[20] More serious side effects may include suicide, mania, irregular heart rate, and pathologically prolonged erections.

[5] Data from open and double-blind trials suggest that the antidepressant efficacy of trazodone is comparable to that of amitriptyline, doxepin, and mianserin.

Unfortunately, a side effect of trazodone, orthostatic hypotension, which may cause dizziness and increase the risk of falling, can have devastating consequences for elderly patients.

[31][36][37][38] Trazodone slightly improves subjective sleep quality (SMDTooltip standardized mean difference = –0.34 to –0.41) and reduces the number of nighttime awakenings (MD = –0.31, SMD = –0.51), on average.

[38][40] The benefits of trazodone for insomnia must be weighed against potential adverse effects, such as morning grogginess, daytime sleepiness, cognitive and motor impairment, and postural hypotension, among others.

[55] While trazodone is not a true member of the SSRI class of antidepressants, it does still share many properties of SSRIs, especially the possibility of discontinuation syndrome if the medication is stopped too quickly.

Compared to the reversible MAOI antidepressant drug moclobemide, more impairment of vigilance occurs with trazodone.

Concomitant administration of drugs that prolong the QT interval or that are inhibitors of CYP3A4 may increase the risk of cardiac arrhythmia.

[61][62] A relatively rare side effect associated with trazodone is priapism, likely due to its antagonism at α-adrenergic receptors.

[63] More than 200 cases have been reported, and the manufacturer estimated that the incidence of any abnormal erectile function is about one in 6,000 male patients treated with trazodone.

Early recognition of any abnormal erectile function is important, including prolonged or inappropriate erections, and should prompt discontinuation of trazodone treatment.

[64] Clinical reports have described trazodone-associated psychosexual side effects in women as well, including increased libido, priapism of the clitoris, and spontaneous orgasms.

[60][65] Rare cases of liver toxicity have been observed, possibly due to the formation of reactive metabolites.

[73] Trazodone appears to be relatively safer than TCAs, MAOIs, and a few of the other second-generation antidepressants in overdose situations, especially when it is the only agent taken.

When trazodone overdoses occur, clinicians should carefully monitor for low blood pressure, a potentially serious toxic effect.

[11] Inhibition or induction of the aforementioned enzymes by various other substances may alter the metabolism of trazodone and/or mCPP, leading to increased and/or decreased blood concentrations.

[17][13] On the other hand, cases of excessive sedation and serotonin syndrome have been reported with a combination of trazodone and fluoxetine or paroxetine.

[11] On the other hand, it may be related to the inhibition of cytochrome P450 enzymes by fluoxetine and paroxetine and consequently increased trazodone and mCPP levels.

[11][81] Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin are thought to mediate their halucinogenic effects by activating serotonin 5-HT2A receptors.

[85] Serotonin 5-HT2A receptor antagonists like ketanserin and risperidone have been found to fully block or dose-dependently reduce the subjective effects of LSD and psilocybin in clinical studies.

[85][87] Specifically, a woman on trazodone 200 mg/day who received a "moderate" dose of LSD was reported to have had reduced LSD-related hallucinogenic and physiological effects.

[85][87] Additionally, trazodone has been used and discussed extensively online as a so-called "trip killer" by recreational psychedelic users.

[12] Trazodone is a 5-HT1A receptor partial agonist similarly to buspirone and tandospirone but with comparatively greater intrinsic activity.

[120][121] Trazodone may act predominantly as a 5-HT2A receptor antagonist to mediate its therapeutic benefits against anxiety and depression.

[107][108][125] The combined actions of 5-HT2A and 5HT2C receptor antagonism with serotonin reuptake inhibition only occur at moderate to high doses of trazodone.

[12][112][113][81] However, research has not supported this hypothesis and mCPP might actually antagonize the efficacy of trazodone as well as produce additional side effects.

[11][12][14] Metabolites are conjugated to gluconic acid or glutathione and around 70 to 75% of 14C-labelled trazodone was found to be excreted in the urine within 72 hours.

[133] After an oral dose of trazodone, it was found to be excreted 20% in the urine as TPA and conjugates, 9% as the dihydrodiol metabolite, and less than 1% as unconjugated mCPP.

[143] In sharp contrast to most other antidepressants available at the time of its development, trazodone showed minimal effects on muscarinic cholinergic receptors.

Trazodone has been used to reduce anxiety and stress, to improve sleep, and to produce sedation in dogs and cats in veterinary medicine.