CNS ‘Stimulants’ and MAOIs
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.
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 (10-9) 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  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.
Sulzer’s recent review of Amphetamine (and other drugs of addiction) is an intoxicating Pierian spring of knowledge, all 14 pages, a weekend read .
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 ; there seems to be little or no risk of precipitating serotonin toxicity, if combined with MAOIs , and low risk with SRIs (see Prior et al ).
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  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 .
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 , 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 .
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  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. ).
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  — cf. see , 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 ). 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 . 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 : 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].
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. , 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.
See full table in Rothman 
* sertraline- for comparison, not from Rothman
|Release (EC50 nm)||Uptake (Ki nm)||Release (EC50 nm)||Uptake (Ki nm)||Release (EC50 nm)||Uptake (Ki nm)|
|Desipramine||> 10,000||350||> 10,000||8.3||> 10,000|
|Citalopram||> 10,000||2.4||> 10,000||> 10,000|
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 . 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 (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 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 . 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 , 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 , 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 , 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’.
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 .
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  & see also [9, 77-80].
releasers are almost a problem of the past, and in any case are unlikely to cause severe reactions in normal moderate therapeutic use.
1. Miller, G.M., Avenues for the development of therapeutics that target trace amine associated receptor 1 (TAAR1). J Med Chem, 2012. 55(5): p. 1809-14.
2. Wimalasena, K., Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry. Med Res Rev, 2011. 31(4): p. 483-519.
3. Eiden, L.E. and E. Weihe, VMAT2: a dynamic regulator of brain monoaminergic neuronal function interacting with drugs of abuse. Ann N Y Acad Sci, 2011. 1216: p. 86-98.
4. Sitte, H.H. and M. Freissmuth, Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci, 2015. 36(1): p. 41-50.
5. Heal, D.J., et al., Amphetamine, past and present–a pharmacological and clinical perspective. J Psychopharmacol, 2013. 27(6): p. 479-96.
6. Sulzer, D., How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron, 2011. 69(4): p. 628-49.
7. Sulzer, D., S. Cragg, and M. Rice, Regulation of extracellular dopamine: Release and uptake, in Handbook of Behavioral Neuroscience. 2017, Elsevier. p. 373-402.
8. Bradbury, A.J., et al., 5-Hydroxytryptamine involvement in the locomotor activity suppressant effects of amphetamine in the mouse. Psychopharmacology (Berl), 1987. 93(4): p. 457-65.
9. Pilgrim, J.L., et al., Involvement of amphetamines in sudden and unexpected death. J Forensic Sci, 2009. 54(2): p. 478-85.
10. Prior, F.H., et al., Serotonin toxicity with therapeutic doses of dexamphetamine and venlafaxine. Med J Aust, 2002. 176(5): p. 240-1.
11. Robertsen, A., et al., [Amphetamine poisoning]. Tidsskrift for Den Norske Laegeforening, 1998. 118(28): p. 4340-3.
12. Wallace, M.E. and R. Squires, Fatal massive amphetamine ingestion associated with hyperpyrexia. Journal of the American Board of Family Practice, 2000. 13(4): p. 302-4.
13. Gillman, P.K., Neuroleptic Malignant Syndrome: Mechanisms, Interactions and Causality. Movement Disorders, 2010. 25(12): p. 1780-1790.
14. Bodner, R.A., et al., Serotonin syndrome. Neurology, 1995. 45: p. 219-223.
15. Krisko, I.E., E. Lewis, and J.E. Johnson, Severe hyperpyrexia due to tranylcypromine amphetamine toxicity. Annals of Internal Medicine, 1969. 70: p. 559.
16. Brownlee, G. and G.W. Williams, Potentiation of amphetamine and pethidine by monoamine oxidase inhibitors. Lancet, 1961. 1([letter]): p. 669.
17. Zeck, P., The dangers of some antidepressant drugs. Medical Journal of Australia, 1961. 2: p. 607-608.
18. Dally, P.J., Fatal reaction associated with tranylcypromine and methylamphetamine. Lancet, 1962. 1: p. 1235-1236.
19. Mason, A., Fatal reaction associated with tranylcypromine and methylamphetamine. Lancet, 1962. 1: p. 1073.
20. Lloyd, J.T. and D.R. Walker, Death after Combined Dexamphetamine and Phenelzine. British Medical Journal, 1965. 5454: p. 168-9.
21. Espelin, D.E. and A.K. Done, Amphetamine poisoning. Effectiveness of chlorpromazine. New England Journal of Medicine, 1968. 278: p. 1361-1365.
22. Kuczenski, R. and D.S. Segal, Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: comparison with amphetamine. Journal of Neurochemistry, 1997. 68(5): p. 2032-7.
23. Feinberg, S.S., Combining stimulants with monoamine oxidase inhibitors: a review of uses and one possible additional indication. J Clin Psychiatry, 2004. 65(11): p. 1520-4.
24. Rothman, R.B. and M.H. Baumann, Monoamine transporters and psychostimulant drugs. Eur J Pharmacol, 2003. 479(1-3): p. 23-40.
25. Rothman, R.B., et al., In vitro characterization of ephedrine-related stereoisomers at biogenic amine transporters and the receptorome reveals selective actions as norepinephrine transporter substrates. J Pharmacol Exp Ther, 2003. 307(1): p. 138-45.
26. Markowitz, J.S., S.D. Morrison, and C.L. DeVane, Drug interactions with psychostimulants. International Clinical Psychopharmacology, 1999. 14(1): p. 1-18.
27. Israel, J.A., Combining Stimulants and Monoamine Oxidase Inhibitors: A Reexamination of the Literature and a Report of a New Treatment Combination. Prim Care Companion CNS Disord, 2015. 17(6): p. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805402/.
28. Markowitz, J.S. and K.S. Patrick, Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder. Clin Pharmacokinet, 2001. 40(10): p. 753-72.
29. Sherman, M., G.C. Hauser, and B.H. Glover, Toxic Reactions to Tranylcypromine. American Journal of Psychiatry, 1964. 120: p. 1019-21.
30. Gillman, P.K., A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action. Biological Psychiatry, 2006. 59(11): p. 1046-51.
31. Jackson, H., H. Rowley, and D. Hackett, Comparison of the effects of equivalent doses of lisdexamfetamine dimesylate and d-amphetamine on extracellular concentrations of striatal dopamine, locomotor activity and plasma amphetamine concentrations in freely moving rats. 2011: p. http://www.SfN.org (accessed August 2012).
32. Krishnan, S. and S. Moncrief, An evaluation of the cytochrome p450 inhibition potential of lisdexamfetamine in human liver microsomes. Drug Metab Dispos, 2007. 35(1): p. 180-4.
33. Ermer, J., M. Corcoran, and P. Martin, Lisdexamfetamine Dimesylate Effects on the Pharmacokinetics of Cytochrome P450 Substrates in Healthy Adults in an Open-Label, Randomized, Crossover Study. Drugs R D, 2015. 15(2): p. 175-85.
34. Ermer, J.C., B.A. Adeyi, and M.L. Pucci, Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder. CNS Drugs, 2010. 24(12): p. 1009-25.
35. Ermer, J.C., M. Pennick, and G. Frick, Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy. Clin Drug Investig, 2016. 36(5): p. 341-56.
36. Pennick, M., Absorption of lisdexamfetamine dimesylate and its enzymatic conversion to d-amphetamine. Neuropsychiatr Dis Treat, 2010. 6: p. 317-27.
37. Ermer, J.C., et al., Pharmacokinetics of lisdexamfetamine dimesylate after targeted gastrointestinal release or oral administration in healthy adults. Drug Metab Dispos, 2012. 40(2): p. 290-7.
38. Rowley, H.L., et al., Lisdexamfetamine and immediate release d-amfetamine – differences in pharmacokinetic/pharmacodynamic relationships revealed by striatal microdialysis in freely-moving rats with simultaneous determination of plasma drug concentrations and locomotor activity. Neuropharmacology, 2012. 63(6): p. 1064-74.
39. Hutson, P.H., M. Pennick, and R. Secker, Preclinical pharmacokinetics, pharmacology and toxicology of lisdexamfetamine: a novel d-amphetamine pro-drug. Neuropharmacology, 2014. 87: p. 41-50.
40. Schmitt, K.C. and M.E. Reith, The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors. PLoS One, 2011. 6(10): p. e25790.
41. Reith, M.E. and M.E. Gnegy, Molecular Mechanisms of Amphetamines. 2019.
42. Rothman, R.B. and M.H. Baumann, Serotonin releasing agents. Neurochemical, therapeutic and adverse effects. Pharmacol Biochem Behav, 2002. 71(4): p. 825-36.
43. Rothman, R.B., et al., Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse, 2001. 39(1): p. 32-41.
44. Fenwick, M.J. and C.L. Muwanga, Anaphylaxis and monoamine oxidase inhibitors–the use of adrenaline. Journal of Accident and Emergency Medicine, 2000. 17(2): p. 143-4.
45. Griesemer, E., et al., Potentiating effect of iproniazid on the pharmacological action of sympathomimetic amines. Experimental Biology and Medicine, 1953. 84(3): p. 699-701.
46. Burn, J.H., F.J. Philpot, and U. Trendelenburg, Effect of denervation on enzymes in iris and blood vessels. British Journal of Pharmacology, 1954. 9: p. 423-428.
47. Corne, S. and J. Graham, The effect of inhibition of amine oxidase in vivo on administered adrenaline, noradrenaline, tyramine and serotonin. The Journal of physiology, 1957. 135(2): p. 339-349.
48. Rivers, N. and B. Horner, Possible lethal interaction between Nardil and dextromethorphan. Canadian Medical Association Journal, 1970. 103([letter]): p. 85.
49. Shamsie, S.J. and C. Barriga, The hazards of monoamine oxidase inhibitors in disturbed adolescents. Canadian Medical Association Journal, 1971. 104([letter]): p. 715.
50. Asch, D.A. and R.M. Parker, The Libby Zion case: One step forward or two steps backward? New England Journal of Medicine, 1988. 318: p. 771-775.
51. Kaplan, R.L., The Libby Zion case. Annals of Internal Medicine, 1991. 115(12 (letter)): p. 985.
52. Gillman, P.K., Serotonin Syndrome: History and Risk. Fundamental and Clinical Pharmacology, 1998. 12(5): p. 482-491.
53. Miller, G.M., The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity. J Neurochem, 2011. 116(2): p. 164-76.
54. Brodie, B.B., et al., Interaction between desipramine, tyramine, and amphetamine at adrenergic neurones. Br J Pharmacol, 1968. 34(3): p. 648-58.
55. Liechti, M.E., et al., Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) are attenuated by the serotonin uptake inhibitor citalopram. Neuropsychopharmacology, 2000. 22(5): p. 513-21.
56. Malberg, J.E., K.E. Sabol, and L.S. Seiden, Co-administration of MDMA with drugs that protect against MDMA neurotoxicity produces different effects on body temperature in the rat. Journal of Pharmacology & Experimental Therapeutics, 1996. 278(1): p. 258-67.
57. Mechan, A.O., et al., The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to rats. British Journal of Pharmacology, 2002. 135(1): p. 170-80.
58. Dostert, P., et al., Reboxetine prevents the tranylcypromine-induced increase in tyramine levels in rat heart. Journal of Neural Transmission, 1994. 41: p. 149-53.
59. Malhotra, S. and P.J. Santosh, An open clinical trial of buspirone in children with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 1998. 37(4): p. 364-71.
60. Kafka, M.P. and J. Hennen, Psychostimulant augmentation during treatment with selective serotonin reuptake inhibitors in men with paraphilias and paraphilia-related disorders: a case series. Journal of Clinical Psychiatry, 2000. 61(9): p. 664-70.
61. Klein-Schwartz, W., Abuse and toxicity of methylphenidate. Current Opinion in Pediatrics, 2002. 14(2): p. 219-23.
62. Klein-Schwartz, W., Pediatric methylphenidate exposures: 7-year experience of poison centers in the United States. Clinical Pediatrics, 2003. 42(2): p. 159-64.
63. Bymaster, F.P., et al., Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology, 2002. 27(5): p. 699-711.
64. Volkow, N.D., et al., Serotonin and the therapeutic effects of ritalin. Science, 2000. 288(5463): p. 11.
65. Gillman, P.K., Moclobemide and the risk of serotonin toxicity (or serotonin syndrome). Central Nervous System Drug Reviews, 2004. 10: p. 83-85.
66. Gillman, P.K., The spectrum concept of serotonin toxicity. Pain Medicine, 2004. 5: p. 231-2.
67. Gillman, P.K., Amitriptyline: Dual-Action Antidepressant? Journal of Clinical Psychiatry, 2003. 64: p. 1391.
68. Gillman, P.K., Linezolid and serotonin toxicity. Clinical Infectious Diseases, 2003. 37: p. 1274-5.
69. Feighner, J.P., J. Herbstein, and N. Damlouji, Combined MAOI, TCA, and direct stimulant therapy of treatment-resistant depression. Journal of Clinical Psychiatry, 1985. 46(6): p. 206-9.
70. Myronuk, L.D., M. Weiss, and L. Cotter, Combined treatment with moclobemide and methylphenidate for comorbid major depression and adult attention-deficit/hyperactivity disorder. Journal of Clinical Psychopharmacology, 1996. 16(6): p. 468-9.
71. Crooks, A., et al., Design, Synthesis and Interaction at the Vesicular Monoamine Transporter-2 of Lobeline Analogs: Potential Pharmacotherapies for the Treatment of Psychostimulant Abuse. Current Topics in Medicinal Chemistry, 2011. 11: p. 1103-1127(25).
72. Alvers, K.M., et al., The effect of VMAT2 inhibitor GZ-793A on the reinstatement of methamphetamine-seeking in rats. Psychopharmacology (Berl), 2012.
73. Beckmann, J.S., et al., The effect of a novel VMAT2 inhibitor, GZ-793A, on methamphetamine reward in rats. Psychopharmacology (Berl), 2012. 220(2): p. 395-403.
74. Horton, D.B., et al., Novel N-1,2-dihydroxypropyl analogs of lobelane inhibit vesicular monoamine transporter-2 function and methamphetamine-evoked dopamine release. J Pharmacol Exp Ther, 2011. 339(1): p. 286-97.
75. Green, A.R., et al., The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”). Pharmacological Reviews, 2003. 55(3): p. 463-508.
76. Vuori, E., et al., Death following ingestion of MDMA (ecstasy) and moclobemide. Addiction, 2003. 98(3): p. 365-8.
77. Pilgrim, J.L., D. Gerostamoulos, and O.H. Drummer, Review: Pharmacogenetic aspects of the effect of cytochrome P450 polymorphisms on serotonergic drug metabolism, response, interactions, and adverse effects. Forensic Sci Med Pathol, 2010.
78. Pilgrim, J.L., D. Gerostamoulos, and O.H. Drummer, Deaths involving contraindicated and inappropriate combinations of serotonergic drugs. International Journal of Legal Medicine, 2010.
79. Pilgrim, J.L., D. Gerostamoulos, and O.H. Drummer, Deaths Involving MDMA and the Concomitant Use of Pharmaceutical Drugs. Journal of Analytical Toxicology, 2011. 35(4): p. 219-26.
80. Pilgrim, J.L., et al., Serotonin toxicity involving MDMA (ecstasy) and moclobemide. Forensic Science International, 2011.