The sigma-1 receptor is an unusual protein that sits mainly inside cells. A 2007 study placed it on the endoplasmic reticulum, where it touches the mitochondria and acts as a calcium-sensitive “chaperone” linked to cell survival under stress (Hayashi and Su, 2007). It was once mistaken for an opioid receptor and in 2009 had no known natural partner (Fontanilla et al., 2009).
That 2009 Science paper found that DMT binds sigma-1 and makes normal mice more active but not mice lacking the receptor, and proposed DMT as an endogenous sigma-1 agonist (Fontanilla et al., 2009). Later lab work reported DMT protecting human cells from very low oxygen through sigma-1 (Szabo et al., 2016).
The catch is concentration. A 2018 review notes that DMT needs far higher levels to act at sigma-1 than at 5-HT2A (Barker, 2018), and a 2009 study found its potency at 5-HT2A about 100-fold better than at sigma-1 (Keiser et al., 2009). No human study has shown sigma-1 playing a part in the DMT experience.
Sources
- Fontanilla et al., 2009, Science: DMT and sigma-1
- Hayashi and Su, 2007, Cell: sigma-1 at the ER–mitochondria contact
- Keiser et al., 2009, Nature: predicting drug targets
- Barker, 2018, Frontiers in Neuroscience
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