[8] It has been implicated in several phenomena, including cardiovascular function, schizophrenia, clinical depression, the effects of cocaine abuse, bipolar disorder, and cancer.

In 1976 Martin reported that the effects of N-allylnormetazocine (SKF-10,047) could not be due to activity at the μ and κ receptors (named from the first letter of their selective ligands morphine and ketazocine, respectively) and a new type of opioid receptor was proposed; σ (from the first letter of SKF-10,047).

It was found to have affinity for the (+)-stereoisomers of several benzomorphans (e.g., (+)-pentazocine and (+)-cyclazocine), as well as various structurally and pharmacologically distinct psychoactive chemicals such as haloperidol (which permanently blocks this receptor[14]) and cocaine, and neuroactive steroids like progesterone.

[17] It shows no homology to other mammalian proteins but strikingly shares 30% sequence identity and 69% similarity with the ERG2 gene product of yeast, which is a C8-C7 sterol isomerase in the ergosterol biosynthetic pathway.

[20] The reasons for these effects are not well understood, even though σ1 receptors have been linked circumstantially to a wide variety of signal transduction pathways.

[25] Also, σ1 receptors have been shown to appear in galactoceramide enriched domains at the endoplasmic reticulum of mature oligodendrocytes.

[29] σ1R is targeted by the nsp6 protein of SARS-CoV-2[30][27] to inhibit autophagosome formation [27] as a process competing with the coronavirus for cellular endomembranes that the virus needs for its own replication.

[33] σ1 receptor knockout mice were created in 2003 to study the effects of endogenous DMT.