Bufotenin

5-hydroxy-N,N-dimethyltryptamine, bufotenine, 5-HO-DMT, mappine

Bufotenin is a naturally-occurring toxin found in the skin secretions of some species of toads as well as the retina and brain tissues of toads.1 In addition, bufotenin is not just in toads but also frogs, mushrooms, higher plants, and mammals. Interestingly, people with schizophrenia often have bufotenin in their brain, plasma, and urine.2–4

Although the compounds have similar names, bufotenin should not be confused with bufotenidine, another toxin.

The Chemistry of Bufotenin

Bufotenin was discovered in 1920 by Hans Handovsky at the University of Prague.5 He isolated bufotenin along with several known compounds from the skin of the toad Bufo vulgaris. Wieland et al. confirmed the chemical structure of bufotenin in 19346 and Hoshino and Shimodaria first synthesized it in 1935.7

The chemical structure of bufotenin is similar to the psychedelic mushroom (aka magic mushroom) compounds psilocin and psilocybin. Bufotenin is psilocin with the hydroxy group at the 5-position instead of the 4-position.

The Pharmacology of Bufotenin

In humans, bufotenin is a potent agonist of the serotonin 5-HT2A receptor, which accounts for its psychoactive properties.8 Historically, the receptor function of bufotenin has been more well-studied in rats and mice than in humans. In addition to 5-HT2A, researchers have found potent binding activity of bufotenin at several serotonin receptors in the rat brain cortex including 5-HT1A and 5-HT1B 9 and 5-HT3.10 Bufotenin is also a potent agonist of 5-HT1A receptors in the rat brain hippocampus.11

Studies have suggested that the presence of bufotenin in the urine may be an indicator of some psychiatric disorders, including autism and schizophrenia.4,12 A 2017 radioligand binding study found that bufotenine from the parotid gland of the toad Bufo bufo had a greater affinity for neuronal α7 nicotinic acetylcholine receptors compared with muscular cholinergic receptors.13 This is an interesting finding because the α7 receptor is believed to be involved in long term memory function in the brain.

The Applications and Potential of Bufotenin

Overall, when it comes to toad secretions, 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is receiving the majority of research attention right now. However, because of its structural and pharmacological similarity to psilocin and psilocybin, bufotenin presents some intriguing research questions. For example, unlike the relationship between the phosphorylated prodrug psilocybin and its bioactive analog psilocin, a phosphorylated version of bufotenin is not known. Does this mean there is there a yet-to-be-discovered phosphorylated prodrug version that is metabolized to bufotenin?

A 2014 study indicated that bufotenine inhibits the rabies virus infection in in vitro.14 A recent dosing study in mice conducted by the Butantan Institute in Brazil found that an effective dose of bufotenin did not significantly affect the physiology or central nervous system.15 Therefore, the authors suggest bufotenin may be a drug prototype for use in rabies treatment.

    References
  1. Axelsson S, Björklund A, Seiler N. Identification of bufotenin in toad brain by chromatography and mass spectrometry of its dans-derivative. Life Sciences. 1971;10(13, Part 1):745-749. doi:10.1016/0024-3205(71)90118-4
  2. Kärkkäinen J, Räisänen M, Naukkarinen H, Spoov J, Rimon R. Urinary excretion of free bufotenin by psychiatric patients. Biological Psychiatry. 1988;24(4):441-446. doi:10.1016/0006-3223(88)90182-5
  3. Narasimhachari N, Himwich HE. GC-MS identification of bufotenin in urine samples from patients with schizophrenia or infantile autism. Life Sciences. 1973;12(10, Part 2):475-478. doi:10.1016/0024-3205(73)90335-4
  4. Takeda N, Ikeda R, Ohba K, Kondo M. Bufotenine reconsidered as a diagnostic indicator of psychiatric disorders. Neuroreport. 1995;6(17):2378-2380. http://europepmc.org/abstract/med/8747157.
  5. Handovsky H. Ein alkaloid im gifte von Bufo vulgaris. Naunyn-Schmiedeberg’s Archives of Pharmacology. 1920;86(1):138-158. doi:10.1007/BF01864237
  6. Wieland H, Konz W, Mittasch H. Die Konstitution von Bufotenin und Bufotenidin. Über Kröten-Giftstoffe. VII. Justus Liebigs Annalen der Chemie. 1934;513(1):1-25. doi:10.1002/jlac.19345130102
  7. Hoshino T, Shimodaira K. Synthesis of bufotenin and 3-methyl-3-β-oxyethyl-indolenine. Syntheses in the indole group. XIV. Justus Liebigs Annalen der Chemie. 1935;520(1):19-30. doi:10.1002/jlac.19355200104
  8. Egan C, Grinde E, Dupre A, et al. Agonist high and low affinity state ratios predict drug intrinsic activity and a revised Ternary complex mechanism at serotonin 5-HT2A and 5-HT2C receptors. Synapse. 2000;35(2):144-150. doi:10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K
  9. Peroutka SJ, Ison PJ, Liu DU, Barrett RW. Artifactual High-Affinity and Saturable Binding of [3H]5-Hydroxytryptamine Induced by Radioligand Oxidation. Journal of Neurochemistry. 1986;47(1):38-45. doi:10.1111/j.1471-4159.1986.tb02828.x
  10. Milburn CM, Peroutka SJ. Characterization of [3H]Quipazine Binding to 5-Hydroxytryptamine3 Receptors in Rat Brain Membranes. Journal of Neurochemistry. 1989;52(6):1787-1792. doi:10.1111/j.1471-4159.1989.tb07258.x
  11. Gozlan H, El SM, Pichat L, Glowinski J, Hamon M. Identification of presynaptic serotonin autoreceptors using a new ligand: 3H-PAT. Nature. 1983;305(5930):140-142. doi:10.1038/305140a0
  12. Emanuele E, Colombo R, Martinelli V, et al. Elevated urine levels of bufotenine in patients with autistic spectrum disorders and schizophrenia. Neuroendocrinology Letters. 2010;31(1):117-121.
  13. Kryukova EV, Lebedev DS, Ivanov IA, et al. N-methyl serotonin analogues from the Bufo bufo toad venom interact efficiently with the α7 nicotinic acetylcholine receptors. Dokl Biochem Biophys. 2017;472(1):52-55. doi:10.1134/S1607672917010136
  14. Vigerelli H, Sciani JM, Jared C, et al. Bufotenine is able to block rabies virus infection in BHK-21 cells. Journal of Venomous Animals and Toxins including Tropical Diseases. 2014;20(1):45. doi:10.1186/1678-9199-20-45
  15. Vigerelli H, Sciani JM, Eula MAC, et al. Biological Effects and Biodistribution of Bufotenine on Mice. BioMed Research International. doi:10.1155/2018/1032638