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Home » MAOIs

CNS ‘Stimulants’ and MAOIs

by Dr Ken Gillman | Last updated Oct 21, 2021 | Published on Nov 14, 2002 | MAOIs,
:
 Anti-Depressants

Introduction
The CNS ‘stimulants’ that are considered here
are methylphenidate, amphetamine, modafinil, and 3,4-
methylenedioxymethamphetamine (MDMA), ephedrine,
adrenaline, and midodrine. I will discuss NE/DA mediated
reactions, especially since there may be some cross-over, as well as
mentioning 5HT-mediated ones (i.e. ST).

The term ‘stimulant’ should now be eschewed, one should now

follow the new recommendations for neuropharmacology-based
nomenclature of drugs. Amphetamines act as ‘releasers’, whereas
methylphenidate acts as re-uptake inhibitor, and others are direct
receptor agonists. These different mechanisms of action have a
profound effect on potential drug interactions, as illustrated in
the serotonin toxicity triangle in the introduction to ST.

To discuss them all under one heading of ‘stimulant’ is to confuse

the different pharmacological mechanisms and different types of
pharmacodynamic interactions with different implications. The
word stimulant will not be used further in this
commentary except when referring to pre-existing literature.

Amphetamine
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
supposed for so long. Care (start low, go slow), experience, and
blood pressure monitoring are required, but it can be done safely
and with considerable benefit for some patients, although
increases in dose can rarely have disproportionate effects.
:
 Amphetamine is a potent DA and NA ‘releaser’ at low nano-molar
-9
(10 ) concentrations. There is still uncertainty about its exact
mechanisms of action and just how it interacts with the
monoamine transporters, principally the DAT. It acts as a
competitive inhibitor of NAT & DAT (this may not be a significant
therapeutic effect) and has actions in the pre-synaptic cytoplasm
by promoting extra-cellular efflux of transmitter via the DAT
(called reverse transport), and it increases cytoplasmic levels of
transmitter by disrupting storage of transmitters in vesicles
through the vesicular monoamine transporter (VMAT). There also
seem to be actions mediated by Trace Amine Associated
receptors TAAR1 receptors. Other reviews outline progress of
relevance and importance, particularly aspects of TAA receptors
and VMAT [1-3]. The latest understanding of this is evolving, is
complex and is beyond the scope of this commentary. Further
details are in: [4-6]. Sulzer recently [7] summed it up by saying:

Dopamine (DA) neurotransmission is generally initiated by fusion

of synaptic vesicles in axonal boutons, with the exceptions of
release by amphetamine-like drugs that can release DA via reverse
transport through the DA uptake transporter (DAT).

Also, in brain areas (like the prefrontal cortex) with lower

expression of DAT dopamine is handled by the NAT: note that may
have implications for the effectiveness of NRIs in depression, and
their interactions with MAOIs.

Amphetamine
Sulzer’s recent review of Amphetamine (and other drugs of
addiction) is an intoxicating Pierian spring of knowledge, all 14
pages, a weekend read [6].

Amphetamine and MAOIs have also been in use together for 50

years, it is perhaps surprising there are so few deaths, either from
:
 serotonin toxicity, or NE/DA toxicity, reported with the
combination. Amphetamine has only weak serotonin-mediated
effects [8]; there seems to be little or no risk of precipitating
serotonin toxicity, if combined with MAOIs [9], and low risk with
SRIs (see Prior et al [10]).

Deaths that only involve amphetamine (without MAOIs) always

seem to be related to cardiac problems or cerebral bleeds without
signs of serotonin toxicity (and about half of these cases seem to
exhibit pre-existing vascular CNS lesions). Elevated dopamine by
itself can cause hyperthermia, so the occurrence of hyperthermic
deaths following amphetamine, which is probably, like with
MDMA, relatively unusual and related to other physical or
environmental factors that promote hyperthermia, do not of
themselves suggest serotonergic mechanisms [11, 12], see Gillman
[13] for a review of hyperthermic mechanisms.

There are various case reports of fatalities with over-doses of

MAOIs and Amphetamine [14-20], & with Venlafaxine +
Amphetamine [10].

Note that this last case (Prior) comes out of the stable of Prof
Whyte who is a sort-of-colleague of mine (in that we have co-
operated and written together because of our shared view and
interest about serotonin toxicity). These guys are highly expert
physicians and toxicologists who spend their time looking after
overdoses in intensive care units, and they know what they are
talking about. That makes this case report worth reading [10], as
will be obvious if you note the meticulous reporting of key
symptoms that are, or are not, present. The probable response to
quite large doses of cyproheptadine is the icing on the cake, which
suggests whatever the mix of elevation of noradrenaline and
serotonin and dopamine, there was enough elevation of serotonin
to justify suggesting the clinical picture was substantially mediated
:
 by serotonin. So, one would conclude that significant serotonin
toxicity is indeed possible in certain circumstances with SRIs and
amphetamine (NB yet again the more toxic of these SRI drugs is
involved, viz venlafaxine). Incidentally, this fits with what was
highlighted above, which is that SRIs or NRIs would not be
expected to affect amphetamine entering the neurone because it
diffuses passively across neuronal cell membranes and is not
dependent on the reuptake pump, as are 5-HT and MDMA.

Amphetamine may not be without some risk in combination with

MAOIs at therapeutic doses, & would seem to produce
noradrenergic potentiation, and even toxicity; presumably in the
same way as tyramine does, by acting as a releaser. Chlorpromazine
appears to ameliorate the toxicity symptoms with
amphetamine/MAOI, as it does with serotonin toxicity [21].

Amphetamine is 50-100 times less potent as a releaser for

serotonin, than it is for dopamine or noradrenaline (see table 3). Its
5-HT transporter affinity (~3800 nmol) is inconsequential.
However, unlike methylphenidate, there is animal work indicating
amphetamine does modestly increase serotonin levels [8, 22].

In summary, amphetamine has been involved in deaths with

MAOIs, and shown significant toxicity with venlafaxine (probably
serotonin toxicity, as opposed to noradrenergic toxicity).

If CNS stimulants are to be used to augment MAOIs

methylphenidate is safe (it does slightly elevate BP, which can be
useful); amphetamine is a little more risky, and can precipitate
noradrenergic toxicity, even at therapeutic doses; however, that
appears to be rare in clinical practice; this combination does have a
place in clinical practice for special cases.

Clinical reviews with some general background are: Feinberg,

Rothman and Markowitz [23-27]. 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, so-called ISAs (indirectly acting sympatho-mimetic
amines), as opposed to serotonin toxicity [23-26].

Markowitz has offered the opinion [28] that: ‘The interactions of

monoamine oxidase inhibitors with psycho-stimulants represent one of
the few strict contraindications’. That is an ill-defined and poorly
informed over-generalisation (based on a very small number of
poor case reports, e.g. [29]).

As Paracelsus stated ‘the dose makes the poison’ and that may be
particularly applicable to amphetamine. Releasers can increase
intra-synaptic transmitter concentrations by more than 100-fold,
compared to a maximum closer to 10-fold with reuptake inhibitors
[5] — cf. see [30], concerning such mechanisms of interactions
involving RIs, releasers and MAOIs.

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 [23, 26].

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.

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 [27]). 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 Tmax is
rather longer and peak levels are lower, about half [31]. It also has a
low potential for cytochrome P450 interactions [32, 33]. Not only
that, but also the inter- and intra-subject plasma levels are much
less variable which produces a ‘smoother’ and more predictable
response [34]: 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 [27, 32, 35-39].

Modafinil
There is a difference between in vitro profile and in vivo findings.
Modafanil does increase extracellular NE (microdialysis reports are
convincing). Probably because the NE transporter has a higher
affinity for DA than NE, so any inhibition of DA uptake causes an
indirect effect (competitive inhibition of NE uptake) [40, 41].

Pseudoephedrine and Ephedrine

Ephedrine is rather less potent than amphetamine [25, 42, 43].
Pseudoephedrine is much less potent than ephedrine.

Pseudoephedrine and Ephedrine, the archetypal drugs of concern,

are still available for 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

(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. [44], 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 [45-47]. 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.

Traditionally concern about interactions has centered around

cough and cold remedies and nasal decongestants because of early
confused reports in the 1960s, e.g. [48, 49] 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 [50-52].

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 [25, 42, 43].

Therefore, over-the-counter drugs are hardly a problem now,

because even pseudoephedrine has 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.

‘Stimulants’: Pharmacological Profile for 5-HT/NE/DA

Release/Re-uptake
See full table in Rothman [25]

* sertraline- for comparison, not from Rothman

5-HT NE

Release Release
Uptake
(EC50 (EC50
(Ki nm)
nm) nm)

Amphetamine 1765 3830 7

Methamphetamine 736 2137 12

Ephedrine >10,000 >50,000 72

Tyramine 2800 1550 41

Fenfluramine 52 150 300

MDMA 57 238 77

>
Cocaine 304 >10,000
10,000

> >
Desipramine 350
10,000 10,000

> >
:
 Citalopram 10,000 2.4 10,000

>
Fluoxetine 9.6
10,000

Sertraline — 0.29*

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 as reuptake inhibitors, substrate releasers
work via VMAT2 and/or reverse transport (see below). Reuptake
inhibitors bind to the transporters, but are not transported into the
pre-synaptic terminal. Releasers are transported into (MDMA), or
diffuse into (amphetamine), the pre-synaptic nerve terminals.
Once there they promote neuro-transmitter release and thereby
elevate extra-cellular neuro-transmitter levels. Reuptake inhibitors
prevent ingress of some releasers into the pre-synaptic terminal, or
block the effect on VMAT2 (vesicular mono-amine transporter 2)
and thus block the post-synaptic release, see reviews for further
information[3, 53].

Norepinephrine re-uptake inhibitors (NRI) block the ingress of

tyramine into the pre-synaptic terminal, thus attenuating the
pressor response, as many studies with TCAs, SNRIs, reboxetine
etc. demonstrate. An early elucidation of tyramine/amphetamine
actions came from the famous lab of Bernard Brodie [54]. That
early Brody paper in 1968 demonstrated that NRI dependence was
true of tyramine at lower concentrations but that it very high
concentrations it was not dependent on the noradrenaline
transporter. Amphetamine is different because it diffuses
passively across the neuronal cell membrane, as do monoamine
oxidase inhibitors like tranylcypromine. Uptake into the neurone is
therefore unaffected by noradrenaline reuptake inhibitors, but
:
 NRIs still have the effect of preventing amphetamine releasing
noradrenaline from synaptic stores. Therefore, they also prevent
the hypertensive response in a dose dependent manner, depending
on their potency. Brodie showed that in rats desipramine 10 mg per
kilogram intra-peritoneally produced complete inhibition, i.e.
completely suppressed the pressor response.

For 5-HT pathways (attenuation of MDMA effects by SRIs) the

same has been demonstrated [24, 55-57].

Tyramine acts as a releaser of noradrenaline (and to a lesser extent

of DA, see table), and, as above, NRIs attenuate that response.

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 ephedrine is much more
problematic than adrenaline in combination with MAOIs [54, 58].

MDMA, ecstasy
MDMA, ecstasy (3,4-methylenedioxymethamphetamine) acts like
tyramine, but as a releaser of serotonin rather than noradrenaline,
and this serotonin-mediated action is blocked by serotonin
reuptake inhibitors. The relative potency of releaser or reuptake
inhibitor effects of drugs determine their differing effect on
serotonin levels, and thus serotonin toxicity, via different
mechanisms, such as interactions with MAOIs compared with
SSRIs (see tables).

In conclusion, it is helpful to be aware of that some reviewers have

not appreciated, or explained, the differences between toxidromes
of serotonin toxicity and noradrenergic toxicity. Failure to make
such distinctions clearly leads to blanket prohibitions concerning
:
 drug classes that are not justified by the evidence pertaining to
individual drugs’ interactions or toxicity profiles. This is
particularly relevant with CNS stimulants, because the evidence
reviewed herein clearly indicates that methylphenidate is
a dopamine re-uptake inhibitor (DRI) and may be safely
combined with MAOIs and is thus different to amphetamine.

Methylphenidate
Methylphenidate and MAOIs have been in use together for 40
years, so it would be astonishing if many people had not ingested
the combination by now: neither death, nor even morbidity, from
such an event has been reported (whereas it has been many times
with amphetamine). Methylphenidate is most widely used as a
treatment for attention-deficit hyperactivity disorder (ADH) in
children. It has been supposed by some to have serotonergic
effects; if that were so it would carry a risk of precipitating
serotonin toxicity with MAOIs. There are no definite case reports
indicating ST with methylphenidate in combination with MAOIs,
or other serotonergic drugs [59, 60].

Also, as with mirtazapine, trazadone and amitriptyline,

methylphenidate does not produce serotonergic side effects, or
signs of serotonin toxicity in over-dose, or if combined with MAOIs
[61, 62], & see Markowitz. E.g. the Sherman case was not serotonin
toxicity, but blood pressure elevation [29]. It does not raise
prefrontal cortex 5-HT levels [22, 63, 64].

The occurrence of serotonin-mediated side effects, and signs of ST

in over-dose, or if combined with MAOIs, are a measure of a drugs’
clinically significant serotonin-mediated effect in humans. If these
effects are not produced, then clinically significant ST is most
unlikely [65-68].

Methylphenidate also appears safe in combination with MAOIs; see

:
 Feinberg’s recent and helpful review of MAOIs and CNS stimulants
[23], which found, in agreement with my database on ST, “no
documented reports […] of hypertensive crises or fatalities
occurring when the stimulant was cautiously added to the MAOI.”
and also see [69, 70].

All the above is in keeping with its negligible 5-HT transporter

affinity (>10,000 nmol), absence of releaser effect and apparent
inability to significantly 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 of 5-
HT (NB it is definitely a DA re-uptake inhibitor) in humans then it
would be predicted that this effect would be lessened by selective
serotonin reuptake inhibitors (SSRIs)s, and its interaction with
MAOIs would exhibited severe ST: none of those things are the
case, so we can be pretty sure it has no significant serotonin-
mediated effects.

The Vesicular Monoamine Transporter (VMAT2)

This is a good point at which to say something about intra-
neuronal vesicular storage of monoamines: the same vesicular
monoamine transporter (VMAT2) is responsible for actively taking
up all monoamines (i.e. dopamine (DA), serotonin (5-HT),
norepinephrine (NE), epinephrine (EPI) and histamine (HIS))
from within the neurone into the storage granules (vesicles)
ready for release into the synapse, which is a nerve-impulse-
dependent phenomenon, whereas overflow from the neurone itself
is not impulse-dependent. NB. Tyramine (TYR) and PEA have
similar affinity for VMAT2 to DA and NE. And the thyroxine
metabolite thyronamine (THYR) is a potent VMAT2 inhibitor. The
search is underway for other drugs that act as VMAT2 inhibitors
[71], and GZ-793A is under investigation [72-74].

Typical psychiatric texts say little or nothing, mostly nothing,

:
 about VMAT and many people may not be familiar with those
drugs known to interfere with this process because they are little
used in psychiatry (viz. ketanserin, reserpine, tetrabenazine,
valbenazine). However, this is a key to understanding differences
between amphetamines and most other drugs. They both
(reserpine & tetrabenazine) competitively inhibit VMAT2 and
deplete vesicular amine content by changing the pH gradient that
drives the vesicular ATPase-dependent transporter.

One key difference between the neuronal & vesicular transporter

mechanisms is that other monoamines (5-HT, NE, DA) are all
packaged into the storage granules against a concentration
gradient by the same transporter mechanism, i.e. VMAT2, whereas
they each have a separate transporter on the neuronal outer
membrane (viz. SERT, NET, DAT). Note that most drugs with
potency at the neuronal membrane transporter are effectively
inactive at VMAT2.

So, amphetamine both inhibits VMAT2 and releases vesicular

dopamine at low micro-molar concentrations likely to be
reached in vivo, thereby, presumably, depleting vesicular stores.

The history and current knowledge on this topic have recently

been reviewed by Eiden [3], whose lab first cloned human VMAT1
and VMAT2. If you are interested in how these mechanisms
evolved, this review explains VMAT evolved from bacterial
transporters that dealt with toxins, a fascinating story that gives
insights into why neurotransmitters themselves are ‘toxic’.

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 [75].

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 3). 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 [76] & see
also [9, 77-80].

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.

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PsychoTropical Research | Dr Ken Gillman
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