One or two recent papers about the mechanisms of action of MAOIs and amphetamine at the molecular level suggest why the combination of amphetamine (with MAOIs) is not unduly risky as has been (mis)stated for so long. Care and experience are required but it can be done safely although small increases in dose do sometimes seem to have disproportionate effects.

Amphetamine is a potent DA and NA releaser (in former terminology, an ISA) at low nano-molar (10^-9) concentrations. There is still uncertainty about its exact mechanisms of action and just how it interacts with the monoamine transporters etc. It acts as a competitive inhibitor (for NAT & DAT) and has actions in the pre-synaptic cytoplasm, at the vesicular monoamine transporter (VMAT) and TAR1 receptors. The latest understanding of this is complex and beyond the scope of this review. Further details are in: (1, 2). Those using these combinations may wish to study these references to understand more about ‘non-exocytotic release’ that does not require any neuronal activity (viz. nerve impulse) to trigger it, and how they inhibit reuptake in a competitive manner and more.

Unsurprisingly, considering the multiple sites at which drugs classed as amphetamines affect the neurotransmitter systems, there are marked differences between closely related drugs: for instance, methylphenidate (which is classified as an amphetamine) seems to be mainly a DA re-uptake inhibitor, and not a releaser. It produces no risk of ST or a pressor response.

As Paracelsus stated ‘the dose makes the poison’ and that may be particularly applicable to amphetamine. Releasers are capable of increasing intra-synaptic transmitter concentrations by more than 1,000-fold, compared to a maximum closer to 10-fold with reuptake inhibitors (2) — cf. see (3), re such mechanisms of interactions involving RIs, releasers and MAOIs.

Amphetamine causes NA increases of a lesser magnitude (400–450% of baseline) compared to dopamine (700–1500% of baseline). This suggests that used carefully the risk of precipitating hypertension is low (as practical experience indicates, see Israel for a recent report and review (4)). The advent of lisdexamfetamine may now add another layer of safety because its slow conversion to the active form (d-amphetamine) occurs in red blood cells by rate-limited enzymatic hydrolysis. This means the time to T_max is rather longer and peak levels are lower, about half (5). It also has a low potential for cytochrome P450 interactions (6, 7). Not only that, but also the inter- and intra-subject plasma levels are much less variable which produces a ‘smoother’ and more predictable response (8): how good does it get! An unusual example of the usefulness of a pro-drug. It is to be confidently expected that this combination (with MAOIs) will be even safer than previous preparations (4, 6, 9-13).

Ephedrine is rather less potent than amphetamine (14-16). Pseudoephedrine is much less potent than ephedrine.

Pseudoephedrineand Ephedrine, the archetypal drugs of concern, are still available for general use in some countries, whereas in most they have been replaced by oxymetazoline (which does not interact with MAOIs). Previously they were components of cough and cold remedies. Reactions are unlikely to be severe or dangerous unless large (oral) doses are used (that usually means an overdose).

Adrenaline (epinephrine) and noradrenaline (norepinephrine) are, obviously, (because they are the body’s neurotransmitters that act at these receptors) direct post-synaptic agonists and therefore do not cause any problematic interaction with MAOIs. Equivocation about that has been evinced repeatedly over the years in most standard texts and has caused mistreatment of patients e.g. (17), yet the lack of an interaction was established at the dawn of modern pharmacology by researchers whose names are prominent in history (Gaddum and Brodie, among others), early papers being (18-20). That work has been forgotten. It is TCAs that have a more pronounced interaction with adrenaline, ironically I cannot recall anyone getting too worried about that.

There is now quite a lot of accumulated experience of the concurrent administration of MAOIs and amphetamine for therapeutic purposes in depression. It is safe when done carefully. Early concerns about frequent hypertension have not materialized and recent clinical reviews indicate judicious use is safe (21, 22). Since amphetamine is substantially more potent than ephedrine it would seem, by extension, that concerns over this drug may also have been be over-rated. If taken in supra-therapeutic doses or overdose the situation may be different.

Traditionally concern about interactions has centered around cough and cold remedies and nasal decongestants because of early confused reports in the 1960s, e.g. (23, 24)and because they may contain both SRIs (e.g. chlorpheniramine (aka chlorphenamine), dextromethorphan and releasers like ephedrine). Note that until the 1990s, and in some reports beyond, there was a failure to understand the toxidromic distinction between a risky pressor response and ST. That failure has caused much confusion. The unrecognised irony was, until my 1998 review, that the chlorphenamine component of such over-the-counter (OTC) remedies is an SRI, and therefore a potential problem for precipitating ST. Indeed, as I noted, chlorphenamine was a possible, but unrecognized, contributor to the death of poor Libby Zion in a much, but inaccurately, commented on case (25-27).

As Rothman states, ‘Historically, it has been difficult to distinguish whether drugs act as reuptake inhibitors or substrate-type releasers using simple test tube assays.’ But it seems now established that amphetamine is a moderately potent NE and DA releaser, but a weak 5-HT releaser (14-16).

Therefore over-the-counter drugs are hardly a problem now, because even pseudoephedrinehas been taken off the market (at least, in many western countries).

The commonest ‘non-releaser’ nasal decongestant is oxymetazoline, which is an adrenergic alpha 2 agonist: it has no interaction with MAOIs and is not a problem.

Directly acting agonists, such as midodrine and adrenaline itself, are not a problem with MAOIs, because there is no potentiation, something that was established over half a century ago.

In summary: releasers are almost a problem of the past, and in any case are unlikely to cause severe reactions in normal moderate therapeutic use.