Are there any interactions between the narcotic substances cannabis, LSD (lysergic acid diethylamid

Fråga: Are there any interactions between the narcotic substances cannabis, LSD (lysergic acid diethylamide) and amphetamine and the antidepressants Efexor (venlafaxine) and Aurorix (moclobemide)?

Sammanfattning: Combining cannabis and venlafaxine could theoretically cause tachycardia and possibly mania due to pharmacodynamic interactions. There is a theoretical risk of interactions on cytochrome P450 CYP3A4 when cannabis is combined with venlafaxine.

There are indications of SSRI:s and MAO-inhibitors attenuating and TCA:s increasing the effects of LSD. Venlafaxine has potentiated the effect of LSD in animal studies.

The combination of amphetamine and moclobemide is known to cause hypertensive crises due to a pharmacodynamic interaction on the adrenergic system. This could probably be the case when amphetamine is combined with venlafaxine as well. Both venlafaxin and moclobemide could hypothetically reduce the rate of amphetamine metabolism by inhibiting CYP2D6.

Svar: Tachycardia is a known adverse effect of both cannabis (1) and venlafaxine (2). Concomitant use could therefore possibly increase the risk of this symptom.

There is one case report of mania elicited by marijuana smoking in a woman treated with fluoxetine (3). 9-tetrahydrocannabinol, one of the active components of cannabis, is a potent inhibitor of serotonin uptake (3) and thus a synergistic effect on serotonergic neurons may have caused the symptoms. As venlafaxine too inhibits serotonin uptake, the same sort of interaction seems possible with this substance.

Cannabis is partially metabolised by the cytochrome P450 CYP3A isoenzyme family (4) and possibly by CYP2C9 (5). Venlafaxine is mainly metabolised by CYP2D6, but also to some extent by CYP3A4, where interactions with cannabis theoretically could occur. Since the tar component of tobacco smoke induces CYP1A2, induction of this isoenzyme seems possible in cannabis smokers as well, although it has not been confirmed. Moclobemide is mainly metabolised by CYPC19, but also by CYP1A2 and CYP2D6 (6). Hypothetically, an interaction could occur on CYP1A2, although it would probably be of small clinical significance.

LSD is a partial agonist at serotonin receptors (7). Since both venlafaxine and moclobemide affect the serotonin system (2), pharmacodynamic interactions would be expected. No specific information on interactions between LSD and these two substances was found, but interactions with other antidepressants have been investigated in two retrospective interview-based studies in LSD users (8-9). Two of the subjects were taking the MAO-inhibitor phenelzine. Both reported decreased physical, hallucinatory and psychological effects of LSD during the period of medication. Of 32 LSD-users taking SSRI (fluoxetine, sertraline or paroxetine) for more than three weeks, 28 (88 percent) reported a moderate to marked decrease in their usual responses to LSD. The opposite was true for the five subjects taking tricyclic antidepressants (imipramine and desipramine), who all reported increased LSD effects. The differences between classes of antidepressants on modulating the effects of LSD are not clearly understood.

In a study where rats had been trained to discriminate between LSD and placebo injections, LSD was recognised at lower doses when the rats were co-medicated with venlafaxine (10). This was interpreted as an amplification of the LSD effect.

Amphetamine has adrenergic effects mainly by inducing the release of norepinephrine (11). There are several reports of hypertensive crises due to amphetamine intake in patients treated with MAO-inhibitors such as moclobemide (12). Theoretically, combining amphetamine and venlafaxin could cause cardiovascular adverse effects also, since venlafaxine inhibits the uptake of norepinephrine. This should not be the case with SSRI:s (13).

Amphetamine is metabolised by CYP2D6 (14). Venlafaxin and moclobemide both inhibit this isoenzyme and pharmacokinetic interactions could be expected (6, 15). This has been confirmed in SSRI:s, known to inhibit CYP2D6 (14), but since amphetamine is mainly excreted unchanged in the urine (16), severe adverse effects by this mechanism seem unlikely. 1 Reynolds JEF, editor. Martindale, The extra pharmacopoeia. 31st ed. London: Royal Pharmaceutical Society; 1996. p. 1558 2 FASS 1999 (The Swedish catalogue of approved medical products) 3 Stockley IH. Drug interactions. 5th ed. London: The Pharmaceutical Press; 1999. p. 736 4 Bornheim LM, Lasker JM, Raucy JL: Human hepatic microsomal metabolism of 1-tatrahydrocannabinol. Drug Metab Dispos 1992; 20: 241-246 5 Drugline no 15180 (year 1998) 6 Drugline no 13133 (year 1997) 7 Backstrom JR, Chang MS, Chu H, Niswender CM, Sanders-Busch E: Agonist-directed signaling of serotonin 5-HT2C receptors: differences between serotonin and lysergic acid diethylamide (LSD). Neuropsychopharmacol 1999: 21: 77S-81S 8 Bonson KR, Murphy DL: Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium. Behav Brain Res 1996; 73: 229-233 9 Bonson KR, Buckholtz W J, Murphy DL: Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans. Neuropsychopharmacol 1996; 14: 425-436 10 Winter JC, Helsley S, Fiorella D, Rabin RA: The acute effects of monoamine reuptake inhibitors on the stimulus effects of hallucinogens. Pharmacol Biochem Behav 1999; 63: 507-513 11 Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Goodman Gilman A, editors. Goodman & Gilman´s The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996

12 Drugline no 12666 (year 1995)
13 Drugline no 11230 (year 1994)
14 Drugline no 13144 (year 1997)
15 Drugline no 15516 (year 1997)

16 Rang HP, Dale MM. Pharmacology. 2nd ed. Edinburgh: Churchill Livingstone; 1991. p. 739