Monoamine oxidase inhibitor
Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression. They are also used in the treatment of Parkinson's disease and several other disorders.
Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed. New research into MAOIs indicates that much of the concern over their dangerous dietary side effects stems from misconceptions and misinformation, and that despite proven effectiveness of this class of drugs, it is underutilized and misunderstood in the medical profession. New research also questions the validity of the perceived severity of dietary reactions, which has historically been based on outdated research. However this research also notes that many practitioners have a poor understanding of drug interactions, and 'drug interactions can be serious, and concomitant medication use must be stringently overseen' as they 'can cause a dangerous or fatal serotonin syndrome/ toxicity'.
Newer MAOIs such as selegiline (typically used in the treatment of Parkinson's disease) and the reversible MAOI moclobemide provide a safer alternative and are now sometimes used as first-line therapy.
MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder. MAOIs appear to be particularly effective in the management of bipolar depression according to a recent retrospective-analysis. There are reports of MAOI efficacy in obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.
MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety.
MAOIs appear to be particularly indicated for outpatients with dysthymia complicated by panic disorder or hysteroid dysphoria, which involves repeated episodes of depressed mood in response to feeling rejected.
Mechanism of action
MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other trace amines; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine is equally deaminated by both types.
The early MAOIs covalently bound to the monoamine oxidase enzymes, thus inhibiting them irreversibly; the bound enzyme could not function and thus enzyme activity was blocked until the cell made new enzymes. The enzymes turn over approximately every two weeks. A few newer MAOIs, a notable one being moclobemide, are reversible, meaning that they are able to detach from the enzyme to facilitate usual catabolism of the substrate. The level of inhibition in this way is governed by the concentrations of the substrate and the MAOI.[medical citation needed]
In addition to reversibility, MAOIs differ by their selectivity of the MAO receptor. Some MAOIs inhibit both MAO-A and MAO-B equally, other MAOIs have been developed to target one over the other.
MAO-A inhibition reduces the breakdown of primarily serotonin, norepinephrine, and dopamine; selective inhibition of MAO-A allows for tyramine to be metabolised via MAO-B. Agents that act on serotonin if taken with another serotonin-enhancing agent may result in a potentially fatal interaction called serotonin syndrome or with irreversible and unselective inhibitors (such as older MAOIs), of MAO a hypertensive crisis as a result of tyramine food interactions is particularly problematic with older MAOIs. Tyramine is broken down by MAO-A and MAO-B, therefore inhibiting this action may result in its excessive build-up, so diet must be monitored for tyramine intake.
MAO-B inhibition reduces the breakdown mainly of dopamine and phenethylamine so there are no dietary restrictions associated with this. MAO-B would also metabolize tyramine, as the only differences between dopamine, phenethylamine, and tyramine are two phenylhydroxyl groups on carbons 3 and 4. The 4-OH would not be a steric hindrance to MAO-B on tyramine. Two MAO-Bi drugs, selegiline and rasagiline have been approved by the FDA without dietary restrictions, except in high-dosage treatment, wherein they lose their selectivity.
Hypertensive Crisis & Tyramine
Patients taking MAOIs generally need to change their diets to limit or avoid foods and beverages containing tyramine. If large amounts of tyramine are consumed, they may suffer hypertensive crisis, which can be fatal. Examples of foods and beverages with potentially high levels of tyramine include liver and fermented substances, such as alcoholic beverages and aged cheeses. (See a List of foods containing tyramine).
Tyramine leads to hypertensive crisis by increasing the release of norepinephrine (NE), which causes blood vessels to constrict (through binding to alpha-1 adrenergic receptors). Ordinarily, MAO-A would destroy the excess NE. When MAO-A is inhibited, though, NE levels get too high, leading to dangerous increases in blood pressure.
Of note, no dietary modifications are needed when taking a reversible inhibitor of MAO-A (i.e., moclobemide) or low doses of selective MAO-B inhibitors (e.g., selegiline 6 mg/24 hours transdermal patch).
The most significant risk associated with the use of MAOIs is the potential for interactions with over-the-counter and prescription medicines, illicit drugs or medications, and some supplements (e.g., St. John's Wort, tryptophan). It is vital that a doctor supervise such combinations to avoid adverse reactions. For this reason, many users carry an MAOI-card, which lets emergency medical personnel know what drugs to avoid. (E.g., adrenaline dosage should be reduced by 75%, and duration is extended.)
MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, both legal and illegal etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, MDMA, meperidine, tramadol, and dextromethorphan. Agents with actions on epinephrine, norepinephrine, or dopamine must be administered at much lower doses due to potentiation and prolonged effect.
Nicotine, a substance frequently implicated in tobacco addiction, has been shown to have "relatively weak" addictive properties when administered alone. The addictive potential increases dramatically after co-administration of an MAOI, which specifically causes sensitization of the locomotor response in rats, a measure of addictive potential. This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally-occurring MAOI compounds in addition to the nicotine.
Antidepressants including MAOIs have some dependence-producing effects, the most notable one being a withdrawal syndrome, which may be severe especially if MAOIs are discontinued abruptly or over-rapidly. However, the dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines. Withdrawal symptoms can be managed by a gradual reduction in dosage over a period of weeks, months or years to minimize or prevent withdrawal symptoms.
MAOIs, as with any antidepressant medications, do not alter the course of the disorder, so it is possible that discontinuation can return the patient to the pre-treatment state.
This consideration greatly complicates switching a patient between a MAOI and a SSRI, because it is necessary to clear the system completely of one drug before starting another. If one also tapers dosage gradually, the result is that for weeks a depressed patient will have to bear the depression without chemical help during the drug-free interval. This may be preferable to risking the effects of an interaction between the two drugs, but it is often not easy for the patient.
Listing of interactions
||This section needs more medical references for verification or relies too heavily on primary sources. (November 2013)|
The MAOIs are infamous for their numerous drug interactions, including the following kinds of substances:
- Substances that are metabolized by monoamine oxidase, as they can be boosted by up to several-fold.
- Substances that increase serotonin, norepinephrine, or dopamine activity, as too much of any of these neurochemicals can result in severe acute consequences, including serotonin syndrome, hypertensive crisis, and psychosis, respectively.
Such substances that can react with MAOIs include:
- Phenethylamines: 2C-B, Mescaline, Phenethylamine (PEA), etc.
- Tryptamines: DMT, Psilocin/Psilocybin ("Magic Mushrooms"), etc.
- Serotonin, Norepinephrine, and/or Dopamine Reuptake Inhibitors:
- Selective Serotonin Reuptake Inhibitors (SSRIs): Citalopram, Dapoxetine, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline.
- Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Desvenlafaxine, Duloxetine, Milnacipran, Venlafaxine.
- Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs): Amineptine, Bupropion, Methylphenidate, Nomifensine.
- Norepinephrine Reuptake Inhibitors (NRIs): Atomoxetine, Mazindol, Reboxetine.
- Tricyclic Antidepressants (TCAs): Amitriptyline, Butriptyline, Clomipramine, Desipramine, Dosulepin, Doxepin, Imipramine, Lofepramine, Nortriptyline, Protriptyline, Trimipramine.
- Tetracyclic Antidepressants (TeCAs): Amoxapine, Maprotiline.
- Phenylpiperidine derivative Opioids: Meperidine/Pethidine, Tramadol, Methadone, Fentanyl, Dextropropoxyphene, Propoxyphene.
- Others: Brompheniramine, Chlorpheniramine, Cocaine, Cyclobenzaprine, Dextromethorphan (DXM), Ketamine, MDPV, Nefazodone, Phencyclidine (PCP), Pheniramine, Sibutramine, Trazodone.
- Serotonin, Norepinephrine, and/or Dopamine Releasers: 4-Methylaminorex (4-MAR), Amphetamine, Benzphetamine, Cathine, Cathinone, Diethylcathinone, Ephedrine, Levmetamfetamine, Lisdexamfetamine, MDMA ("Ecstasy"), Methamphetamine, Pemoline, Phendimetrazine, Phenethylamine (PEA), Phentermine, Propylhexedrine, Pseudoephedrine, Phenylephrine, Tyramine.
- Serotonin, Norepinephrine, and/or Dopamine Supplemental Precursors: 5-HTP, L-DOPA, L-Phenylalanine, L-Tryptophan, L-Tyrosine.
- Local and general anesthetic in surgery and dentistry in particular those containing Epinephrine. There is no universally taught or accepted practice regarding dentistry and use of MAOIs such as Phenelzine and it is, therefore, vital to inform all clinicians especially dentists of the potential effect of MAOIs and Local Anesthesia. In preparation for dental work, withdrawal from Phenelzine is specifically advised, however since this takes two weeks it is not always a desirable or practical option. Dentists using Local Anesthesia are advised to use a non-epinephrine anesthetic such as Carbocaine at a level of 3%. Specific attention should be paid to blood pressure during the procedure and the level of the anesthetic should be regularly and appropriately topped up since non-epinephrine anestetics take longer to come into effect and wear off faster. Patients taking Phenelzine are advised to notify their Psychiatrist prior to any dental treatment.
- Certain other supplements: Hypericum perforatum ("St John's Wort"), Inositol, Rhodiola rosea, S-Adenosyl-L-Methionine (SAMe), L-Theanine.
- Other Monoamine Oxidase Inhibitors.
MAOIs started off due to the serendipitous discovery that iproniazid was a weak MAO inhibitor (MAOI). Originally intended for the treatment of tuberculosis, in 1952, iproniazid antidepressant properties were discovered when researchers noted that the depressed patients given iproniazid experienced a relief of their depression. Subsequent in vitro work led to the discovery that it inhibited MAO and eventually to the monoamine theory of depression. MAOIs became widely used as antidepressants in the early 1950s. The discovery of the 2 isoenzymes of MAO has led to the development of selective MAOIs that may have a more favorable side-effect profile.
The older MAOIs' heyday was mostly between the years 1957 and 1970. The initial popularity of the 'classic' non-selective irreversible MAO inhibitors began to wane due to their serious interactions with sympathomimetic drugs and tyramine-containing foods that could lead to dangerous hypertensive emergencies. As a result, the use by medical practitioners of these older MAOIs declined. When scientists discovered that there are two different MAO enzymes (MAO-A and MAO-B), they developed selective compounds for MAO-B, (for example, selegiline, which is used for Parkinson's disease), to reduce the side-effects and serious interactions. Further improvement occurred with the development of compounds (moclobemide and toloxatone) that not only are selective but cause reversible MAO-A inhibition and a reduction in dietary and drug interactions. Moclobemide, was the first reversible inhibitor of MAO-A to enter widespread clinical practice.
List of MAO inhibiting drugs
- Nonselective MAO-A/MAO-B inhibitors
- Selective MAO-A inhibitors
- Selective MAO-B inhibitors
Drugs withdrawn from the market
- Nonselective MAO-A/MAO-B inhibitors
- Benmoxin (Nerusil, Neuralex)
- Iproclozide (Sursum)
- Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida) (discontinued worldwide except for France)
- Mebanazine (Actomol)
- Octamoxin (Ximaol, Nimaol)
- Pheniprazine (Catron)
- Phenoxypropazine (Drazine)
- Pivalylbenzhydrazine (Tersavid)
- Safrazine (Safra) (discontinued worldwide except for Japan)
- Caroxazone (Surodil, Timostenil)
- Selective MAO-A inhibitors
- Minaprine (Cantor)
- Cristancho, Mario. "Atypical Depression in the 21st Century: Diagnostic and Treatment Issues". Psychiatric Times. Retrieved 23 November 2013.
- Mayo Clinic Staff, "Depression (major depression): Treatment and drugs"
- Grady, Meghan M.; Stahl, Stephen M. (2012). "Practical guide for prescribing MAOIs: debunking myths and removing barriers". CNS Spectrums 17: 17, pp 2–10. doi:10.1017/S109285291200003X.
- McCabe-Sellers, Beverly J.; Staggs, Cathleen G.; Bogle, Margaret L. "Tyramine in foods and monoamine oxidase inhibitor drugs: A crossroad where medicine, nutrition, pharmacy, and food industry converge". Journal of Food Composition and Analysis 19 (2006) S58–S65 19: S58–S65. doi:10.1016/j.jfca.2005.12.008.
- Liebowitz MR, Hollander E, Schneier F; et al. (1990). "Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders". Acta Psychiatr Scand Suppl 360: 29–34. doi:10.1111/j.1600-0447.1990.tb05321.x. PMID 2248064.
- Buigues, J; Vallejo, J (1987). "Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks". Journal of Clinical Psychiatry 48 (2): 55–9.
- Liebowitz, MR; Schneier, FR; Campeas, R; Hollander, E; Hatterer, J; Fyer, A; et al. (1992). "Phenelzine vs atenolol in social phobia: A placebo-controlled comparison". Archives of General Psychiatry 49 (4): 290–300.
- Versiani M, Nardi AE, Mundim FD, Alves AB, Liebowitz MR, Amrein R. Pharmacotherapy of social phobia. A controlled study with moclobemide and phenelzine. BJP [Internet]. 1992 Sep 1 [cited 2013 Oct 4];161(3):353–60. Available from: http://bjp.rcpsych.org/content/161/3/353
- Heimberg, RG; Liebowitz, MR; Hope, DA; et al. "Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome". Arch Gen Psychiatry 55 (12): 1133–41. doi:10.1001/archpsyc.55.12.1133.
- Jarrett, RB; Schaffer, M; McIntire, D; Witt-Browder, A; Kraft, D; Risser, RC. "Treatment of atypical depression with cognitive therapy or phenelzine: A double-blind, placebo-controlled trial". Arch Gen Psychiatry 56 (5): 431–7. doi:10.1001/archpsyc.56.5.431.
- Liebowitz, MR; Quitkin, FM; Stewart, JW; et al. "Phenelzine v imipramine in atypical depression: A preliminary report". Arch Gen Psychiatry 41 (7): 669–77. doi:10.1001/archpsyc.1984.01790180039005.
- Walsh, B; Stewart, JW; Roose, SP; Gladis, M; Glassman, AH. "Treatment of bulimia with phenelzine: A double-blind, placebo-controlled study". Arch Gen Psychiatry 41 (11): 1105–9. doi:10.1001/archpsyc.1983.01790220095015.
- Rothschild, R; Quitkin, HM; Quitkin, FM; Stewart, JW; Ocepek-Welikson, K; McGrath, PJ; et al. "A double-blind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives". International Journal of Eating Disorders 15 (1): 1–9. doi:10.1002/1098-108X(199401)15:1<1::AID-EAT2260150102>3.0.CO;2-E.
- Walsh, BT; Stewart, JW; Roose, SP; Gladis, M; Glassman, AH. "A double-blind trial of phenelzine in bulimia". Journal of Psychiatric Research 19 (2–3): 485–9. doi:10.1016/0022-3956(85)90058-5.
- Walsh, B; Gladis, M; Roose, SP; Stewart, JW; Stetner, F; Glassman, AH (May 1988). "Phenelzine vs placebo in 50 patients with bulimia". Arch Gen Psychiatry 45 (5): 471–5. doi:10.1001/archpsyc.1988.01800290091011. PMID 3282482.
- Davidson, J; Ingram, J; Kilts, C (1987). "A pilot study of phenelzine in the treatment of post-traumatic stress disorder". The British Journal of Psychiatry 150: 252–5. doi:10.1192/bjp.150.2.252.
- Soloff, PH; Cornelius, J; George, A; Nathan, S; Perel, JM; Ulrich, RF. "Efficacy of phenelzine and haloperidol in borderline personality disorder". Arch Gen Psychiatry 50 (5): 377–85. doi:10.1001/archpsyc.1993.01820170055007.
- Mallinger, AG; Frank, E; Thase, ME; Barwell, MM; DiazGranados, N; Luckenbaugh, DA; et al. "Revisiting the Effectiveness of Standard Antidepressants in Bipolar Disorder: Are Monoamine Oxidase Inhibitors Superior?". Psychopharmacol Bull 42 (2): 64–74.
- http://www.psycom.net/hysteroid.html Dowson, JH (1987). "MAO inhibitors in mental disease: their current status. [Review]". Journal of Neural Transmission. Supplementum 23: 121–38. PMID 3295114.
- Edward J. Massaro, Handbook of Neurotoxicology
- Nowakowska E, Chodera A; Chodera (July 1997). "[Inhibitory monoamine oxidases of the new generation]". Pol. Merkur. Lekarski (in Polish) 3 (13): 1–4. PMID 9432289.
- ScienceDirect "Structural insights into the mechanism of amine oxidation by monoamine oxidases A and B" Check
value (help). Archives of Biochemistry and Biophysics 464: 269–276. doi:10.1016/j.abb.2007.05.006.
- "FDA Approves Emsam (Selegiline) as First Drug Patch for Depression." (Press release). U.S. Food and Drug Administration. 2006-02-28. Retrieved 2009-11-19.
- BLTC Research  (2006). "Rasagiline: a neuroprotective smart drug?". The Good Drug Guide. Retrieved 2007-12-02.
At dosages above around 2 mg per day, rasagiline loses its selectivity for MAO type B and also inhibits MAO type A. An MAO-B selective regimen does not cause significant tyramine potentiation, the dreaded 'cheese effect' common to users of older unselective and irreversible MAOIs who eat tyramine-rich foods. This will be taken with and without food. Thus, low-dosage rasagiline demands no special dietary restrictions.
- Mosher, Clayton James, and Scott Akins. Drugs and Drug Policy : The Control of Consciousness Alteration. Thousand Oaks, Calif.: Sage, 2007.
- Stahl, Stephen (2011). Case Studies: Stahl's Essential Psychopharmacology.
- FDA. "EMSAM Medication Guide" (PDF).
- Lavian, G.; Finberg, J. P.; Youdim, M. B. (1993-01-01). "The advent of a new generation of monoamine oxidase inhibitor antidepressants: pharmacologic studies with moclobemide and brofaromine". Clinical Neuropharmacology. 16 Suppl 2: S1–7. ISSN 0362-5664. PMID 8313392.
- Boyer, EW; Shannon, M (2005). "The serotonin syndrome" (PDF). N Engl J Med 352 (11): 1112–20. doi:10.1056/NEJMra041867. PMID 15784664.
- Pharmacology from H.P. Rang, M.M. Dale, J.M. Ritter, P.K. Moore, year 2003, chapter 38
- Guillem K, Vouillac C, Azar MR; et al. (September 2005). "Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats". J. Neurosci. 25 (38): 8593–600. doi:10.1523/JNEUROSCI.2139-05.2005. PMID 16177026.
- Villégier AS, Blanc G, Glowinski J, Tassin JP; Blanc; Glowinski; Tassin (September 2003). "Transient behavioral sensitization to nicotine becomes long-lasting with monoamine oxidases inhibitors". Pharmacol. Biochem. Behav. 76 (2): 267–74. doi:10.1016/S0091-3057(03)00223-5. PMID 14592678.
- Amsterdam, J. V.; Talhout, R.; Vleeming, W.; Opperhuizen, A. (2006). "Contribution of monoamine oxidase (MAO) inhibition to tobacco and alcohol addiction". Life Sciences 79 (21): 1969–1973. doi:10.1016/j.lfs.2006.06.010. PMID 16884739.
- Berlin, I.; m. Anthenelli, R. (2001). "Monoamine oxidases and tobacco smoking". The International Journal of Neuropsychopharmacology 4 (1): 33–42. doi:10.1017/S1461145701002188. PMID 11343627.
- Fowler, J. S.; Volkow, N. D.; Wang, G. J.; Pappas, N.; Logan, J.; Shea, C.; Alexoff, D.; MacGregor, R. R.; Schlyer, D. J.; Zezulkova, I.; Wolf, A. P. (1996). "Brain monoamine oxidase a inhibition in cigarette smokers". Proceedings of the National Academy of Sciences of the United States of America 93 (24): 14065–14069. doi:10.1073/pnas.93.24.14065. PMC 19495. PMID 8943061.
- Fowler, J. S.; Volkow, N. D.; Wang, G-J.; Pappas, N.; Logan, J.; MacGregor, R. R.; Alexoff, D.; Shea, C.; Schlyer, D. J.; Wolf, A. P.; Warner, D.; Zezulkova, I.; Cilento, R. (1996). "Inhibition of monoamine oxidase B in the brains of smokers". Nature 379 (6567): 733–736. doi:10.1038/379733a0. ISSN 0028-0836. PMID 8602220.
- van Broekhoven F, Kan CC, Zitman FG; Kan; Zitman (June 2002). "Dependence potential of antidepressants compared to benzodiazepines". Prog. Neuropsychopharmacol. Biol. Psychiatry 26 (5): 939–43. doi:10.1016/S0278-5846(02)00209-9. PMID 12369270.
- Dobson, Keith S.; et al. (2008). "Randomized Trial of Behavioral Activation, Cognitive Therapy, and Antidepressant Medication in the Prevention of Relapse and Recurrence in Major Depression". Journal of Consulting and Clinical Psychology 76 (3): 468–77. doi:10.1037/0022-006X.76.3.468. PMC 2648513. PMID 18540740.
- "Active ingredient: Amphetamine - Brands, Medical Use, Clinical Data". DrugLib.com. Retrieved 26 May 2013.
- Shulman, KI; et al. (Oct 2013). "Current place of monoamine oxidase inhibitors in the treatment of depression". CNS Drugs 27 (10): 789–97. doi:10.1007/s40263-013-0097-3. PMID 23934742.
- Livingston MG, Livingston HM; Livingston (April 1996). "Monoamine oxidase inhibitors. An update on drug interactions". Drug Saf 14 (4): 219–27. doi:10.2165/00002018-199614040-00002. PMID 8713690.
- Nair NP, Ahmed SK, Kin NM; Ahmed; Kin (November 1993). "Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide". J Psychiatry Neurosci 18 (5): 214–25. PMC 1188542. PMID 7905288.
- Baldwin D, Rudge S; Rudge (1993). "Moclobemide: a reversible inhibitor of monoamine oxidase type A". Br J Hosp Med 49 (7): 497–9. PMID 8490690.
- Lawrence KR, Adra M, Gillman PK; Adra; Gillman (June 2006). "Serotonin toxicity associated with the use of linezolid: a review of postmarketing data". Clinical Infectious Diseases 42 (11): 1578–83. doi:10.1086/503839. ISSN 1058-4838. PMID 16652315.
- "Azure B, a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase". Toxicol. Appl. Pharmacol. 258: 403–9. 2012. doi:10.1016/j.taap.2011.12.005. PMID 22197611.