However, patients (only males were included in these early studies) reported aversive and depressive signs (including dysphoria) after treatment with non-selective KOR agonists such as cyclazocine, spiradoline, and the more selective KOR agonist MR2033 (Pfeiffer et al., 1986; Chappell et al., 1993). This evidence concerns the gene OPRK1 and dysphoria.