Posted: 2026-02-18

Sigma Receptors And Psychosis

This is an investigatory and speculative concept. There is no evidence base or no detailed mechanism. But it might be interesting to think about and explore.

Virtually all of our provably effective antipsychotics are ultimately dopamine antagonists. Even a lot of the non-dopaminergic concepts which are showing genuine promise (M1/M4 and TAAR1 shine brightly as candidates) are still largely explained as upstream modulators of dopamine tone.

If dopamine dysregulation was the root cause of psychosis, antipsychotics would work much better than they do. These drugs sorta-kinda work for some people, and yield massive and profound side effects for the privilege.

Sigma receptors are notorious for being "everything and nothing" sites: they are involved in a great deal of processes in the body, but there is no clear endogenous ligand for them, and knockout mice which don't have these receptors aren't obviously different. They are well understood as a kind of mitochondrial "volume control" which influences metabolic processes in cells.

Sigma receptors (type 1 and 2) are over-represented in many kinds of cancer cell.

Tumours are well known for not having very effective vasculature.

Nerve cells exposed to hypoxic conditions in vitro tend to survive longer in the presence of many sigma ligands.

What if one of the functions of sigma receptors was a last-ditch mechanism to keep nerve cells alive when under severe metabolic stress (not just hypoxia), at the cost of normal information processing?

Many sigma ligands also possess genuine psychotomimetic effects (not just psychedelic ones). The elephant in the room is dimethyltriptamine (DMT), which is well known for creating temporary psychosis (above and beyond 5ht2a agonist psychedelia) as well as increasing the resilience of nerve cells under metabolic stress. DMT itself doesn't have to be involved, but we've created a clear empirical link between sigma receptors, psychosis and cellular survival. We also see psychotomimetic effects from a range of dissociative NMDA antagonists (PCP, DXM) which also activate sigma receptors.

In bipolar disorder proper, by definition we only see psychosis during severe affective states (mania or depression). Both of these states reflect forms of metabolic stress on the brain. The psychosis generated by excessive stimulant use might too. Lithium, a well known treatment for bipolar disorder, is also known for doing the opposite and stabilising demand on mitochondria.

This model would allow us to easily infer things which are not controversial, such as: bipolar psychosis usually responds rapidly and effectively when dampening drugs are introduced, while schizophrenia (where the "last ditch survival mechanism" is firing independently of load) responds partially and unreliably to the same medications.

What's nice about this theory is that we can construct falsifiable tests of it, but this is where we've hit the limit of what I can contribute as a layperson.

🔗 Checkin

Version: 1

Written: 2026-02-18

Written on: 7.5mg olanzapine since 2025-11-11

Mental health was: extremely poor - estimate 10% brain