MAO-inhibitors with stimulants (a comment to Murple)
I had to start a new topic because I consider this one as a really important interaction. Also the conflicting information of the severity of this interaction makes it important.
I'll comment Murple's message posted to another thread on trip reports forum.
From a person like Murple, who is regarded usually as a knowledgeable person in internet drug community, I consider the following comment very irresponsible and ignorant:
Originally posted by Murple:
I and other have mixed MAO-A inhibitors (harmine, though moclobemide is also an MAO-A-I) with MDMA before on multiple occasions with no problems. Mixing an MAO-B inhibitor or a nonselective MAOI with MDMA could theoretically lead to a hypertensive crisis and could theoretically be dangerous and maybe even fatal... However, MAO-A inhibitors are (in theory) just going to make the MDMA affect you stronger (andome psychedelic effects in the case of harmala alkaloids).
The thing that you have mixed it succesfully doesn't mean that it can considered as "safe". Moclobemide-MDMA -combination has caused at least four deaths in Finland within a year [1].
Murple states that "mixing an MAO-B inhibitor or a nonselective MAOI with MDMA could theoretically lead to a hypertensive crisis..."
This is not completely true. Norepinephrine (noadrenaline) is the primary neurotransmitter of the sympathetic nervous system, which controls for example blood pressure. Norepinephrine controls blood pressure both centrally and peripherally. Drug induced hypertension is usually mediated via noradrenergic mechanisms [2]. It should be noted that MAO-B doesn't metabolize norepinephrine in the human brain [3]. In my opinion, for this reason the risk of hypertensive crisis is more likely with MAO-A-inhibitors (but possible also with MAO-B-inhibitors). Supporting my opinion, there is evidence that the cardiovascular effects of high-dose ephedrine is potentiated by moclobemide treatment [4]. Also serotonin is metabolized by MAO-A. Thus, the risk of serotonin syndrome is more likely with MAO-A-inhibitors. Combination of SSRI and moclobemide has been reported to cause fatal serotonin syndrome [5]. Good examples about the lethality of serotonin releasing effects combined with selective MAO-A-inhibition is PMA and 4-MTA, which both have caused several deaths and near-death situations in short time [6,7,8]. Both PMA and 4-MTA are serotonin releasers and potent MAO-A-inhibitors, which probably accounts their increased toxicity [7,9,10]
In conclusion, combining MDMA or amphetamine with moclobemide causes unpredictable potentiation of the effects of MDMA or amphetamine and thus is highly unadvisable.
If you do try mixing MDMA with MAOIs, be aware of these factors, and use low doses of MDMA (less than half what you normally would). Never use MAO-B inhibitors or nonselective MAOIs with MDMA - the only "safe" MAOIs to use with MDMA are MAO-A inhibitors such as harmine, harmaline or moclobemide. Taking MDMA with Deprenyl or any other substances that inhibit MAO-B could be potentially fatal, although no fatalities have been recorded (a few frightening physical reactions have been documented involving Deprenyl though).
It's good that you note that the dosage of MDMA should be very small. But you didn't mention that the MAO-A selectivity of harmala-alkaloids are lost in higher dosages. This can also contribute to the risk of this combination. For example, the amount of harmala-alkaloids ingested typically in hoasca are most likely so high that it's aufficient to inhibit both isozymes of MAO [11].
References:
[1] Personal communication with finnish forensic medicine professor.
[2] Hessler R. Cardiovascular Principles. In: Goldfrank's Toxicologic Emergencies, 6th edition (Ed. Goldfrank, Flomenbaum, Lewin, Weisman, Howland, Hoffman). Appleton & Lange 1998. pp. 353-378.
[3] Pepper JP, Baumann MH, Ayestas M, Rothman RB.
Inhibition of MAO-A fails to alter cocaine-induced increases in extracellular dopamine and norepinephrine in rat nucleus accumbens.
Brain Res Mol Brain Res. 2001 Mar 5;87(2):184-9.
[4] Dingemanse J, Guentert T, Gieschke R, Stabl M.
Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide.
J Cardiovasc Pharmacol. 1996 Dec;28(6):856-61.
[5] Neuvonen PJ, Pohjola-Sintonen S, Tacke U, Vuori E.
Five fatal cases of serotonin syndrome after moclobemide-citalopram or
moclobemide-clomipramine overdoses.
Lancet. 1993 Dec 4;342(8884):1419.
[6] Martin TL.
Three cases of fatal paramethoxyamphetamine overdose.
J Anal Toxicol. 2001 Oct;25(7):649-51
[7] Kraner JC, McCoy DJ, Evans MA, Evans LE, Sweeney BJ.
Fatalities caused by the MDMA-related drug paramethoxyamphetamine (PMA).
J Anal Toxicol. 2001 Oct;25(7):645-8.
[8] De Letter EA, Coopman VA, Cordonnier JA, Piette MH.
One fatal and seven non-fatal cases of 4-methylthioamphetamine (4-MTA)
intoxication: clinico-pathological findings.
Int J Legal Med. 2001;114(6):352-6.
[9] Huang X, Marona-Lewicka D, Nichols DE.
p-methylthioamphetamine is a potent new non-neurotoxic serotonin-releasing agent.
Eur J Pharmacol. 1992 Dec 8;229(1):31-8.
[10] Scorza MC, Carrau C, Silveira R, Zapata-Torres G, Cassels BK, Reyes-Parada M.
Monoamine oxidase inhibitory properties of some methoxylated and alkylthio
amphetamine derivatives: structure-activity relationships.
Biochem Pharmacol. 1997 Dec 15;54(12):1361-9.
[11] Callaway JC, McKenna DJ, Grob CS, Brito GS, Raymon LP, Poland RE, Andrade EN, Andrade EO, Mash DC.
Pharmacokinetics of Hoasca alkaloids in healthy humans.
J Ethnopharmacol. 1999 Jun;65(3):243-56.
Originally posted by quale:
Alright I think I am going to have to disagree with you on a couple points. First of all are you doubting that murple has succesfully combined these agents? If he and others indeed have we have significantly more evidence for the safety of these combinations than the untried MAO-B combinations.
No, I don't doubt that murple has combined MDMA with MAOA-inhibitor, I just questioned his assumption that it can be regarded as safe. I have combined deprenyl (a MAO-B inhibitor) with amphetamine and MDMA without problems. However, I don't like to boast with it, because I can't be sure about the safety of this combination.
First of all serotonin syndrome is not the primary cause of ecstasy overdose (ignoring stupid shit like dehydration) it is heart failure/hypertension induced.
Could you give a journal reference for this? Serotonin syndrome and hyperthermia seems to contribute significantly to the lethality of MDMA [1,2,3,4]. As I argued in my previous post, also the cardiovascular toxicity of MDMA is likely potentiated by MAO-A inhibitors. Thus, I can't understand the point of this comment of yours.
Moreover it seems that it is the overload in the sympathetic nervous system (outside of the brain) seems to be heavily implicated in this. Take a look at the various threads about stims and beta-blockers. Thus we have very good reason to believe MAO-B blockers are likely to incite a hypertensive crisis.
Again, I can't understand the reasoning of yours. What makes you think that it's the MAO-B inhibitors behind the hypertensive crisis? Yes, the cardiovascular effects of amphetamines can be alleviated with beta1-antagonists but how does this link with MAO-B? The combination of inhibition of MAO-A with inhibition of reuptake of serotonin and norepinephrine may result in a flood of serotonin and norepinephrine into the synapse, exceeding its capacity for enzymatic catabolism. The only effective route of catabolism for excess serotonin is through MAO, thus making serotonin syndrome likely. Catecholamines, on the other hand, can be catabolized also by catechol-o-methyl transferase (COMT). Circulating catecholamines are usually inactivated by a combination of uptake 1, uptake 2 and COMT. It is generally assumed that MAO-A is responsible for the oxidative deamination of norepinephrine in sympathetic nerve endings [9].
I note that for all those citations about death you put up they all seem to say just they died of heart problems.
The spectrum of serotonin syndrome includes cardiac arrhythmia and respiratory arrest [5].
BTW MDMA has MAOA-inhibition propoerties and pure MDMA is pretty hard to overdose on.
PMA is 30-fold more potent inhibitor of MAO-A than MDMA. PMA doesn't inhibit MAO-B [6].
In fact as your entier argument is based on the theory of serotonin syndrome fatality you must deal with the huge gaping hole, E realeases a fuckton of serotonin why doesn't it cause this toxicity. In fact agents like MDAI which are more selective at releasing serotonin seem less lethal.
My argument was not solely based on serotonin syndrome. It was based on potentiation of BOTH serotonergic AND noradrenergic transmission by MAO-A-inhibitors. Thus making the incidence of hyperthermic and cardiovascular fatalities more likely. There is some evidence that enhancement of overall serotonergic neurotransmission is necessary but possibly not sufficient cause of the serotonin syndrome. Some researchers even considered that inhibition of both MAO-A and MAO-B is essential for the development of the serotonin syndrome [7].
The hyperthermia by psychostimulants is most likely mediated by dopaminergic mechanisms (so this could be in theory be potentiated by MAO-B inhibitors) and the serotonergic neurotransmission has synergistic contributing role in this [8].
Some more evidence comes from this article which seems to imply the overdose effects of taking e plus an MAO resembeled those of amphetamine. Thus suggesting that it is the ampetaminelike MAOI-B potentiated toxicity that we need to worry about most.
Phenelzine is non-selective MAO-inhibitor, so how can you tell how much the MAO-B-inhibiting properties of it contributed to the interaction?
References:
[1] Gill JR, Hayes JA, deSouza IS, Marker E, Stajic M.
Ecstasy (MDMA) deaths in New York City: a case series and review of the literature. J Forensic Sci 2002;47(1):121-126.
[2] Demirkiran M, Jankovic J, Dean JM.
Ecstasy intoxication: an overlap between serotonin syndrome and neuroleptic malignant syndrome.
Clin Neuropharmacol. 1996 Apr;19(2):157-64
[3] Appendix 1, In: Kalant H.
The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs.
CMAJ. 2001 Oct 2;165(7):917-28.
[4] Mueller PD, Korey WS.
Death by "ecstasy": the serotonin syndrome?
Ann Emerg Med. 1998 Sep;32(3 Pt 1):377-80.
[5] Bodner RA, Lynch T, Lewis L, Kahn D.
Serotonin syndrome.
Neurology. 1995 Feb;45(2):219-23.
[6] Mash DC, Izenwasser S, Quyang Q, Wade D, Dal Cason TL, Hearn WL.
Para-methoxyamphetamine (PMA) inhibits MAO-A: Implications for fatal hyperthermia associated with club use of psychoactive amphetamines. Drug Alcohol Depend 2001;63(Suppl 1):S99.
[7] Sternbach H.
The serotonin syndrome.
Am J Psychiatry. 1991 Jun;148(6):705-13.
[8] Callaway CW, Clark RF.
Hyperthermia in psychostimulant overdose.
Ann Emerg Med. 1994 Jul;24(1):68-76.
[9] Bitsios P, Langley RW, Tavernor S, Pyykko K, Scheinin M, Szabadi E, Bradshaw CM.
Comparison of the effects of moclobemide and selegiline on tyramine-evoked mydriasis in man.
Br J Clin Pharmacol. 1998 Jun;45(6):551-8.
If the falling tide can turn and then recover, all alone we must be part of one another
) thinks it would be pretty