See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/23423713

Monoamine Oxidase Inhibitors: A Modern Guide to an Unrequited Class of

Antidepressants

Article  in  CNS spectrums · November 2008

DOI: 10.1017/S1092852900016965 · Source: PubMed

CITATIONS READS

102 4,102

2 authors, including:

Angela Felker
University of California, San Diego
3 PUBLICATIONS   141 CITATIONS   

SEE PROFILE

All content following this page was uploaded by Angela Felker on 31 May 2014.

The user has requested enhancement of the downloaded file.

 Trends in Psychopharmacology

Monoamine Oxidase Inhibitors:

A Modern Guide to an Unrequited
Class of Antidepressants
By Stephen M. Stahl, MD, PhD, and Angela Felker, MA

NEW TREND IN of these mechanisms may provide a rationale to

PSYCHOPHARMACOLOGY
Monoamine oxidase inhibitors (MAOIs) cur-
rently have a “bad rap” and are thus infre-
quently used in psychopharmacology, even by
experienced clinicians. Misinformation about
the dietary and drug interactions of MAOIs is
widespread, whereas pragmatic tips for utiliz-
ing MAOIs to minimize risks and to maximize
therapeutic actions are largely lacking in the con-
temporary literature. While clearly not first-line
treatments, MAOIs, in the hands of experienced
and well-informed clinicians, can be a powerful
therapeutic intervention for patients with depres-
sion, panic disorder, and other anxiety disorders
who have failed first-line treatments.
This article focuses on the pharmacologic
mechanisms of MAOIs, since an understanding
empower experts to expand their use of these
agents. Discussed here are not only the mecha-
nisms of therapeutic action of MAOIs, but also
the mechanisms explaining their side effects,
including hypertensive interactions with dietary
tyramine (so-called “cheese reactions”) and drug
interactions that can lead to hypertensive reac-
tions with some drugs and serotonin toxicities
with others.
This article also provides practical tips on
how to use MAOIs, including debunking certain
myths and giving specific guidance about which
foods and drugs to avoid. Those with no previ-
ous interest in MAOIs may discover in this article
a new “secret weapon” to add to their thera-
peutic armamentarium for patients who fail to
respond to the better-known agents.

Dr. Stahl is adjunct professor of psychiatry in the Department of Psychiatry at the University of California–San Diego in La Jolla. Ms. Felker
is an associate medical writer at the Neuroscience Education Institute in Carlsbad.
Faculty Disclosures: Dr. Stahl receives grant/research support from AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli
Lilly, Forest, GlaxoSmithKline, Janssen, Neurocrine Biosciences, Organon, Pfizer, Sepracor, Shire, Somaxon, and Wyeth; is a consultant to
Acadia, Amylin, Asahi, AstraZeneca, Biolaunch, Biovail, Boehringer-Ingelheim, Bristol-Myers Squibb, Cephalon, CSC Pharma, Cyberonics,
Cypress Bioscience, Eli Lilly, Epix, Fabre Kramer, Forest, GlaxoSmithKline, Jazz, Neurocrine Biosciences, NeuroMolecular, Neuronetics,
Nova Del Pharma, Novartis, Organon, Otsuka, PamLab, Pfizer, Pierre Fabre, Sanofi-Synthelabo, Schering-Plough, Sepracor, Shire, Solvay,
Somaxon, Takeda, Tetragenex, and Wyeth; and is on the speaker’s bureau of Pfizer. Ms. Felker does not have an affiliation with or financial
interest in any organization that might pose a conflict of interest.
Disclaimer: As this is widely excerpted with all figures and tables from Stahl’s Essential Psychopharmacology textbook, and much of the
text is adapted from chapter 12 of the textbook, the copyright for the work as a whole, the tables, figures and text, will continue to be held
by Cambridge University Press, with permission to publish in CNS Spectrums without charge. Every effort has been made in preparing this
material to provide accurate and up-to-date information that is in accord with accepted standards and practice at the time of publication.
Nevertheless, the authors, editors and publisher can make no warranties that the information contained herein is totally free from error,
not least because clinical standards are constantly changing through research and regulation. The authors, editors and publisher therefore
disclaim all liability for direct or consequential damages resulting from the use of material contained in this article. Readers are strongly
advised to pay careful attention to information provided by the manufacturer of any drugs that they plan to use.
If you would like to comment on this column or submit a suggestion to Dr. Stahl for future columns, please e-mail vj@mblcommunications.com.
CNS Spectr 13:10 647 October 2008
 Trends in Psychopharmacology

INTRODUCTION to a more prominent place on the sophisticated

The antidepressant effects of monoamine oxi- clinician’s pharmaceutical shelf. (This article is
dase inhibitors (MAOIs) were discovered ser- excerpted and adapted [with permission] from the
endipitously when an antituberculosis drug, antidepressant chapter of the recently published
iproniazid, was observed to help depression that textbook, Stahl’s Essential Psychopharmacology
Psychopharmacology.2
coexisted in some of the patients who had tuber- The reader is also encouraged to consult standard
culosis.1-3 This antituberculosis drug was eventu- reference sources for prescribing information on
ally found to work in depression by inhibiting the MAOIs, including the companion prescriber’s
the enzyme MAO. However, inhibition of MAO guide to this textbook.10)
was unrelated to its antituberculosis actions.2,4
MAOIs, while best known for their powerful
antidepressant effects, can also be efficacious OVERVIEW OF THE MECHANISM OF
in treating certain anxiety disorders, including THERAPEUTIC ACTION OF MAOI S
panic disorder and social phobia.3,5-7 Additionally, Three of the original MAOIs are still clinically
some selective MAO-B inhibitors may also available: phenelzine, tranylcypromine, and iso-
be efficacious in treating Parkinson’s disease, carboxazid (Table 1). 11 Each of these is an irre-
though at lower doses than necessary to achieve versible enzyme inhibitor that binds to MAO
antidepressant effects. 8 MAOIs, however, are covalently, destroying its function forever. 4,11
rarely utilized anymore in psychopharmacology Activity returns only after new enzyme is syn-
practice. Only a few thousand prescriptions for thesized.
antidepressant use of MAOIs are written in the Perhaps surprising to many clinicians is the fact
United States annually, almost all by a few hun-
dred psychiatrists, whereas several million sero-
TABLE 1.
tonin selective reuptake inhibitors (SSRIs) and
Current Approved MAOIs
serotonin-norepinephrine reuptake inhibitors
prescriptions are written in the US annually by Medication Inhibition Inhibition Amphetamine
many thousands of practitioners, mostly primary (Trade Name) of MAO-A of MAO-B Properties
care physicians.9 Phenelzine + + –
There are many reasons for the low use of (Nardil)
MAOIs, including the fact that numerous other
Tranylcypromine + + +
options exist for treatment, preventing many (Parnate)
modern-day clinicians from gaining experience
Isocarboxazid + + –
with MAOIs. Since these are old drugs with essen- (Marplan)
tially no marketing support, there is also a good
Amphetamines + + +
deal of misinformation and mythology about their (at high doses)
present-day dietary and drug-interaction dangers.
It may simply be that clinicians are unaware of the Selegiline
transdermal
potential benefits of treating a current patient with system
an MAOI; how to manage patients taking these (EMSAM)
drugs, including diet and concomitant drugs; and Brain + + +
how to determine the risk-benefit ratio for an indi- Gut +/– + +
vidual patient.2,7 Selegiline low – + +
This review will attempt to heighten awareness dose oral
of MAOIs as second- or third-line therapeutics for (Deprenyl;
Eldepryl)
patients who fail to respond to first-line treatments.
Mechanisms of action for therapeutic and adverse Rasagiline – + –
(Agilect/
effects will be discussed, including the mecha- Azilect)
nism of dietary interactions with tyramine, and
the reasons behind the drug interactions to avoid. Moclobemide + – –
(Aurorix,
With renewed understanding of the mechanisms Manerix)
of action behind the potentially important and
MAOIs=monoamine oxidase inhibitors.
effective therapeutic effects as well as the man-
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.
ageable adverse effects, the MAOIs may return

CNS Spectr 13:10 2 October 2008

 Trends in Psychopharmacology

that amphetamine is actually a reversible MAOI
in addition to its better known and more potent
actions inhibiting the dopamine (DA) transporter
and the norepinephrine (NE) transporter (Table
1).2,13 Interestingly, some MAOIs, such as tranyl-
cypromine, have chemical structures modeled
on amphetamine and thus, in addition to their
well-known MAO inhibitor properties, also have
amphetamine-like DA- and NE-releasing properties
due to additional inhibitory actions on DA trans-
porter and NE transporter (Table 1). 2 Selegiline
itself does not have amphetamine-like properties
but is metabolized to both l-amphetamine and l-
methamphetamine (Table 1).14-16 Thus, some MAOIs
have amphetamine-like properties, and amphet-
amines themselves are, in fact, reversible MAOIs
(Table 1). Since some MAOIs have a mechanism of
action that combines MAO inhibition with amphet-
amine-like actions of DA and NE release, it is not
surprising that one of the augmenting agents uti-
lized to boost MAOIs in especially treatment-resis-
tant depression (TRD) patients, is amphetamine,
administered by experts with great caution while
monitoring blood pressure.10,17-19 The actions of
stimulants and MAOIs may thus be additive or
synergistic, both for antidepressant efficacy and
tially metabolizes serotonin (5-HT) and NE, the
monoamines most closely linked to depression
(Table 2 and Figure 1).2 The B form preferentially
metabolizes trace amines, including phenethyl-
amine (Table 2 and Figure 1).2 MAO-A and MAO-
B metabolize DA and tyramine (Table 2).
Both forms of MAO are present in the brain.23,24
Specifically, noradrenergic and dopaminergic
neurons are thought to contain MAO-A and
MAO-B, with perhaps MAO-A activity predomi-
nant, whereas serotonergic neurons are thought
to contain only MAO-B. 2 MAO-A can thus be
found in the locus ceruleus, the reticular forma-
tion, and the presynaptic terminals of dopami-
nergic neurons, whereas MAO-B is located in
the dorsal raphe nucleus and basal ganglia. 25
MAO-A is the major form of this enzyme outside
of the brain, with the exception of platelets and
FIGURE 1.
MAO-A enzyme metabolizes 5-HT (top
panel), NE (middle panel), and DA
(lower panel) *
������������������
����������������������

for raising blood pressure in some patients. This ����������� �����������

combination is not for amateurs to administer but � �

5-HT boosted to
high concentrations

can be a heroic and life-saving combination for ������������������������ ������ ������������������������

selected patients. ����������������������

�
����������� ����������������������

MAO-A
destroys 5-HT

ROLE OF MAO SUBTYPES IN THE

� �
����� �����
�������������� ��������������
������������� �������������

MECHANISM OF ANTIDEPRESSANT �������������� ��������������

ACTION OF MAOI S ����������

�������
����������
�������������
��������������������
��������
MAO exists in two subtypes, A and B. The ��
� �
������
original MAOIs are nonselective, inhibiting ������������

both forms. 20-22 The A form of MAO preferen- � �

� ������� �
��������
��
����� �����
������������
TABLE 2.
������������
������������ ������������
�������������� ��������������

MAO Enzymes ���������� ����������

������������
�������
�������� �����������
���

MAO-A MAO-B �
������
�

������������

Substrates 5-HT Phenylethylamine � �

NE � �������
��������
���
�
�����
������������

DA
�����
������������

Tyramine * MAO-B selectively metabolizes DA. Therefore, MAO-A inhibition can

increase 5-HT ( red circle, top panel), NE (red circle, middle panel), and
Tissue Brain, gut, liver, Brain, platelets, DA (red circle, bottom panel), but the increase in DA is not as great as
distribution placenta, skin lymphocytes that of 5-HT and NE because MAO-B can continue to destroy DA.
MAO=monoamine oxidase; 5-HT=serotonin; NE=norepinephrine; MAO=monoamine oxidase; 5-HT=serotonin; NE=norepinephrine;
DA=dopamine. DA=dopamine.
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008. Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.

CNS Spectr 13:10 3 October 2008

 Trends in Psychopharmacology

lymphocytes, which have only MAO-B (Table but inhibition of MAO-A alone does not appear to
2). The ratio of MAO-A to MAO-B in the human lead to robust increases in brain DA levels since
brain is 25%:75%, whereas in the liver, the ratio MAO-B can still metabolize DA (Figure 1).
is 50%:50%. The ratio is 80%:20% in the intestine, Inhibition of MAO-B is not effective as an
and in the peripheral adrenergic neurons, the antidepressant,26-28 as there is no direct effect on
ratio is 90%:10%.25 either 5-HT or NE metabolism, and little or no
Brain MAO-A must be inhibited for antide- DA accumulates due to the continued action of
pressant efficacy to occur (Figure 1).2,22,26-27 This is MAO-A (Figure 2). What, therefore, is the ther-
not surprising, since this is the form of MAO that apeutic value of MAO-B inhibition? When this
metabolizes 5-HT and NE, two of the three com- enzyme is selectively inhibited, it can boost the
action of concomitantly administered levodopa
ponents of the trimonoaminergic neurotransmitter
in Parkinson’s disease.8,29 Evidently, in the pres-
system linked to depression and to antidepressant
ence of a large amount of DA derived from
actions; both 5-HT and NE demonstrate increased
administration of a large dose of its precursor
brain levels after MAO-A inhibition (Figure 1).
levodopa, selective MAO-B inhibition is suffi-
MAO-A, along with MAO-B, also metabolizes DA,
cient to boost DA action in the brain.8,14,30 MAO-B
is also thought to convert some environmentally
FIGURE 2. derived amine substrates, called “protoxins,”
Selective MAO-B inhibition cannot into toxins that may cause damage to neurons
produce an effective antidepressant and possibly contribute to the cause or decline
response* of function in Parkinson’s disease. 2,8 Inhibiting
������������������ MAO-B may thus halt this process, and there is
speculation that this may slow the degenerative
������������������������
course of various neurodegenerative disorders,
����������� �����������
including Parkinson’s disease. Thus, two MAOIs
� � in Table 1, selegiline and rasagiline, when admin-
������������������������
����������������������
�����
������������
istered orally in doses selective for inhibition of
� �
MAO-B, are approved for use in patients with
������
�������������
������
��������
Parkinson’s disease, but they are not effective
� ����
�����
��������������
�������������
�
�����
�����������
at these selective MAO-B doses as antidepres-
�����������
sants.
��������������

����������
�������
����������
������� Perhaps the most important role of MAO-B in
�������� ��������
��
�
��
�
psychopharmacology is when it is inhibited simul-
MAO-B
inhibition taneously with MAO-A (Figure 3). In that case,
�
�
there is a robust triple monoaminergic boost of
�������
� �������
��������
� ��������
��
DA as well as 5-HT and NE (Figure 3).22This would
��
�����
������������
������������
�����
����������� theoretically provide the most powerful antide-
�������������� �����������

���������� ����������
pressant efficacy across the range of depressive
�������
��������
�������
��������
������������
����������� symptoms. Indeed, MAO-A plus B inhibition is
��� ���
�
�����
� one of the few therapeutic strategies available to
������������
increase DA in depression and, therefore, to treat
� �

�
refractory symptoms of diminished positive affect
������� �
theoretically linked to DA deficiency.31 Symptoms
�������� �������
��� ��������
���
�����
������������
associated with reduced positive affect include
* This is due to the selectivity of MAO-B for DA metabolism (bottom panel) not only depressed mood but also loss of happi-
compared with 5-HT metabolism (top panel) and NE metabolism (middle
panel), plus the fact that MAO-A continues to metabolize DA when
ness and joy, loss of interest and pleasure, loss of
MAO-B is inhibited selectively. Thus, selective inhibition of MAO-B energy and enthusiasm, decreased alertness, and
has somewhat limited effects on DA concentrations (red circle, bot-
tom panel), apparently insufficient to exert antidepressant actions but
decreased self-confidence.2,31 This action on DA
sufficient to boost the actions of DA from levodopa administration in theoretically treating such symptoms of reduced
Parkinson’s disease.
positive affect is an incentive for specialists in
MAO=monoamine oxidase; 5-HT=serotonin; NE=norepinephrine; psychopharmacology to become adept at admin-
DA=dopamine.
istering MAOIs; it will give them an additional
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.
strategy within their armamentarium for cases

CNS Spectr 13:10 4 October 2008

 Trends in Psychopharmacology

with treatment-resistant symptoms of diminished dangerous levels, due to the efficient destruction
positive affect, a common problem in a referral of NE by MAO-A (Figure 4). 2 When foods high
practice.1,2,17-19 in tyramine content are ingested, MAO-A in the
intestinal wall and liver safely destroys massive
amounts of tyramine before it is absorbed. 32,33
MECHANISM OF “TYRAMINE If any tyramine escapes into the systemic cir-
REACTIONS” AND RATIONALE FOR culation and is delivered to the noradrenergic
MODERN DIETARY RESTRICTIONS sympathetic neuron, the MAO-A there destroys
Utilizing MAOIs has often been considered any synaptic NE that tyramine releases (Figure
risky due to the potential of developing a hyper- 5). Thus, there is a large capacity to protect the
tensive crisis (Table 3) after ingesting high sympathetic nervous system from ingested tyra-
amounts of tyramine from the diet.16 Tyramine is a mine. The average person can handle ~400 mg of
potent releaser of NE and can thus elevate blood ingested tyramine before excessive stimulation
pressure.32 Normally, NE cannot accumulate to of postsynaptic adrenergic receptors occurs, and
thus results in elevated blood pressure (Figure
5).2 Since a “high tyramine meal” generally con-
FIGURE 3. tains only about 40 mg of tyramine, a tyramine
Combined inhibition of MAO-A and reaction usually does not occur in a normal
MAO-B can theoretically have the unmedicated person eating a normal diet.32
most robust antidepressant actions When MAO-A is inhibited, the capacity to han-
due to increases in 5-HT (top panel), dle dietary tyramine is significantly reduced. A
NE (middle panel), and DA (bottom high-tyramine meal is sufficient to increase blood
pressure when a substantial amount of MAO-A is
panel)*
������������������������������ irreversibly inhibited (Figure 6). It may take only 8–
10 mg of dietary tyramine to increase blood pres-
�����������������������������
�������������������������� sure when MAO-A is “knocked out” by high doses
����������� �����������
of an MAOI, which is discussed later in Figure 11.34
���������������������
� � �������������������
Such blood pressure elevations can potentially be
������������������������
����������������������
�������
������������
sudden and dramatic, creating a hypertensive cri-
� �
sis, which can (rarely) cause intracerebral hemor-
������
rhage or even death (Table 3).2 This risk is generally
� �������������
�����
��������������
�
alleviated by restricting the diet so foods high in
�������������
��������������
tyramine are eliminated (Table 4). Until recently,
����������
�������
����������
������������������
dietary restrictions and the risk of a hypertensive
�������� ��������������������
��
� �
crisis were the price most patients had to pay in
�������
������������ order to receive the therapeutic benefits of the
� � MAOIs in the treatment of depression (Tables 3
� �������
��������
�
��
�����

TABLE 3.
������������
������������
��������������

����������
�������
����������
��������������������
Hypertensive Crisis
�������� ��������������������
���
�
�������
�
Defined as having a diastolic blood pressure >120
������������
mmHg
� �

� �������
Potentially fatal reaction characterized by:
�
• Occipital headache that may radiate frontally
��������
���
�����
������������ • Palpitation
• Neck stiffness or soreness
* Inhibition of both MAO-A (which metabolizes 5-HT, NE, and DA) and
MAO-B (which metabolizes primarily DA) leads to greater increases in
• Nausea
each of these neurotransmitters than inhibition of either enzyme alone. • Vomiting
Compare the amounts of neurotransmitter in red circles here with the • Sweating (sometimes with fever)
amounts of neurotransmitter in the red circles of Figures 1 and 2. • Dilated pupils, photophobia
MAO=monoamine oxidase; 5-HT=serotonin; NE=norepinephrine; • Tachycardia or bradycardia that can be associated
DA=dopamine. with constricting chest pain
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008. Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.

CNS Spectr 13:10 5 October 2008

 Trends in Psychopharmacology

and 4).32,33,35-38 EXPLOITING THE MECHANISM OF

Due to this potential danger of a hypertensive TYRAMINE REACTIONS TO INCREASE
crisis from a tyramine reaction in patients taking SAFETY: NEW DEVELOPMENTS WITH
an irreversible MAOI (Table 3),2 various myths have MAOI S
arisen surrounding the amount of tyramine in cer- Two recent developments appear to mitigate
tain foods and which dietary restrictions are nec-
essary. The “cheese reaction” has led to the myth
that all cheese must be restricted.7,32-39 This is not FIGURE 4.
the case, as only aged cheeses (eg, English Stilton) MAO-A normally acts to destroy NE *
are high in tyramine, whereas most processed
���������������������
cheeses (Figure 7, top panel) or those utilized on
commercial chain pizzas (Figure 7, middle panel) ������
�������������

do not contain high levels of tyramine.36-38 �

Another myth is that patients on an MAOI must
avoid all wine and beer. Canned and bottled beer
are low in tyramine, and many wines, including
��������
Chianti, contain low levels of tyramine (Figure 7, �������������� ���������

��
bottom panel).36-38 Generally, only draft and unpas- �

teurized beers should be avoided.2,36-38 Thus, unless ������

�������������

someone taking an irreversible inhibitor of MAO-A �������������������

��������
is going to eat 25–100 pieces of standard pizza or ��������
���������

drink 25–100 glasses of most wines or 25–100 cans

or bottles of most beers at a party, it is likely that
they can still have a moderate amount of fun. Of
course, every prescriber should counsel patients
taking MAOIs about diet and advise patients to
keep up-to-date with the tyramine content of foods
they wish to eat.
* Abnormal accumulation of NE can cause vasoconstriction and elevated
blood pressure via increased binding at alpha 1 and other adrenergic
receptors. Normal destruction by MAO-A helps prevent these negative
effects.
MAO=monoamine oxidase; NE=norepinephrine; BP=blood pressure.
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.

FIGURE 5.
TABLE 4.
Tyramine, depicted here as a piece of
Suggested Tyramine Dietar y
cheese, is an amine present in vari-
Modifications for MAOIs *
ous foods *
Food to Avoid Food Allowed �����������������������
����������������������
Dried, aged, smoked, Fresh or processed meat, �����������������
�������������������
fermented, fish, and fish, and poultry ������������� �
�������������
poultry �

Broad bean pods† All other vegetables

�
�
Aged cheeses Processed and cottage �
cheese, ricotta cheese, ��������������
�

and yogurt �

Tap and unpasteurized Canned or bottled beers

beers and alcohol �������������������
��������
Marmite and sauerkraut Brewer’s and baker’s ��������
���������

yeast ��������
���������������
�������������

Soy products/tofu
* No dietary modifications needed for low doses of transdermal selegiline * If any tyramine from a high-tyramine meal gets access to noradrenergic
or for low oral doses of selective MAO-B inhibitors. sympathetic neurons (cheese binding to the presynaptic NE neuron),
it will release NE (1), but MAO-A readily destroys the NE-released by
† Contain levodopa as the pressor agent. tyramine (2) and no physiological harm results.
MAOIs=monoamine oxidase inhibitors. NE=norephinephrine; MAO=monoamine oxidase; BP=blood pressure.
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008. Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.

CNS Spectr 13:10 6 October 2008

 Trends in Psychopharmacology

the risk of tyramine reactions with MAOIs. First,

FIGURE 7.
inhibitors have been developed that are not only
Tyramine content in common foods
selective for MAO-A, but are also reversible.23-34
associated with potential tyramine
Second, an MAOI can now be delivered through
a skin patch, resulting in inhibition of both MAO-A reactions*
and MAO-B in the brain, but with much less MAO- ��������������������������
A simultaneously inhibited in the gut.40,41 While nei-
ther of these innovations enhances MAOI efficacy, ������
�����������
�������
both reduce the risk of a hypertensive crisis with
ingestion of tyramine. ������� ����
�������

Reversible Inhibitors of Monamine

Reversible inhibitors of monoamine (RIMAs)
�������
are an ingenious development because they ������ PARMESAN
���

��������
have the potential of providing MAO-A inhibi-
tion with decreased risk of a tyramine reaction
��������������
����� PHILADELPHIA �
CREAM CHEESE
������

FIGURE 6.
When tyramine (depicted as a piece
of cheese) acts to increase the presyn- ��������������������������������������������

aptic release of NE (1) in the presence �������

�����
of MAO-A inhibition by an irrevers- �������

ible MAO-A inhibitor, the result is a

�����������
lack of destruction of this released ��������������� �����

a o’s
��������

zz in
NE (2). MAO-A inhibition in itself

Pi om
����������

D
�

causes an accumulation of NE. Thus, �����������

when MAO-A inhibition occurs in the ���������������
��������
�����

presence of tyramine, this combina- ����������

tion can result in excessive synaptic

NE within the sympathetic neuron,
�����������
��������������� pizza ���

which can lead to excessive stimula-

��������
���������� pizza
tion of postsynaptic adrenergic recep-
tors (3) and dangerous physiological ������������������������
changes, such as vasoconstriction and
�����������
elevated blood pressure ����
�������
����������������������������
�������������������������
����������������������
������������������������
������� CHIANTI ����
��������������� �������
RUFFINO
�������������������
����������������
����������������
�
������������ 2
���������������
������������� ����������������
������ ������������������ ���������� ����
��������� � ����� BLUE NUN
�
QUALATSWEIN

�
�������
��������
CINZANO �
�

����������������
����������������
��������
��������� * Aged cheeses (eg, English Stilton) are high in tyramine, whereas pro-
cessed cheeses are often quite low in tyramine (top panels). In addition,
commercial chain pizzas utilize cheese low in tyramine content (middle
panels). Canned and bottled beers, as well as many wines, are actually
NE=norepinephrine; MAO=monoamine oxidase. quite low in tyramine (bottom panels).

Stahl SM, Felker A. CNS Spectr

Spectr. Vol 13, No 10. 2008. Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.

CNS Spectr 13:10 7 October 2008

 Trends in Psychopharmacology

(Figure 8).6,23,24,30,42-45 For example, if someone tak-
ing a RIMA eats aged cheese high in tyramine,
as the tyramine is absorbed it will release NE;
however, this released NE will chase the revers-
ible inhibitor off the MAO-A enzyme, reactivating
MAO-A in the intestine, liver, and sympathomi-
metic neurons and allowing destruction of the
dangerous amines (Figure 9).2,23,34 Recent trials4,30
have shown that RIMAs can be effective in treat-
ing patients with endogenous depression and
geriatric depression.
Moclobemide is the best known RIMA and has
demonstrated efficacy similar to amitriptyline, clo-
mipramine, fluvoxamine, and imipramine.4
Numerous studies have indicated that
moclobemide can maintain its antidepressant
effects for 6–12 months. 4 There is still a warn-
ing posted regarding tyramine reactions with
moclobemide, as some degree of dietary cau-
tion is still recommended. Nevertheless, when
adequately dosed, there is much less likelihood of
a dangerous reaction when tyramine is ingested
in conjunction with a reversible MAOI. Although
the risk for a hypertensive reaction from dietary
tyramine may be reduced by RIMAs, the risk for
serotonin syndrome with drugs that block 5-HT
reuptake may not be similarly reduced, as the
mechanism of 5-HT toxicity is different, as dis-
cussed in the section below.
Transdermal Delivery of a Selective MAO-
B Inhibitor
While RIMAs may be as efficacious as irre-
versible MAOIs and may theoretically require
less dietary tyramine restriction, transdermal
delivery of an MAOI can allow the patient to
have a diet without any dietary tyramine restric-
tions. Selective MAO-B inhibitors given orally at
low doses do not inhibit a significant amount of
MAO-A (Figure 2), and thus there is little risk of
hypertension from dietary amines.45-48 However,
at low oral doses, MAO-B inhibitors are also not
effective antidepressants due to the lack of sig-
nificant elevations in brain 5-HT or NE (Figure
2).26-28 An antidepressant effect, however, can be
achieved when the MAO-B inhibitor selegiline
is given orally in doses that cause it to lose its
selectivity and inhibit MAO-A as well (Figure 10,
left).49,50 However, this type of dose would also
cause a tyramine reaction (Figure 10, left).27
In order to prevent this problem, selegiline is
administered transdermally, thus delivering the
drug directly into the systemic circulation, hit-
ting the brain in high doses and avoiding a first
pass through the liver (Figure 10, right).2,40-41,51
Once the drug recirculates to the intestine and
liver, the levels have decreased and mostly
MAO-B is inhibited (Figure 10, right). This action
is sufficiently robust and selective that for low

FIGURE 8.
MAO-A is present in the brain and gut (left). To evoke an antidepressant response,
MAO-A in the brain must be inhibited *
How RIMAs Reduce the Risk of Tyramine Reactions
The dilemma The solution

Reverse
Reverse
A A
A A
Reverse
A A

Must inhibit MAO-A Simultaneous inhibition When tyramine increases

in brain for of MAO-A in liver and NE release, this reverses MAO-A
antidepressant action intestinal mucosa inhibition and NE can be destroyed,
causes risk of reducing risk of tyramine reactions
tyramine reactions

* However, simultaneous MAO-A inhibition in the liver and intestinal mucosa causes risk of a tyramine reaction (left). Reversible MAO-A inhibitors (RIMAs) can be
removed from the MAO enzyme by competitors (right). Therefore, when tyramine increases NE release, it is also increasing the competition of NE for MAO-A,
which leads to the reversal of MAO-A inhibition with subsequent destruction of NE and a reduced risk of tyramine reaction (right).

MAO=monoamine oxidase; RIMAs=reversible inhibitors of monoamine; NE=norephinephrine.

Stahl SM, Felker A. CNS Spectr

Spectr. Vol 13, No 10. 2008.

CNS Spectr 13:10 8 October 2008

 Trends in Psychopharmacology

doses of transdermal selegiline, no dietary tyra- tions can be incredibly dangerous and potentially
mine restrictions are necessary. At high doses of lethal.53,54 Also, drug interactions with MAOIs are
transdermal selegiline, there is likely some MAO- poorly understood by many practitioners. Most
A inhibition in the gut, and thus some dietary candidates for MAOI treatment will require treat-
tyramine restrictions may be prudent.7 In some ment with many concomitant drugs over time,
studies of depressed patients receiving transder- including treatment for coughs and colds, so not
mal selegiline,46 dietary restrictions were not fol- knowing which drugs are safe to give and which
lowed, yet tyramine reactions were not reported. ones to avoid can unnecessarily prevent a practi-
Therefore, at high doses of transdermal selegi- tioner from using an MAOI at all for someone who
line, some dietary caution may be warranted, requires any concomitant medications.
but it appears that at low doses, dietary restric- There are two general types of potentially dan-
tions may not be necessary (Figure 11).52 gerous drug interactions with MAOIs for a prac-
Although the risk for a hypertensive reaction titioner to understand: those that can raise blood
from dietary tyramine may be reduced by trans- pressure by sympathomimetic actions (discussed
dermal delivery of selegiline, the risk for serotonin in this section; Tables 5 and 6) and those that can
syndrome with administration of drugs that block cause a potentially fatal serotonin syndrome by
5-HT reuptake is not similarly reduced. The mecha- 5-HT reuptake inhibitory actions (discussed in the
nism of 5-HT toxicity is different, as discussed in section below; Table 7).
the section below. When drugs that boost adrenergic stimulation
by a mechanism other than MAO inhibition are
added to an MAOI, potentially dangerous hyper-
MECHANISM OF DANGEROUS
tensive reactions can occur. For example, many
DRUG INTERACTIONS WITH MAOI S :
decongestants can adversely interact with MAOIs
DECONGESTANTS AND DRUGS THAT
to elevate blood pressure (Table 5 and Figure 12).2
BOOST SYMPATHOMIMETIC AMINES
Decongestants to be avoided with an MAOI include
While MAOIs are famous for their tyramine reac-
those that add to the pro-noradrenergic actions of
tions, drug-drug interactions are potentially more
MAO inhibition to stimulate alpha 1 postsynaptic
important clinically. Drug-drug interactions may
vascular receptors excessively.55 Currently, this
not only be more common, but also some interac-
applies mostly to over-the-counter phenylephrine
and oxymetazoline, both relatively selective alpha
FIGURE 9. 1 agonists, since ephedrine, phenylpropanolamine,
The MAO-A inhibitor shown here is and pseudoephedrine have either been withdrawn
reversible* from the US and other markets or are available
only by signing for them at a pharmacy (eg, pseu-
���������������������������
��������������������������
doephedrine) (Table 5).2 An additional ingredient
����������������������������
�����������������������
found in cold medicines is the cough suppressant
�������������������
�������������������
� and opiate derivative dextromethorphan, which
������������� �
� should be avoided not because it is a sympathomi-
metic agent but because it is a weak 5-HT reuptake
�
� inhibitor (discussed below; Table 7).
�
Decongestants work by constricting nasal blood
�
vessels.2 If topically applied (eg, nasal oxymetazo-
� �
line) or taken in low doses, they generally do not
have sufficient systemic actions to elevate blood
�������������������
��������
pressure by themselves (Figure 12). However, in
��������
��������� potentially vulnerable patients (such as those with
hypertension, especially those whose hyperten-
sion is not controlled), decongestants, particularly
* Thus, accumulation of NE released by tyramine (1) can displace the when systemically administered orally, can elevate
RIMA (2), allowing for normal destruction of extra NE (3) and no physi-
ological harm. blood pressure by themselves.
MAOIs alone can potentiate NE, but this alone
MAO=monoamine oxidase; RIMAs=reversible inhibitors of monoamine;
NE=norephinephrine; BP=blood pressure. is generally insufficient to cause hypertension
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008. (Figure 12). In fact, in the past, MAOIs have been

CNS Spectr 13:10 9 October 2008

 Trends in Psychopharmacology

marketed as antihypertensives and, by themselves,
are probably more likely to cause hypotension,
especially orthostatic hypotension. 56 However,
a hypertensive drug interaction can occur when
the mechanisms of decongestants and MAOIs are
combined, especially in vulnerable patients. In
these patients, the pro-noradrenergic actions of
MAO inhibition in concert with the direct stimula-
tion of alpha 1 receptors by an agent like phenyl-
ephrine can result in elevated blood pressure or a
hypertensive crisis (Figure 12).57
It is a myth that a patient on an MAOI cannot
take any cough or cold medication. Generally, a
patient on an MAOI should avoid oral phenyleph-
rine in order to minimize the risk of a hypertensive
reaction (Figure 12). For different reasons, namely
to avoid the serotonin syndrome, patients on an
MAOI should also avoid ingredients in cough and
cold preparations that inhibit 5-HT reuptake, as
discussed in the next section. (This includes dex-
tromethorphan and some antihistamines, espe-
cially chlorpheniramine and brompheniramine;
Table 7.) Other antihistamines and cough suppres-
sants, including codeine, are generally acceptable
to be administered with MAOIs.
MAOIs are sometimes combined with tricyclic
antidepressants (TCAs) in heroic cases, 2,10,18,58
though MAOIs are formally contraindicated in
the prescribing information for patients taking
antidepressants that are NE reuptake inhibitors,
such as most TCAs (Table 5). This is because
the sudden addition of NE reuptake blockade in
someone on an MAOI may result in a hyperten-
sive reaction. On the other hand, MAOIs can be
combined with some TCAs (never clomipramine;
Table 7) that inhibit NE reuptake if both agents
are started simultaneously, at low doses, and if
the titration of both agents is done carefully, with
blood pressure monitoring, by someone experi-
enced in this rather heroic combination. 2,10,18,58
Combining TCAs (though never clomipramine)
with an MAOI has fallen out of favor due to the
potential danger of this combination; the legal
risks, since it is mentioned as contraindicated in
prescribing information; and the paucity of clini-
cians who understand the risks and the benefits
of this controversial approach to heroic manage-
ment of TRD.
Stimulants such as methylphenidate, which
potentiate NE at adrenergic synapses by blocking

FIGURE 10.
Selegiline, a selective MAO-B inhibitor at low doses, has antidepressant efficacy
when given at doses high enough to also inhibit MAO-A *

How Transdermal Selegiline Reduces the Risk of Tyramine Reactions

The dilemma The solution

Selegiline
transdermal
patch

A
A B

A Bypasses gut
High brain delivery
delivery (first pass)
A B A

Must inhibit MAO-A Simultaneous inhibition

and MAO-B in brain for
antidepressant action
of MAO-A in liver and
intestinal mucosa
causes risk of
tyramine reactions
A
Antidepressant actions No risk of tyramine
reactions at low dose

* However, oral administration at this dose can also cause a tyramine reaction (left panel). Transdermal administration delivers the drug directly into the systemic
circulation, hitting the brain in high doses and producing an antidepressant effect, but avoiding a first pass through the liver and therefore reducing the risk of a
tyramine reaction (right panel). Transdermal delivery of selegiline can thus lead to inhibition of both MAO-A and MAO-B in the brain and therefore an antidepres-
sant effect, yet selective inhibition of only MAO-B in the gut and therefore no need for dietary tyramine reactions (right panel).

MAO=monoamine oxidase

Stahl SM, Felker A. CNS Spectr

Spectr. Vol 13, No 10. 2008.

CNS Spectr 13:10 10 October 2008

 Trends in Psychopharmacology

NE reuptake, and amphetamines, which do this lants (Table 6), so it is also not surprising that
and also release NE, can elevate blood pressure stimulants can sometimes be combined with
on their own and are formally contraindicated in MAOIs to attain antidepressant efficacy in heroic
prescribing information even as monotherapies cases, with extreme caution, with careful blood
for patients with structural cardiac abnormalities pressure and cardiovascular monitoring and
or uncontrolled hypertension. with appropriate risk-benefit assessment for that
It is therefore not surprising that combining individual.2,10,17-18,58
stimulants with MAOIs is also formally contra- In the 1960s, fatalities were reported when
indicated in prescribing information because, amphetamine was used to increase the potential
together, MAOIs and stimulants increase the of MAOIs for refractory depression.17 However,
chances of a hypertensive reaction (Tables 5 and perhaps surprisingly, one current study has indi-
6). 2,10,17-19 Thus, use of this combination should cated that up to 40 mg of intravenous cocaine
generally be reserved for the most treatment- added to an existing transdermal selegiline regi-
resistant cases. On the other hand, as mentioned men 20 mg/day was well tolerated in a group
earlier in this article, some MAOIs are them-
selves stimulants or are metabolized to stimu- FIGURE 12.
Decongestants that stimulate post-
FIGURE 11. synaptic alpha 1 receptors (A) can
In patients not taking an MAOI, it can interact with MAOIs that increase NE
take as much as 400 mg of tyramine levels (B) and thereby increase the
to elevate blood pressure (fifth bar risk of a hypertensive reaction (C)
graph on the far right) �����������������������������������������������
How Much Tyramine Is Dangerous With Irreversible MAO-A Inhibitors? ������������������������ ��������������������

������
���������
��
� �
450

400 mg 400 mg+ �

400 �

350 � ������
��������� �
��
300 ������
�����������
250 mg
mean 250
pressor
dose 200

150 40 mg � ������������������ � �������������������

high = ����������������������� ��������
100 tyramine ��������
80 mg
meal

50
�����������������������������������������
10 mg

tranylcypromine high dose low dose oral low oral tyramine

and phenelzine transdermal transdermal dose alone,
(MAO-A & selegiline selegiline selegiline fasting
MAO-B (CNS MAO-A (CNS MAO-A & (CNS & gut (no MAO �
irreversible) & MAO-B inhibition; MAO-B inhibition; MAO-B inhibition)
gut MAO-B > gut MAO-B > selective
MAO-A inhibition) MAO-A inhibition) inhibition)
�

A B A B A B A B A B
BRAIN
�

A B A B A B A B A B
GUT

* Patients on low-dose oral selegiline may ingest as much tyramine as

someone not taking an MAOI, but they will not also experience an antide- ����
�
pressant effect (fourth bar graph). Patients taking nonselective irrevers- �������������������� ����������������
����������������
ible MAOIs may experience antidepressant effects, but may experience ������������������

a hypertensive tyramine reaction when ingesting as little as 8–10 mg of

dietary tyramine (first bar graph on the far left). Transdermal selegiline
can produce an antidepressant effect at low doses, and patients may
be able to ingest a high-tyramine meal of much more than 40 mg without
experiencing a tyramine reaction (third bar graph). At high doses of
transdermal selegiline, relatively high doses of tyramine (>40 mg) could
potentially be ingested, but this is not well studied (second bar graph).
MAOI=monoamine oxidase inhibitor; CNS=central nervous system.
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.
* Decongestants work by constricting nasal blood vessels but do not
generally elevate blood pressure at normal doses (A). An MAOI alone
increases NE but does not create vasoconstriction or hypotension (B).
When combined, though, these two mechanisms of action may be suf-
ficient to cause hypertension and potentially a hypertensive crisis (C).
MAOIs=monoamine oxidase inhibitors; NE=norephinephrine; BP=blood
pressure
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.

CNS Spectr 13:10 11 October 2008


of cocaine-dependent subjects.59 Also, selective
case reports document the usefulness of com-
bining an MAOI with a stimulant.17 A general rule
of thumb if attempting to utilize this combina-
tion is to prescribe a slow titration and start with
a low dose (ie, amphetamine 2.5 mg/day and
methylphenidate 5 mg/day) added to ongoing
MAOI therapy.17
Any drugs that block NE reuptake, including
not only the stimulants but also antidepressants,
attention-deficity/hyperactivity drugs (such as
atomoxetine), appetite suppressants (such as
sibutramine and other sympathomimetics),
and the analgesic tramadol should generally be
FIGURE 13.
Inhibition of SERT leads to increased
synaptic availability of 5-HT (A).
Inhibition of MAO also leads to
increased 5-HT levels (B). When com-
bined, these two mechanisms can
cause excessive stimulation of post-
synaptic 5-HT receptors, which can
lead to hyperthermia, seizures, coma,
cardiovascular collapse, and death
(C).
��������������������������������������
������
��������
����
� �
� �
� ������
��������
����
�����
�����
�������������
� �
���������������������������������
��������������������������
�
�����
����� �
������ ��
SERT=serotonin transporter; 5-HT=serotonin; MAO=monoamine oxidase.
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.
CNS Spectr 13:10
Trends in Psychopharmacology
avoided in combination with an MAOI or used
only by experts if deemed necessary, with ade-
quate monitoring (Table 5).60,61
MECHANISM OF DANGEROUS
DRUG INTERACTIONS WITH
MAOI S : COMBINING MAOI S WITH
SEROTONIN REUPTAKE BLOCKADE
A potentially much more dangerous combina-
tion than that of adrenergic stimulants and MAOIs
can occur when combining agents that inhibit 5-HT
reuptake with those that inhibit MAO (Table 7). One
particular combination that has gained substan-
tial attention in psychopharmacology lore is when
a patient taking an MAOI is given an injection of
meperidine (an opioid analgesic and inhibitor of 5-
TABLE 5.
Potentially Dangerous Hypertensive
Combinations: Agents that can Cause
Hypertension When Combined With
MAOIs (Theoretically via Adrenergic
Stimulation)
Decongestants
• Phenylephrine (alpha 1 selective agonist)
• Oxymetazoline (alpha 1 preferring agonist)
���������������������� • Ephedrine (ma huang, ephedra) (alpha and beta
��������������������������
agonist; central NE and DA releaser)*
• Pseudoephedrine (active stereoisomer of ephedrine—
same mechanism as ephedrine)*
• phenylpropanolamine (alpha 1 agonist; less effective
central NE/DA releaser than ephedrine)*
�
Stimulants
• Amphetamines
�����
• Methylphenidate
Antidepressants with Norepinephrine Reuptake
Inhibition
• Tricyclic antidepressants
• Norepinephrine selective reuptake inhibitors
• Serotonin-norepinephrine reuptake inhibitors
• Norepinephrine and dopamine reuptake inhibitors (eg,
bupropion)
Appetite Suppressants with Norepinephrine Reuptake
Inhibitory Properties
�
• Sibutramine
� • Phentermine
Analgesics with Norepinephrine Reuptake Inhibitory
Properties
• Tramadol
* Withdrawn or restricted from direct over the counter access in the United
States and some other countries
MAOIs=monoamine oxidase inhibitors; NE=norepinephrine; DA=dopamine
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.
12 October 2008
 Trends in Psychopharmacology
HT reuptake) for pain relief in the emergency room
and perishes as a result of this preventable interac-
tion and resulting 5-HT toxicity.62
Inhibition of the serotonin transporter (SERT)
leads to increased synaptic availability of 5-HT
(Figure 13).61 Similarly, inhibition of MAO leads
to increased synaptic 5-HT levels. When these
mechanisms are combined, excessive stimulation
of postsynaptic 5-HT receptors occurs, which can
lead to the collective symptoms known as “sero-
tonin syndrome” (Figure 13).63 Theoretically, exces-
sive stimulation of postsynaptic 5-HT receptors
causes a disruption in thermoregulation, result-
ing in dangerous hyperthermia.2 Since the 5-HT
neuron has MAO-B (or the “wrong” form of MAO
for its substrate 5-HT that is actually preferentially
metabolized by MAO-A; Figure, 1 top panel), the
5-HT neuron may normally prevent excessive con-
centrations of 5-HT from accumulating by being
vitally dependent on the integrity of functioning
of the 5-HT reuptake pump.64 Thus, blocking 5-HT
transporter alone robustly elevates 5-HT at 5-HT
neurons.2 When extrasynaptic removal of 5-HT by
MAO-A is also inhibited, a potentially dangerous
accumulation of 5-HT can occur.
Consequences from this situation are grouped
into a triad of features including neuromuscular
hyperactivity, autonomic hyperactivity, and altered
mental status. Presenting symptoms range from
migraines, myoclonus, diarrhea, agitation, and psy-
chosis at the lower end of the severity spectrum,
to hyperthermia, seizures, coma, cardiovascular
collapse, permanent hyperthermic brain damage,
and death at the higher end.65,66 The Hunter Area
Toxicology Service in Australia66 has documented
>2,000 cases of serotonergic drug overdose. This
particular research group has labeled 5-HT toxic-
TABLE 6.
MAOIs With Amphetamine Actions or
Amphetamines With MAO Inhibition?
Drug Comment
Amphetamine MAOI at high doses
Tranylcypromine Also called phenylcyclopropylamine;
(Parnate) structure closely related to
amphetamine
Selegiline Metabolized to l-methamphetamine;
metabolized to l-amphetamine; less
amphetamine formed transdermally
MAOIs=monoamine oxidase inhibitors.
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.
CNS Spectr 13:10
ity as a spectrum concept of serotonin syndrome,
with weak 5-HT reuptake inhibitors (eg, pethidine,
also known as meperidine, an opioid analgesic)
sometimes precipitating 5-HT toxicity, but only
in susceptible individuals or when taken in large
doses, and other drugs with more robust 5-HT
reuptake inhibition often instigate 5-HT toxicity.66
It is suggested that agents with potent 5-HT
reuptake inhibition should never be combined with
agents that cause substantial MAO inhibition.66
This would include any SSRI or serotonin-nor-
epinephrine reuptake inhibitors, and clomip-
ramine, a TCA. Occasionally, tricyclics with weak
5-HT reuptake inhibition can be combined with
MAOIs, but, as mentioned earlier, this is rarely
done.45,58,63,67 Opioids that block 5-HT reuptake,
including meperidine, methadone, propoxyphene,
dextromethorphan, and tramadol, especially at
high doses, must be avoided in the presence of
an MAOI (Table 7). Injection of meperidine given
concomitantly with an MAOI may be the most fre-
quent drug combination causing serious complica-
tions and even death.68 However, any agent with
TABLE 7.
Potentially Lethal Combinations:
Agents that, When Combined With
MAOIs, can Cause Hyperthermia/
Serotonin Syndrome (Theoretically via
Serotonin Reuptake Inhibition)
Antidepressants
• SSRIs
• SNRIs
• TCAs (especially clomipramine)
Other TCA structures
• Cyclobenzapine
• Carbamazepine
SNRI prescribed for weight loss
• Sibutramine
Opioids with 5-HT reuptake inhibitory properties
• Dextromethorphan
• Meperidine
• Tramadol
• Methadone
• Propoxyphene
Antihistamines with 5-HT inhibitory properties
• Chlorpheniramine
• Brompheniramine
MAOIs=monoamine oxidase inhibitors; SSRIs=selective serotonin reup-
take inhibitors; SNRIs=serotonin-norepinephrine inhibitors; TCAs=tricyclic
antidepressants; 5-HT=serotonin.
Stahl SM, Felker A. CNS Spectr
Spectr. Vol 13, No 10. 2008.
13 October 2008
 Trends in Psychopharmacology
5-HT reuptake blockade has the potential to cause
serotonin syndrome. Analgesics, including opi-
ates, that are safe to administer with an MAOI are
those lacking 5-HT reuptake inhibiting properties,
such as aspirin, acetaminophen, nonsteroidal anti-
inflammatory drugs, codeine, oxycodone, fentanyl,
buprenorphine, and morphine.
Usually, the serotonin syndrome caused by
an MAOI together with a 5-HT reuptake inhibitor
results from the prescriber not recognizing that
a patient on an MAOI is also on a drug with 5-HT
reuptake inhibiting properties, such as certain anal-
gesics, appetite suppressants, antihistamines, etc.
(Table 7). More recently, the serotonin syndrome
is being caused by the prescriber not recognizing
that a patient on a 5-HT reuptake inhibitor is also
on an antibiotic that is also an MAOI, namely, line-
zolid (Zyvox). Linezolid exhibits MAO-A and MAO-
B inhibitory effects.55 Linezolid was approved by
the Food and Drug Administration in 2000 and is
the first oxazolidinone antimicrobial approved for
use in the US.55 It is used in the treatment of van-
comycin-resistant Enterococcus and methicillin-
resistant Staphylococcus aureus.57 Oxazolidinones
are similar in chemical structure to toloxatone,
which is an inhibitor of MAO. Linezolid appears to
have weak reversible MAO-A and MAO-B inhibi-
tory effects,55 and there are now appeared numer-
ous case reports57 of serotonin syndrome when
linezolid was combined with SSRIs.
Treatment of serotonin syndrome includes dis-
continuation of all serotonergic agents and sub-
sequent supportive care. Moderate cases may
benefit from administration of 5-HT2A antagonists.
Severe cases with hyperthermia may also require
intubation and sedation. Benzodiazepines may be
useful in alleviation of agitation, while diazepam
may improve hyperadrenergic symptoms. Some
evidence61 has also supported the use of β-block-
ers, which may also block 5-HT1A receptors.
CONCLUSION
MAOIs should not be discounted in the fight
against TRD, as well as various treatment-resis-
tant anxiety disorders. While patients on MAOI
pharmacotherapy should maintain a watch-
ful eye over their dietary intake, they may not
need to be fully restricted from certain foods
once erroneously thought to be high in tyramine
content and, therefore, potentially dangerous,
especially with certain MAOIs. Educating clini-
cians and patients on recent findings regard-
ing tyramine reactions and MAOIs may aid in
CNS Spectr 13:10
dispelling this particular stigma surrounding
MAOIs. Furthermore, clinicians who are fully
aware of drugs with the ability to inhibit the
SERT should be able to avoid them when they
prescribe MAOIs. Clinicians should also be able
to determine when a combination or augmen-
tation pharmacotherapy, risky or otherwise, is
needed. Expert clinicians may carefully adminis-
ter and monitor specific drugs that may require
close supervision in conjunction with MAOIs,
such as stimulants, as this tactic may help cer-
tain refractory cases of depression. In addition,
recent advancements in technology may alle-
viate some of the issues surrounding admin-
istration and resulting blockade of MAO-A by
administering MAO inhibitors transdermally,
such as the transdermal selegiline patch. The
RIMA moclobemide, may create less concern
over potential side effects and interactions from
dietary tyramine. With knowledge of MAOI ther-
apeutic mechanisms as well as the mechanisms
underlying dietary tyramine reactions and vari-
ous potentially dangerous drug interactions, the
MAOIs may enjoy renewed interest and may
be revived as a therapeutic tool in the modern
psychopharmacologist’s toolkit for the treatment
of difficult cases of depression and other psychi-
atric disorders. CNS
REFERENCES
1. Amsterdam, JD. Monoamine oxidase inhibitor therapy in severe and resistant
depression. Psychiatr Ann. 2006;36:607-613.
2. Stahl SM. Stahl’s Essential Psychopharmacology
Psychopharmacology. 3rd ed. New York, NY: Cambridge
University Press; 2008.
3. Zisook S. A clinical overview of monoamine oxidase inhibitors. Psychosomatics.
1985;26:240-246,251.
4. Krishnan KR. Revisiting monoamine oxidase inhibitors. J Clin Psychiatry Psychiatry.
2007;68(suppl 8):35-41.
5. Tollefson GD. Monoamine oxidase inhibitors: a review. J Clin Psychiatry Psychiatry.
1983;44:280-288.
6. Versiani M, Nardi AE, Mundim FD, et al. The long-term treatment of social phobia
with moclobemide. Int Clin Psychopharmacol. 1996;11(suppl 3):83-88.
7. Cole JO, Bodkin JA. MAO inhibitors: an option worth trying in treatment-resistant
cases. Current Psychiatry
Psychiatry. 2002;1:40-47.
8. Rascol O. Rasagiline in the pharmacotherapy of Parkinson’s disease—a review.
Expert Opin Pharmacother
Pharmacother. 2005;6:2061-2075.
9. Cascade EF, Kalali AH, Preskorn SH. Emsam: The first year. Psychiatry
Psychiatry. 2007;19-21.
10. Stahl SM. Essential Psychopharmacology: The Prescribers Guide. New York, NY:
Cambridge University Press; 2006.
11. Schatzberg AF. Safety and tolerability of antidepressants: weighing the impact on
treatment decisions. J Clin Psychiatry
Psychiatry. 2007;68(suppl 8):26-34.
12. Jacob CP, Muller J, Schmidt M, et al. Cluster B personality disorders are associated
with allelic variation of monoamine oxidase A activity. Neuropsychopharmacoloy.
Neuropsychopharmacoloy
2005;30:1711-1718.
13. Ballas CA, Evans DL, Dinges DF. Psychostimulants in psychiatry: amphetamine,
methylphenidate and modafinil. In: Textbook of Psychopharmacology
Psychopharmacology. Schatzberg A,
Nemeroff C, eds. Washington, DC: American Psychiatric Publishing, Inc.; 2004:671-
684.
14. Kupiec TC, Chaturvedi AK. Stereochemical determination of selegiline metabolites
in postmortem biological specimens. J Forensic SciSci. 1999;44:222-226.
15. Shin H. Metabolism of selegiline in humans: identification, excretion, and stereo-
chemistry of urine metabolites. Drug Metab Dispos. 1997;25:657-662.
14 October 2008
 Trends in Psychopharmacology
16. Magyar MK, Szatmary I, Szebeni G, Lengyel J. Pharmacokinetic studies of (-)-depre-
nyl and some of its metabolites in mouse. J Neural Transm Suppl. 2007;72:165-
173.
17. Feinberg SS. Combining stimulants with monoamine oxidase inhibitors: a review of
uses and one possible additional indication. J Clin Psychiatry
Psychiatry. 2004;65:1520-1524.
18. Feighner JP, Herbstein J, Damlouji N. Combined MAOI, TCA and direct stimulant
therapy of treatment-resistant depression. J Clin Psychiatry
Psychiatry. 1985;46:206-209.
19. Fawcett J, Kravitz HM, Zajecka JM, Schaff MR. CNS stimulant potentiation
of monoamine oxidase inhibitors in treatment-refractory depression. J Clin
Psychopharmacol. 1991;11:127-132.
20. Schoepp DD, Azzarro AJ. Specificity of endogenous substrates for types A and B
monoamine oxidase in rat striatum. J Neurochem. 1981;36:2025-2031.
21. Fowler CJ, Tipton KF . On the substrate specificities of the two forms of monoamine
oxidase. J Pharm Pharmacol. 1984;36:111-115.
22. Chen K, Holschneider DP, Wu W, Rebrin I, Shih JC. A spontaneous point mutation
produces monoamine oxidase A/B knock-out mice with greatly elevated mono-
amines and anxiety-like behavior. Biol Chem. 2004;279:39645-39652.
23. Da Prada M, Kettler R, Keller HH, Burkard WP, Muggli-Maniglio D, Haefely WE.
Neurochemical profile of moclobemide, a short-acting and reversible inhibitor of
monoamine oxidase type A. Pharmacol Exp Ther Ther. 1989;248:400-414.
24. Lotufo-Neto F, Trivedi M, Thase ME. Meta-analysis of the reversible inhibitors of
monoamine oxidase type A moclobemide and brofaromine for the treatment of
depression. Neuropsychopharmacology
Neuropsychopharmacology. 1999;20:226-247.
25. Patkar AA, Pae CU, Masand PS. Transdermal selegiline: the new generation of
monoamine oxidase inhibitors. CNS Spectr
Spectr. 2006;11:363-373.
26. Mendis N, Pare CM, Sandler M, Glover V, Stern GM. Is the failure of (-) deprenyl, a
selective monoamine oxidase B inhibitor, to alleviate depression related to freedom
from the cheese effect? Psychopharmacology
Psychopharmacology. 1981;73:87-90.
27. Mann JJ, Frances A, Kaplan RD, Kocsis J, Peselow ED, Gershon S. The relative effi-
cacy of l-deprenyl, a selective monoamine oxidase type B inhibitor, in endogenous
and nonendogenous depression. J Clin Psychopharmacol. 1982;2:54-57.
28. Sunderland T, Cohen RM, Molchan S, et al. High-dose selegiline in treatment resis-
tant older depressive patients. Arch Gen Psychiatry
Psychiatry. 1994;51:607-615.
29. Birkmeyer W. Implications of combined treatment with “Madopar” and L-deprenyl
in Parkinson’s disease: a long-term study. Lancet
Lancet. 1977;26:439-443.
30. Postma JU, Vranesic D. Moclobemide in the treatment of depression in demented
geriatric patients. Acta Ther
Ther. 1985;11:249-252.
31. Nutt D, Demyttenaere K, Janka Z, et al. The other face of depression, reduced posi-
tive affect: The role of catecholamines in causation and cure. Psychopharmacol.
2007;21:461-471.
32. McCabe B, Tsuang MT. Dietary consideration in MAO inhibitor regimens. J Clin
Psychiatry. 1982;43:178-181.
Psychiatry
33. Gardner DM, Shulman KI, Walker SE, Tailor SA. The making of a user friendly MAOI
diet. J Clin Psychiatry
Psychiatry. 1996;57:99-104.
34. Da Prada M, Zurcher G, Wuthrich I, Haefely WE. On tyramine, food, beverages and
the reversible MAO inhibitor moclobemide. J Neural Transm Suppl. 1988;26:31-56.
35. Sweet RA, Brown EJ, Heimberg RG, et al. Monoamine oxidase inhibitor dietary
restrictions: what are we asking patients to give up? J Clin Psychiatry
Psychiatry. 1995;56:196-
201.
36. Shulman KI, Walker SE, MacKenzie S, Knowles S. Dietary restriction, tyramine,
and the use of monoamine oxidase inhibitors. J Clin Psychopharmacol. 1989;9:397-
402.
37. Shulman KI, Walker SE. Refining the MAOI diet: tyramine content of pizzas and soy
products. J Clin Psychiatry
Psychiatry. 1999;60:191-193.
38. Shulman KI, Walker SE. Psychiatr Ann. 2001;31:378-384.
39. Knoll J, Magyar K. Some puzzling pharmacological effects of monoamine oxidase
inhibitors. Adv Biochem Psychopharmacol. 1972;5:393-408.
40. Wecker L, Copeland JS, Pacheco MA. Transdermal selegiline: targeted effects on
monoamine oxidases in the brain. Biol Psychiatry
Psychiatry. 2003;541099-541104.
41. Mawhinney M, Cole D, Azzaro AJ. Daily transdermal administration of selegiline
to guinea-pigs preferentially inhibits monoamine oxidase activity in brain when
compared with intestinal and hepatic tissues. J Pharm Pharmacol. 2003;55:27-34.
42. Keller HH, Kettler R, Burkard WP, et al. Preclinical characteristics of moclobemide,
a short-acting MAO-A inhibitor with low liability to enhance the tyramine pressor
effect. Abstract presented at: annual meeting of the Collegium Internationale
Neuro-Psychopharmacologicum. Session 3102: Antidepressants and MAO inhibi-
CNS Spectr 13:10
View publication stats
tors. August 16, 1988; Munich, Germany
43. Priest RG. Recent clinical development with reversible and selective amine oxidase
inhibitors: a valuable addition to the armamentarium. J Clin Psychopharmacol.
1995;15(suppl 2):1-3.
44. Stabl M, Biziere K, Schmid-Burgk W, Amrein R. Moclobemide vs tricyclic antide-
pressants and vs placebo in depressive states. J Neural Transm Suppl. 1989;28:77-
89.
45. Angst J, Amrein R, Stabl M. Moclobemide and tricyclic antidepressants in severe
depression: meta-analysis and prospective studies. J Clin Psychopharmacol.
1995;15(4 suppl 2):16S-23S.
46. Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy
of selegiline transdermal system without dietary restrictions in patients with major
depressive disorder. J Clin Psychiatry. 2003;64:208-214.
47. Robinson DS. Transdermal selegiline: A new-generation MAOI. Primary Psychiatry
Psychiatry.
2006;13:33-35.
48. Zsilla G, Foldi P, Held G, Szekely AM, Knoll J. The effect of repeated doses of (-)
deprenyl on the dynamics of monoaminergic transmission: comparison with clorgy-
line. Pol J Pharmacol Pharm. 1986;38:57-67.
49. Bodkin JA, Siris SG, Bermanzohn PC, Hennen J, Cole JO. Double-blind, placebo-
controlled, multicenter trial of selegiline augmentation of antipsychotic medication
to treat negative symptoms in outpatients with schizophrenia. Am J Psychiatry
Psychiatry.
2005;162:388-390.
50. Shimazu S, Minami A, Kusumoto H. Yoneda F. Antidepressant-like effects of selegi-
line in the forced swim test. Eur Neuropsychopharmacol. 2005;15:563-571.
51. Feiger AD, Rickels K, Rynn MA, Zimbroff DL, Robinson DS. Selegiline transdermal
system for the treatment of major depressive disorder: an 8-week, double-blind,
placebo-controlled, flexible-dose titration trial. J Clin Psychiatry
Psychiatry. 2006;67:1354-
1361.
52. Blob, LF, Sharoky M, Campbell BJ, et al. Effects of a tyramine-enriched meal on
blood pressure response in healthy male volunteers treated with selegiline trans-
dermal system 6 mg/24 hour. CNS Spectr
Spectr. 2007;12:25-34.
53. Sternbach H. Serotonin syndrome: how to avoid, identify, and treat dangerous drug
interactions. Current Psychiatry
Psychiatry. 2003;2:15-23.
54. Gillman PK. A review of serotonin toxicity data: implications for the mechanisms of
antidepressant drug action. Biol Psychiatry
Psychiatry. 2006;59:1046-1051.
55. Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of
linezolid: a review of postmarketing data. Clin Infect Dis. 2006;42:1578-1583.
56. Gillman PK. Understanding toxidromes: serotonin toxicity. J Clin Psychopharmacol.
2005;25:625-626.
57. Ginsberg DL. Psychopharmacology Reviews: serotonin syndrome due to interaction
between antibiotic linezolid and norfluoxetine. Primary Psychiatry
Psychiatry. 2005;12:27-28.
58. Berlanga C, Ortega-Soto HA. A 3-year follow-up of a group of treatment-resis-
tant depressed patients with a MAOI/tricyclic combination. J Affect Disord Disord.
1995;34:187-192.
59. Houtsmuller EJ, Notes LD, Newton T, et al. Transdermal selegiline and intravenous
cocaine: Safety and interactions. Psychopharmacology
Psychopharmacology. 2004;172:31-40.
60. Gillman PK. Extracting value from case reports: lessons from serotonin toxicity.
Anaesthesia. 2006;61:419-422.
61. Dvir Y, Smallwood P. Serotonin syndrome: a complex but easily avoidable condition.
Gen Hosp Psychiatry
Psychiatry. 2008;30:284-287.
62. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med Med. 2005;352:1112-
1120.
63. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interac-
tions updated. Br J Pharmacol. 2007;151:737-748.
64. Sabelli HC. Rapid treatment of depression with selegiline-phenylalanine combina-
tion. J Clin Psychiatry
Psychiatry. 1991;52:137.
65. Taylor BP, Quitkin FM, McGrath PJ, Stewart JW. Do antihypertensives make tranyl-
cypromine safer? Three case reports. J Clin Psychiatry
Psychiatry. 2005;66:657-658.
66. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxic-
ity. Br J Anaesth. 2005;95:434-441.
67. Joffe RT, Bakish D. Combined SSRI-moclobemide treatment of psychiatric illness. J
Clin Psychiatry
Psychiatry. 1994;55:24-25.
68. Fuller RW, Snoddy HD. Inhibition of serotonin uptake and the toxic interaction
between meperidine and monoamine oxidase inhibitors. Toxicol Appl Pharmacol.
1975;32:129-134.
15 October 2008