Serotonin regulates a wide variety of brain functions and behaviours.

Serotonin (5-HT) was first identified in the 1940s and was initially thought to have its primary effect on vascular tone. Now serotonin is recognized as having an important role in several central nervous system processes and peripheral physiology, particularly in the gastrointestinal tract. The vast majority of serotonin (90%) is synthesized in the periphery, but brain serotonin levels are the main factor in development of serotonin toxicity.

The main sites of serotonin production in the brain are the midline raphe nuclei, found in the brainstem from the midbrain to the medulla. In presynaptic neurons, the amino acid tryptophan is decarboxylated and hydroxylated to produce serotonin. Serotonin is released into the intrasynaptic space after axonal stimulation, and receptors on the presynaptic neuron play a role in regulating release. Following reuptake into the presynaptic neuron, intrasynaptic serotonin is metabolized by the enzyme monoamine oxidase.

There are 7 serotonin receptor families (5-HT1 to 5-HT7), which are further subdivided into groups based on different activities in neural and peripheral organ systems.

Main Action Related to Seratonin

• 5-HT1A Neuronal inhibition, regulation of sleep, feeding, thermoregulation, hyperactivity associated with anxiety, hypoactivity associated with depression
• 5-HT1D Locomotion, muscle tone
• 5-HT2A Neuronal excitation, learning, peripheral vasoconstriction, platelet aggregation
• 5-HT2B                 Stomach contraction
• 5-HT3                 Nausea and vomiting, anxiety
• 5-HT4                 Gastrointestinal motility
• 5-HT7 Stimulates the production of the intracellular signaling molecule cAMP

As a consequence of the greater use of agents affecting the serotonergic system, a syndrome of serotonin hyperstimulation has been recognized more frequently. The serotonin syndrome is characterized by a constellation of symptoms that include mental status changes, agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhoea, lack of coordination, and fever. Deaths have been reported. [Source: Br J Gen Pract. 1999 Nov; 49(448): 871–874].

Despite the common use of medications with direct or indirect serotonergic effects, many physicians are not aware of the presentation and management of serotonin excess. This is particularly true of less severe presentations of serotonin syndrome, which still contribute to patient morbidity.

Cochrane Database of Systematic Reviews, MEDLINE, and Google were searched from January 1990 to December 2006 for articles on serotonin syndrome or serotonin toxicity. Although there are research papers related to diagnosis, there are few high-quality data on prospective treatment. No guidelines or consensus statements have been published for either diagnosis or management. Recommendations were drawn from the literature, but there is minimal high-level evidence, especially in the realm of treatment.

Various medications are associated with serotonin syndrome.

• Citalopram (Celexa)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Paroxetine (Paxil, Pexeva)
• Sertraline (Zoloft)
• Vilazodone (Viibryd)
• Fluvoxamine (Luvox)
• Venlafaxine (Effexor)
• Clomipramine (Anafranil)
• Imipramine (Tofranil)
• Vortioxetine (Trintellix, Brintellix)
• Trazadone

[Linezolid (Zyvox) is an antibiotic commonly used to treat bacterial infections that are resistant to other antibiotics (such as streptococci, VRE and MRSA). Linezolid can also slightly block the breakdown of serotonin (by blocking MAO). There are several case reports of serotonin syndrome caused by Linezolid, especially when taken with other drugs that alter serotonin such as SSRIs or other MAOIs].

[Metoclopramide (Reglan) is commonly used for stomach issues such as heartburn, nausea, vomiting, and indigestion. Two cases have been reported of patients with serotonin syndrome caused by taking a combination of metoclopramide and antidepressants].

Medications that affect any of the steps in serotonin metabolism or regulation can provoke toxicity. Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are among the most commonly implicated drugs. Drug interactions can cause severe toxicity and can involve common over-the-counter medications. Drugs with long half-lives can interact several weeks after discontinuation; fluoxetine interactions have been reported up to 5 weeks after discontinuation. Even single doses of SSRIs have been implicated in serotonin syndrome. It is relevant to note that serotonin syndrome is not considered to be an idiosyncratic drug reaction but is a predictable response to elevated levels of serotonin.

There are no published clinical trials on the treatment of serotonin syndrome. Most recommendations are based on case studies or epidemiological data. The most important component to treating serotonin syndrome is to discontinue use of whatever substance caused the episode

Most evidence suggests that supplementing with Vitamin D or Fish Oil (Omega-3s) can be beneficial for depression without affecting serotonin levels. It has been alternatively suggested that omega-3 fatty acids and Vitamin D may help depression by increase serotonin production and action, but there is no evidence that this could trigger serotonin syndrome.

In very severe cases of serotonin syndrome, Cyproheptadine, may be administered. Cyproheptadine is traditionally used as an antihistamine but also blocks serotonin receptors [REF], [REF]

 

As a Supplement

5-HT(P) is POSSIBLY SAFE when taking by mouth appropriately. 5-HT(P) has been used safely in doses up to 400 mg daily for up to one year. However, some people who have taken it have developed a condition called eosinophilia-myalgia syndrome (EMS), a serious condition involving extreme muscle tenderness (myalgia) and blood abnormalities (eosinophilia). Some people think EMS might be caused by an accidental ingredient or contaminant in some 5-HT(P) products. However, there is not enough scientific evidence to know if EMS is caused by 5-HT(P), a contaminant, or some other factor. Until more is known, 5-HT(P) should be used cautiously. Other potential side effects of 5-HT(P) include heartburn, stomach pain, nausea, vomiting, diarrhea, drowsiness, sexual problems, and muscle problems. 5-HT(P) is POSSIBLY UNSAFE when taken by mouth in large doses. Doses from 6-10 grams daily have been linked to severe stomach problems and muscle spasms.