurotoxicity shown to occur in rodents, primates and now in man suggests that they have a potential to cause permanent brain damage.

The structures of some of these ''designer drugs'' are shown in Figure 15.5. Their relationship to the amphetamines and opiates is apparent.

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