Diverse avenues of research support the transmethylation theory of psychosis: implications for neuroprotection

The paper reviews how the folate cycle, which supplies methyl groups for biochemical reactions, can become dysregulated in ways linked to psychotic symptoms. Dysregulation leads to buildup of homocysteine and S-adenosylhomocysteine (SAH) and a temporary drop in S-adenosylmethionine (SAM). Alternative pathways then produce methylated compounds—N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome—that have been associated with hallucinogenic or neurotoxic effects. Electrotopological state (E-state) data show these compounds closely resemble hallucinogens, especially in the nitrogen of their tertiary amine groups. The authors suggest neuroprotective strategies to prevent transition to psychosis and caution that folate supplementation can be harmful depending on other biochemicals' status.

Study at a glance

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.