Biological Effects and Biodistribution of Bufotenine on Mice.

Bufotenine is an alkaloid derived from serotonin, structurally similar to LSD and psilocin. This molecule is able to inhibit the rabies virus infection in in vitro and in vivo models, increasing the survival rate of infected animals. Being a very promising molecule for an incurable disease and because of the fact that there is no consensus regarding its neurological effects, this study aimed to evaluate chronic treatment of bufotenine on behavior, pathophysiology, and pharmacokinetics of mice. Animals were daily treated for 21 consecutive days with 0.63, 1.05, and 2.1 mg/animal/day bufotenine and evaluated by open field test and physiological parameters during all the experiment. After this period, organs were collected for histopathological and biodistribution analysis. Animals treated with bufotenine had mild behavioral alterations compared to the control group, being dose-response relationship. On the other hand, animals showed normal physiological functions and no histological alterations in the organs. With high doses, an inflammatory reaction was observed in the site of injection, but with no cellular damage. The alkaloid could be found in the heart and kidney with all doses and in the lungs and brain with higher doses. These results show that the effective dose, 0.63 mg/day, is safe to be administered in mice, since it did not cause significant effects on the animals' physiology and on the CNS. Higher doses were well tolerated, causing only mild behavioral effects. Thus, bufotenine might be a drug prototype for rabies treatment, an incurable disease.

Potentially hallucinogenic 5-hydroxytryptamine receptor ligands bufotenine and dimethyltryptamine in blood and tissues.

Bufotenine and N,N-dimethyltryptamine (DMT) are hallucinogenic dimethylated indolethylamines (DMIAs) formed from serotonin and tryptamine by the enzyme indolethylamine N-methyltransferase (INMT) ubiquitously present in non-neural tissues. In mammals, endogenous bufotenine and DMT have been identified only in human urine. The DMIAs bind effectively to 5HT receptors and their administration causes a variety of autonomic effects, which may reflect their actual physiological function. Endogenous levels of bufotenine and DMT in blood and a number of animal and human tissues were determined using highly sensitive and specific quantitative mass spectrometric techniques. A new finding was the detection of large amounts of bufotenine in stools, which may be an indication of its role in intestinal function. It is suggested that fecal and urinary bufotenine originate from epithelial cells of the intestine and the kidney, respectively, although the possibility of their synthesis by intestinal bacteria cannot be excluded. Only small amounts of the DMIAs were found in somatic or neural tissues and none in blood. This can be explained by rapid catabolism of the DMIAs by mitochondrial monoamino-oxidase or by the fact that the dimethylated products of serotonin and tryptamine are not formed in significant amounts in most mammalian tissues despite the widespread presence of INMT in tissues.

Bufotenine: toward an understanding of possible psychoactive mechanisms.

A review of the neuropharmacology of the alleged hallucinogen bufotenine is presented, including recent experimental results showing activity similar to LSD and other known hallucinogens (psilocin and 5-MeO-DMT) at the purported hallucinogenic serotonin (5-HT) receptors, 5-HT2A and 5-HT2C. In addition, current reports of computer modeling of the receptors and ligand binding sites give evidence of bufotenine's ability to bind and activate these receptors. While binding and activation of the purported hallucinogenic receptors are not the full extent of the hallucinogenic signature, this evidence shows support for the rationale that the reported lack of the drug's classic hallucinogenic response in human experiments is due to poor ability to cross the blood brain barrier (BBB), not lack of activation of the appropriate brain receptors. Further evidence is reviewed that in some physiological states, some drugs with characteristics similar to bufotenine which do not normally cross the BBB, cross it and enter the brain. While direct human experimental evidence of bufotenine's hallucinogenic activity seems lacking, the above combined factors are considered, and possible explanations of bufotenine's reported psychoactivity are suggested. Additionally, updated experimental models testing the possible nature of bufotenine's hallucinogenic potential are proposed.

Observations on the metabolism of the psychotomimetic indolealkylamines: implications for future clinical studies.

Although the psychotomimetic indolealkylamines N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, and 5-hydroxy-N,N-dimethyltryptamine have been unequivocally identified in human body fluids, evidence relating their concentration to the presence of psychotic illness in humans remains controversial. A series of studies on the metabolism of the compounds in the rat have highlighted the rapidity and with which these are metabolized and renally excreted. The implications of our observation for the interpretation of past clinical studies and the design of future ones is discussed.