CNS stimulants with MAOIs
See also more recent note http://www.psychotropical.com/maois-and-releasers-including-amphetamines
CNS stimulants considered here are methylphenidate, amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). There is not sufficient data, either theoretical, or well-documented practical experience, to make any reliable statement about other stimulants.
A recent review with some useful general comments and background is Feinberg , and Rothman’s recent paper, currently not on the PDSP - Database at http://pdsp.cwru.edu/pdsp.asp has much valuable affinity data, whilst Markowitz  deals comprehensively with all clinical CNS stimulant drug interactions (not just serotonin toxicity, as herein). These reviews illustrate the desirability of ensuring the clearest possible understanding of the distinction between different toxidromes; especially blood pressure elevation, due to tyramine or other ‘indirectly’ acting amines (the ‘cheese’ reaction), as opposed to serotonin toxicity.
As I have pointed out previously [3-5], there is much misinformation and misunderstanding in what have hitherto been regarded as authoritative sources and texts. It is not possible to adequately understand the current evidence without appreciating that much comment failed to recognised the characteristics of serotonin syndrome, nor were the relevant properties of many of the drugs concerned known about, or recognised and understood.
Feinberg stated ‘As in other fields of medicine, potentially hazardous medication combinations are utilized in psychiatry after cautiously weighing the danger of the treatment against the morbidity and risk of not adequately addressing the illness. Particularly, as the potential arrival of the apparently safer transdermal selegiline may increase the use of MAOIs, we feel this combination deserves additional controlled study.’ I agree with this, and also the comment by Bonnet [6-7] made in his ‘CNS Drug Reviews’ article about moclobemide, on which I commented . However, I would also point out that some researchers, even from eminent institutions, have performed experiments (drug trials) when they did not know as much as they might have about he extent of the risks . Those who work and experiment in this area have a a particularly high obligations to do their utmost to ensure that they are as fully informed as current knowledge can possibly enable them to be. I suggest that the history of serotonin syndrome in Western Psychiatry illustrates that psychiatrists in general, including academic psychiatrists at reputable institutions, have not got an ideal record in this respect.
Pharmacological Profile for 5-HT release and 5-HT uptake inhibition
See full table in Rothman 
* sertraline- for comparison, not from Rothman
5-HT NE DA
Release (EC50 nm) Uptake (Ki nm) Release (EC50 nm) Uptake (Ki nm) Release (EC50 nm) Uptake (Ki nm)
Amphetamine 1765 3830 7 39 25 34
Ephedrine >10,000 >50,000 72 225 1350 4398
Fenfluramine 52 150
MDMA 57 238 77 462 376 1572
Cocaine > 10,000 304 >10,000 780 >10,000 478
Desipramine > 10,000 350 > 10,000 8.3 > 10,000
Citalopram > 10,000 2.4 > 10,000 > 10,000
Fluoxetine > 10,000 9.6
Sertraline --- 0.29*
More significant values highlighted
Reuptake inhibition is mediated by the effect of drugs on the transporters for serotonin, norepinephrine and dopamine (often abbreviated as SERT, NET and DAT respectively). Drugs that affect these transporters act either as reuptake inhibitors or substrate releasers. Reuptake inhibitors bind to the transporters, but are not transported into the pre-synaptic terminal. Releasers are transported into the pre-synaptic nerve terminals. Once transported into the pre-synaptic nerve terminals they promote neurotransmitter release and thereby elevate extracellular neurotransmitter levels. Reuptake inhibitors prevent ingress of releasers into the pre-synaptic terminal, and thus block their effects [9-14].
It remains uncertain even now as to whether the serotonergic effect of opioid analgesics is due to a weak SRI effect or a serotonin releasing effect. .
In the past sympathomimetic amines like ephedrine, amphetamine and tyramine have been termed ‘indirectly acting sympathomimetic amines’ or ‘indirect agonists’ and there has been concern and uncertainty about the extent to which they may interact with MAOIs, which they can do via both the noradrenergic (norepinephrinergic) and serotonergic systems. In this discussion I shall follow Rothman’s example and use the term ‘releasers’, not indirect agonists, because that terminology facilitates an easier understanding of the mechanism of action and the commonalities between ST and the elevated blood pressure of the ‘cheese reaction’, which share the same type of mechanism.
Tyramine acts as a releaser of noradrenaline, thus precipitating the well know hypertensive response (cheese reaction); however it is less well known that noradrenaline reuptake inhibitors (NRIs), like reboxetine and nortriptyline, will prevent that reaction because they block tyramine’s entry into the pre-synaptic terminal . Directly acting amines are better termed post-synaptic receptor agonists, which is what other drugs that stimulate post-synaptic receptors are usually called. Post-synaptic receptor agonists cause a lesser interaction with either tricyclic antidepressants (TCAs) or MAOIs than do releasers; hence amphetamine is more problematic than adrenaline in combination with MAOIs.
MDMA, ecstasy (3,4-methylenedioxymethamphetamine) acts like tyramine, but seemingly more as a releaser of serotonin than noradrenaline, and its serotonergic action is blocked by serotonin reuptake inhibitors .
In conclusion, it is helpful to be aware of that some reviewers have not fully appreciated the differences between different toxidromes, such as serotonin toxicity and noradrenergic toxicity. Failure to make such distinctions leads to blanket prohibitions concerning drug classes that that are not justified by the evidence pertaining to individual drugs’ interaction or toxicity profiles. This is particularly relevant with CNS stimulants, because the evidence reviewed herein clearly indicates that methylphenidate is significantly different to amphetamine and may be safely combined with MAOIs.
Methylphenidate and MAOIs have been in use together for 40 years, so it would be surprising if someone had not ingested the combination by now: death, or morbidity, from such an event has not been reported (whereas it has with amphetamine). Methylphenidate is most widely used as a treatment for attention-deficit hyperactivity disorder (ADH) in children. It has been supposed to have serotonergic effects; if that is so it would be predicted to be at high risk of precipitating serotonin toxicity if combined with MAOIs. There are no definite case reports indicating serotonin toxicity with methylphenidate in combination with MAOIs, or other serotonergic drugs (see above) [17-20].
Also, as with mirtazapine and amitriptyline, methylphenidate does not produce serotonergic side effects, or signs of serotonergic toxicity in over-dose or if combined with MAOIs (see Markowitz). Eg the Sherman case was not serotonin toxicity, but blood pressure elevation [21-28].
These observations of serotonergic side effects, and signs of serotonergic toxicity in over-dose, or if combined with MAOIs, have been proposed as a measure of a drugs clinically significant serotonergic effect in humans. If these effects are not produced clinically significant serotonergic effects are unlikely. [29-32].
Methylphenidate also appears safe in combination with MAOIs; see Feinberg’s recent and helpful review of MAOIs and CNS stimulants.[1-33-35].
This is in keeping with its negligible 5-HT transporter affinity (>10,000 nmol) and apparent inability to raise brain serotonin levels. Unfortunately Rothman’s data does not include methylphenidate so there is no ‘releaser’ potency data. If methylphenidate acts as a releaser in humans then it would be predicted that its effect would be lessened by selective serotonin reuptake inhibitors (SSRIs)s [21-23-36].
Amphetamine and MAOIs have also been in use together for 40 years and there are few deaths from apparent serotonin toxicity reported with amphetamine. Amphetamine has weak serotonergic effects; and there seems little risk of precipitating serotonin toxicity if combined with MAOIs. All the case reports with MAOIs and Amphetamine were prior to 1969. The only fatalities have been with MAOIs [37-44].
Amphetamine itself does not seem to produce typical serotonergic side effects, or signs of serotonergic toxicity in over-dose, except hyperreflexia, hyperkinesia (agitation) and hyperpyrexia. Deaths from hyperpyrexia and other causes, but without classic features of serotonin toxicity, have been described. [45-46].
Amphetamine may not be safe in combination with MAOIs (see Feinberg’s and Markowitz’s recent and helpful reviews of MAOIs and CNS stimulants). It seems to produce noradrenergic toxicity; presumably in the same way as tyramine does, by acting as a releaser. None of these cases were reported to exhibit features that would suggest serotonin toxicity. Several of these cases were fatalities (2 of these below are not cited in the Markowitz paper) [38-41-44].
However, chlorpromazine appears to ameliorate the toxicity symptoms with amphetamine / MAOI as it does with serotonin toxicity..
Amphetamine is 50-100 times less potent for serotonin, both as a releaser and reuptake inhibitor, than for dopamine or noradrenaline (see table). Its 5-HT transporter affinity (~3800 nmol) is extremely weak. However, unlike methylphenidate there is animal work indicating amphetamine does increase serotonin levels [9-22].
In summary, amphetamine definitely has been involved in deaths with MAOIs, and exhibits significant toxicity with venlafaxine (probably serotonin toxicity, as opposed to noradrenergic toxicity). To what degree the toxicity with MAOIs is serotonergic remains uncertain, but most fatalities have been from intra-cerebral bleeding, not serotonin toxicity .
If CNS stimulants are to be used to augment monoamine oxidase inhibitors methylphenidate is probably safe; amphetamine is more risky, and can produce moderate noradrenergic toxicity, even at therapeutic doses and perhaps serotonergic side effects, and even serotonin toxicity in over-dose.
MDMA (Ecstasy) 3,4-methylenedioxymethamphetamine
Ecstasy is the street name for 3,4-methylenedioxymethamphetamine (MDMA). Large doses of MDMA cause a rapid release of endogenous serotonin from the stores in the presynaptic nerves; so much so that a substantial MDMA dose will deplete about eighty percent of the serotonin stores. The "half life" of endogenous serotonin is short and the usual duration of symptoms does not frequently allow the development of hyperthermia, although this is influenced by ambient temperature and physical activity.[48-49]
MDMA will occasionally produce, among other things, a picture which is essentially that of serotonin toxicity; however serotonin toxicity sufficiently severe to cause death with MDMA alone is rare.
However such reports as do exist conform with predictions from the spectrum concept of serotonin toxicity and the data in Rothman (see table). No cases of serotonin toxicity with MAOIs had been reported in the literature till 2003. There have been one or two cases where people taking moclobemide, presumably to enhance effects, have been too successful and have experienced severe reactions. I know of one death (unpublished) seemingly from cerebral infarction secondary to arterial spasm. The Vuori report is of four deaths, probably from serotonin toxicity .
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