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Spontaneous orgasm is characterized by a spontaneous onset of orgasm without any preceding sexual or nonsexual trigger. It sheds insight on the mechanisms underlying orgasms and the sexual response cycle in humans.We report a male patient of repetitive spontaneous orgasm under trazodone treatment and systematically review the literature on drug-associated spontaneous orgasm (DASO).A total of 25 patients (18 women and 7 men), including our reported case, experienced 27 DASO events. Over half of them were under 50 years of age during the DASO event. Depression was the leading morbidity for these patients, and a limited list of antidepressants and antipsychotics were involved in 92.5% of all DASO events. Although offending drugs possess variable pharmacological properties, their common effect is an augmentation of serotonin-1A (5HT1A) neurotransmission. Offending drugs seemingly increase personal susceptibility to DASO. Over half of the patients, especially men, did not concurrently experience sexual arousal or desire during the DASO event. In the remaining patients, the orgasm was accompanied by or ensued with arousal or desire. A reduction of dose or discontinuation of the offending drug usually abolished DASO.It appears that 5HT1A has a key role in generating orgasm. Orgasms may be activated through arousal-independent or arousal-dependent pathways, and both orgasms and sexual arousal are bidirectionally activated. This double-bidirectional model of sexual response cycle may promote the success of sexual procreation and recreation, and further research on this pathway could offer an innovative method to manage anorgasmia in the future.