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Mar 26, 2004
Is It Safe to Use "Natural" Sleep Aids While Taking Antidepressants?
by Joel Lamoure, RPh, BSP, FASCP
Medscape Pharmacists, 2007

Question: I have a patient with bipolar depression who is taking several prescription medications. Is it safe for patients on antidepressants to use common nonprescription sleep aids such as melatonin and tryptophan?

Response: Sleep disorders are commonly associated with psychiatric conditions such as depression and bipolar disorder.[1,2] Consequently, it is not uncommon for these patients to seek additional drug or nondrug therapies to facilitate a normal sleep pattern. Whereas physicians commonly prescribe traditional sleep aids in such situations, patients increasingly are looking for more "natural" products. In recent years, there has been an upsurge in the use of nonprescription products such as melatonin and tryptophan.[3] Many patients view these medications as better for the body because they are "natural" substances, but potential drug interactions, side effects, and contraindications should be considered. The underlying goal of pharmaceutical care is to get the right medication to the right person at the right strength for the right condition.

Basic questions should be posed to the patient: Why are you not sleeping? What are your sleep patterns and habits? Are you slow to sleep or quick to wake?

Tryptophan has been indicated in the treatment of sleep disorders because it acts as a precursor molecule for melatonin, a neurohormone that is responsible for regulating sleep cycles.[4] It also has the advantage of not limiting cognitive performance or interfering with arousal from sleep, as some of the more traditional sleep agents do. This essential amino acid also acts as an immediate metabolic precursor of the neurotransmitter serotonin, which regulates mood and emotion.[2] The subsequent conversion of tryptophan to serotonin is what causes concern about the concomitant use of this supplement with antidepressants.

Through a variety of mechanisms, most antidepressants increase the level of neurotransmitters (e.g., serotonin, dopamine, norepinephrine) at the neuronal synapse. Therefore, if a patient is taking a selective serotonin reuptake inhibitor (SSRI) or monoamine oxidase inhibitor (MAOI) along with tryptophan, the level of serotonin in the synapse may increase significantly. This could precipitate a pharmacodynamic interaction known as serotonin syndrome, which is characterized by agitation, confusion, delirium, tachycardia, diaphoresis, fluctuations in blood pressure, and extrapyramidal side effects.[5,6] These symptoms often develop within 2 hours, but they can be resolved about 70% of the time within 24 hours simply by discontinuing the serotonergic drugs.[7] In light of the potential seriousness of serotonin syndrome, which has been documented in published case reports,[3] patients should be advised against taking tryptophan concurrently with MAOIs or SSRIs.

Clinicians should also be aware that tryptophan is found in many commonly used combination protein supplements, so they should ask patients about any dietary supplements they may be taking.[8]

Finally, patients with liver cirrhosis have an additional reason to avoid the concurrent use of tryptophan with MAOIs or SSRIs. The activity of tryptophan pyrrolase will be reduced by more than 20%, leading to higher levels of tryptophan and decreased clearance of the amino acid. These patients are at an even higher risk for the development of serotonin syndrome.[3]

Melatonin is another natural product that is popular as a sleep aid, but it has only shown benefit in patients experiencing delayed sleep phase disorder or disrupted initial sleep quality.[9,10] Melatonin is the end product in the metabolism of L-tryptophan and is converted from serotonin by the enzyme S-adenosyl-L-methionine. After it is formed, it is metabolized hepatically by 2 cytochrome P450 enzymes, CYP1A2 and 2C19.[11]

Several antidepressants, mood stabilizers, and antipsychotic drugs that are typically used for patients with bipolar depression are also metabolized by CYP1A2 and/or 2C19 and may in fact be inhibitors or inducers of these hepatic enzymes. Specifically, the largest concern lies with the concurrent use of melatonin and fluvoxamine, which is primarily metabolized by CYP1A2 with a small contribution from 2C19. Fluvoxamine is a potent inhibitor of CYP1A2 and therefore will cause an increase in endogenous blood levels of melatonin and increased daytime drowsiness.[12,13]

Other antidepressants and antipsychotics that are substrates of CYP1A2 and which may influence melatonin metabolism include amitriptyline, clomipramine, mirtazapine, carbamazepine, chlorpromazine, perphenazine, trifluoperazine, clozapine, haloperidol, and olanzapine.[14] Published case reports have also noted interactions with fluoxetine (a CYP1A2 inhibitor that can lead to psychotic symptoms), warfarin (decreased prothrombin time and increased minor bleeding), and zolpidem (increased daytime drowsiness, confusion, and nausea). Other drug classes that may interact with melatonin include antiplatelets/anticoagulants, oral hypoglycemic agents, antihypertensives, anticonvulsants, and sedatives.[8]

In addition to reviewing a patient's prescription medication profile, clinicians should consider food and environmental substances that may increase the metabolism of melatonin and lead to enhanced daytime drowsiness. Specifically, caffeine intake and cigarette smoking should be considered, as caffeine and the polycyclic aromatic hydrocarbons found in cigarette smoke significantly induce CYP1A2.[8,15]

The patient's medical history is also important. Melatonin should be avoided in patients with a history of seizures, as it lowers the seizure threshold. It should also be avoided during pregnancy because of its potential to alter pituitary-ovarian function, induce uterine contractions, or cause developmental disorders in the fetus.[8]

Finally, patients should be reminded that natural products are not always produced according to accepted manufacturing standards. For example, several brands of melatonin have been found to contain impurities.[8] In 1989, the FDA recalled products containing L-tryptophan, which were linked to 1543 cases of eosinophilia-myalgia syndrome (EMS) and 28 deaths.[8] A precursor to tryptophan known as 5-hydroxytrytamine is now widely available, and similar impurities leading to the development of EMS have been reported.[8]

In conclusion, patients taking prescription antidepressants should be advised against taking tryptophan or melatonin to improve their sleep. In getting the right drug to the right patient, clarifying the cause of the sleep disturbance will help determine which medications or therapies should be used. For example, if it is secondary to the patients psychiatric illness, it may resolve when medications used to treat that illness begin to take effect. Alternatively, clinicians could consider prescribing an antidepressant that is known to have sedative properties, such as mirtazapine. Finally, several nonpharmacologic methods may help resolve a sleep disorder: good sleep hygiene, stimulus control, relaxation strategies, or cognitive behavioral therapy.[8,16] If a sleep disorder persists, prescription sleep aids should be considered.

  1. McClung CA. Circadian genes, rhythms and the biology of mood disorders. Pharmacol Ther. 2007;114:222-232. Abstract
  2. Hallonquist JD, Goldberg MA, Brandes JS. Affective disorders and circadian rhythms. Can J Psychiatry. 1986;31:259-272. Abstract
  3. Maurizi CP. The therapeutic potential for tryptophan and melatonin: possible roles in depression, sleep, Alzheimer's disease and abnormal aging. Med Hypotheses. 1990;31:233-242. Abstract
  4. L-Tryptophan: Monograph. Altern Med Rev. 2006;11:52-56. Abstract
  5. Mitchell, PB. Drug interactions of clinical significance with selective serotonin reuptake inhibitors. Drug Saf. 1997;17:390-406. Abstract
  6. van der Mast RC, Fekkes D. Serotonin and amino acids: partners in delirium pathophysiology? Semin Clin Neuropsychiatry. 2000;5:125-131.
  7. Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006;109:325-338. Abstract
  8. Cauffield JS, Forbes HJ. Dietary supplements used in the treatment of depression, anxiety, and sleep disorders. Lippincotts Prim Care Pract. 1999;3:290-304. Abstract
  9. Werneke U, Turner T, Priebe S. Complementary medicines in psychiatry: review of effectiveness and safety. Br J Psychiatry. 2006;188:109-121. Abstract
  10. Buscemi N, Vandermeer B, Hooton N, et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med. 2005;20:1151-1158. Abstract
  11. Huuhka K, Riutta A, Haataja R, Ylitalo P, Leinonen E. The effect of CYP2C19 substrate on the metabolism of melatonin in the elderly: a randomized, double-blind, placebo-controlled study. Methods Find Exp Clin Pharmacol. 2006;28:447-450. Abstract
  12. Brosen K. Drug interactions and the cytochrome P450 system. The role of cytochrome P450 1A2. Clin Pharmacokinet. 1995;29(suppl 1):20-25. Abstract
  13. Ursing C, von Bahr C, Brismar K, Rojdmark S. Influence of cigarette smoking on melatonin levels in man: Eur J Clin Pharmacol. 2005;61:197-201. Abstract
  14. Lamoure J. M3 clinical clerk educational opportunity: psychopharmacology drug interactions. Presented at South Street Hospital, London Health Sciences Centre, London, Ontario, August 10, 2007.
  15. Ursing C, von Bahr C, Brismar K, Rojdmark S. Influence of cigarette smoking on melatonin levels in man. Eur J Clin Pharmacol. 2005;61:197-201 Abstract
  16. Vaillancourt R. Insomnia. In: Canadian Pharmacists Association. Patient Self-Care: Helping Patients Make Therapeutic Choices. 1st ed. Ottawa, Ontario: Canadian Pharmacists Association; 2002.


May 8, 2005
Sometimes I find that mirtazapine doesn't do its full zap for my sleep - like with stress around the recent move - and I have to take a low dose of zopiclone as well. It just helps my mind to... shut down and mellow out.
I used to take passiflora based natural sleep aids before I got on meds. Interestingly this article says nothing about those kinds of supplements, maybe because they are more UK based, and this article is US/Canada based. Melatonin isn't available here.

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