Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection
Exploration of Neuroprotective Therapy May 21, 2024 Peer reviewed DOI: 10.37349/ent.2024.00079 via DOAJ
Summary
Dysregulation of the folate cycle can lead to increased levels of homocysteine and S-adenosylhomocysteine, which may contribute to psychotic symptoms. The paper reviews how this cycle's perturbations are linked to hallucinogenic compounds and suggests that while folate supplementation might be beneficial, it could also be harmful depending on other biochemical factors. Additionally, electrotopological data indicates that certain methylated amines share similarities with known hallucinogens.
Study at a glance
| Design | review |
|---|---|
| Key finding | The paper highlights the connection between dysregulated folate cycle activity and psychotic symptoms, suggesting potential neuroprotective strategies. |
Abstract
Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals.