Psychostimulants are frequently used in combination with other substances. Use of other drugs in combination with psychostimulants may influence either the acute effects of either drug, or the longer-term risks associated with psychostimulant use.



Ethanol

Nicotine

Cannabis

Opiates

Antidepressants



Ethanol

Nicotine

Cannabis

Opiates

Antidepressants

Increased risk of serotonin toxicity

Reuptake inhibitors — a special case?

Sympathomimetic toxicity

Changes in metabolism

Ethanol is often consumed before or during cocaine use. Some research suggests that the concurrent use of alcohol and cocaine leads to greater increases in blood pressure and heart rate than when using cocaine alone ( Foltin & Fischman, 1988 ) and may increase the risk of cardiodepression, cardiac myopathies and other cardiovascular toxicities. It has been suggested that this toxicity may result from the formation of an active, ethanol-induced metabolite, cocaethylene, which is more toxic than cocaine or ethanol alone ( Knuepfer, 2003 ). Studies suggest that cocaethylene is more euphorigenic and reinforcing than cocaine and that its pharmacological effects are additive or synergistic to cocaine and potentially more toxic ( Hearn, Rose, Wagner, Ciarleglio & Mash, 1991 Randall, 1992 ).In humans, the combination of cocaine and ethanol appears to exert more cardiovascular toxicity than either drug alone ( Foltin & Fischman, 1988 ). In addition, ethanol appears to potentiate cocaine hepatotoxicity ( Jover, Ponsoda, Gomez-Lechon, Herrero et al., 1991 Landry, 1992 ).Some evidence suggests that concurrent alcohol and methamphetamine use may slow metabolism of methamphetamine, potentially increasing risk of adverse effects ( Shimosato, 1988 ). Mendelson and colleagues (1995) report that the concurrent administration of methamphetamine and ethanol reduced the subjective effects of ethanol, but did not alter the subjective effects of methamphetamine. The combination also increased systolic blood pressure without any changes in heart rate; they suggest that this increase in cardiac work associated with the combination could produce more adverse cardiovascular effects than observed when either drug is taken alone.Laboratory studies suggest that cocaine may reverse certain alcohol-related psychomotor deficits ( Pennings et al., 2002 ). One study ( Hernandez-Lopez, Farre, Roset, Menoyo et al., 2002 ) reported that concurrent use of MDMA and alcohol produced greater MDMA plasma concentrations and greater euphoria. The combination also reversed the perception of alcohol-related sedation but did not reverse psychomotor impairment, which the authors conclude may impact upon issues such as road safety. Top of page Cocaine has also been reported to interact with nicotine, producing a synergistic effect on dopamine release in the reward areas of the brain. Amphetamines are considered by some to be behavioural psychostimulants ( Kolta, Shreve, De Souza & Uretsky, 1985 ), meaning that use of amphetamines increases the rate of learned and stereotypic behaviours. One study has demonstrated that use of dexamphetamine led to dose-related increases in the number of cigarettes smoked, total puffs, weight of tobacco consumed, expired air carbon monoxide levels and subject-rated satisfaction derived from smoking ( Henningfield & Griffiths, 1981 ).Cocaine and nicotine may also exert synergistic effects on myocardial oxygen supply, arterial pressure and cardiac contractility ( Moliterno, Willard, Lange, Negus et al., 1994 ). Since nicotine, like cocaine, is a risk factor for cardiac disease, it is thought that smoking may increase the incidence of cardiac complications arising from cocaine use ( Lange & Hillis, 2001 ).Smoking methamphetamine in combination with tobacco produces the pyrolysis product cyanomethylmethamphetamine ( Sekine & Nakahara, 1987 ). This is thought to possess psychostimulant properties ( Sekine, Nagao, Kuribara & Nakahara, 1997 ), but the potential toxicity of this product has not been established.A number of reports suggest that cannabis may increase the subjective effects of cocaine, reduce duration of dysphoric effects and cause a greater increase in heart rate compared to use of either drug ( Foltin, Fischman, Pedroso & Pearlson, 1987 Lukas, Sholar, Kouri, Fukuzako & Mendelson, 1994 ). Concomitant marijuana use may increase the pharmacologic and toxic effects of cocaine. Cannabis levels seem to be unaffected by cocaine. The mechanism of this interaction is not well established. It has been suggested that cannabis-induced vasodilation of the nasal mucosa leads to increased cocaine absorption, although these effects have also been demonstrated using intravenous cocaine ( Foltin et al., 1987 ). Whether such an interaction exists between amphetamine-related compounds and cannabis has not been demonstrated.There are no particular interactions documented between opiates and psychostimulants. However, it has been reported that opiate withdrawal may increase the risk of aggressive behavioural reactions to psychostimulants ( Miczek & Tidey, 1989 ). Top of page Antidepressants may be co-ingested with psychostimulants for a number of reasons such as concurrent treatment of depression, treatment of psychostimulant dependence or inappropriate attempts to enhance the effects of psychostimulants (MDMA in particular). A number of antidepressants can interact with psychostimulants to increase the risk of harms arising from psychostimulant use.Most antidepressants enhance serotonergic activity, sometimes acting on the serotonin transporter, which is also the site of action for MDMA. Concurrent use with other serotonergic agents may increase the risk of serotonergic side-effects. Assessment and management of serotonin toxicity is discussed in more detail in Chapter 5: Psychosocial interventions Vuori and colleagues ( Vuori et al., 2003 ) describe four deaths following ingestion of MDMA and the antidepressant, moclobemide. The mode of death in each case was consistent with a serotonin syndrome. Another report ( Kaskey, 1992 ) describes what was probably a serotonin syndrome after ingestion of MDMA and phenelzine. These antidepressants are monoamine oxidase inhibitors (MAOIs), which inhibit the enzyme responsible for metabolism of serotonin, noradrenaline and dopamine.Most antidepressants used in Australia act by inhibiting reuptake of serotonin, rather than interfering with its metabolism, e.g. selective serotonin reuptake inhibitors (SSRIs). Both MDMA and SSRIs act on the serotonin transporter. Via this transporter, MDMA produces serotonin release and SSRIs remove serotonin from the synapse. The drug interaction arising from concomitant administration of MDMA and SSRIs depends on the temporal ordering of drug use.Initial use of an SSRI will inhibit serotonin transporter function, impairing the activity of any subsequently used MDMA. The ability of pre-treatment with an SSRI to block the effects of MDMA has been demonstrated in animal studies ( Shankaran, Yamamoto & Gudelsky, 1999 Stein & Rink, 1999 ). However, in the reverse scenario, if SSRIs are used after MDMA, the opposite interaction may occur. Initial use of MDMA increases release of serotonin; use of an SSRI after this release may prevent its removal from the synapse, leading to potentiation of serotonergic effects and possible toxicity.The actual clinical outcome produced in real situations is difficult to predict. One report ( Lauerma, 1998 ) describes a case where ingestion of the SSRI citalopram and an unknown quantity of MDMA led to symptoms resembling 'serotonin syndrome' which improved after cessation of the citalopram. Another case ( Prior, Isbister, Dawson & Whyte, 2002 ) describes a patient maintained on dexamphetamine (15 mg daily) who developed signs of serotonin toxicity after initiating venlafaxine (a noradrenaline and serotonin reuptake inhibitor). After venlafaxine was discontinued and symptoms abated, he was initiated on citalopram, which led to re-emergence of serotonergic symptoms. Top of page Sympathomimetic toxicity may also occur. Concurrent use of amphetamine-related substances and non-selective MAOIs results in severe hypertension. Acute elevations in blood pressure have also been noted after co-ingestion of methylphenidate and a tricyclic antidepressant ( Flemenbaum, 1971 ). This interaction has the potential to occur with other antidepressants that enhance noradrenergic activity, including moclobemide, tricyclic antidepressants and venlafaxine.Amphetamines, methamphetamine and MDMA are metabolised in the liver by a range of enzymes, one of which is cytochrome P450 2D6 (CYP2D6). Many antidepressants inhibit this enzyme and thus may have the potential to increase the blood levels of the psychostimulant and alter toxicity profiles ( Ramamoorthy et al., 2002 ). Antidepressants which may inhibit CYP2D6 include paroxetine and fluoxetine and to a lesser extent sertraline ( Hemeryck & Belpaire, 2002 ).