Serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) signaling is essential for the actions of classical psychedelic drugs. In this study, we examined whether sequence variations in the 5-HT2AR gene affect the signaling of four commonly used psychedelic drugs. We examined the in vitro pharmacology of seven non-synonymous single-nucleotide polymorphisms (SNPs), which give rise to Ser12Asn, Thr25Asn, Asp48Asn, Ile197Val4.47, Ala230Thr, Ala447Val, and His452Tyr variant 5-HT2A serotonin receptors. We found that these non-synonymous SNPs exert statistically significant, although modest, effects on the efficacy and potency of four therapeutically relevant psychedelics. Significantly, the in vitro pharmacological effects of the SNP drug actions at 5-HT2AR are drug specific.