The Resurgence of Hallucinogen Drugs in Clinical Research.

Since the dawn of civilization, ancient cultures have utilized hallucinogens from plants and fungi in the context of religious and healing practices. Recently, their use has expanded to other cultures. Hallucinogens are natural or synthetic substances that alter the perception of reality at nontoxic doses, producing intense psychological and physiological effects. The initial research on hallucinogens began in the 1950s. However, their non-medical use, studies without proper controls, and negative social opinion resulted in legal restrictions that limited their use for clinical and preclinical research for more than two decades. A renewed interest in studying hallucinogens as potential therapeutic agents for treating different psychiatric conditions has recently re-emerged. This review summarizes the effects of main hallucinogen drugs and their therapeutic potential. Classic hallucinogens such as LSD, dimethyltryptamine, psilocin, and mescaline have chemical structures similar to serotonin and directly activate 5-hydroxy-tryptamine (5-HT2A) receptors. Ketamine is a dissociative anesthetic with antagonist effects at the glutamatergic N-methyl-D-aspartate receptor, indirectly activating 5-HT2A receptors. Ketamine has rapid antidepressant effects and reduces suicidal ideation, but its effects are short-lasting. Other hallucinogens are under study. It is necessary to continue this research with a more rigorous methodology and include studying the long-term effects of psychedelics use.

Dark Classics in Chemical Neuroscience: Mescaline.

Archeological studies in the United States, Mexico, and Peru suggest that mescaline, as a cactus constituent, has been used for more than 6000 years. Although it is a widespread cactus alkaloid, it is present in high concentrations in few species, notably the North American peyote ( Lophophora williamsii) and the South American wachuma ( Trichocereus pachanoi, T. peruvianus, and T. bridgesii). Spanish 16th century chroniclers considered these cacti "diabolic", leading to their prohibition, but their use persisted to our days and has been spreading for the last 150 years. In the late 1800s, peyote attracted scientific attention; mescaline was isolated, and its role in the psychedelic effects of peyote tops or "mescal buttons" was demonstrated. Its structure was established by synthesis in 1929, and alternative routes were developed, providing larger amounts for pharmacological and biosynthetic research. Although its effects are attributed mainly to its action as a 5-HT2A serotonin receptor agonist, mescaline binds in a similar concentration range to 5-HT1A and α2A receptors. It is largely excreted unchanged in human urine, and its metabolic products are apparently unrelated to its psychedelic properties. Its low potency is probably responsible for its relative neglect by recreational substance users, as the successful search for structure-activity relationships in the hallucinogen field focused largely on finding more potent analogues. Renewed interest in the possible therapeutic applications of psychedelic drugs may hopefully lead to novel insights regarding the commonalities and differences between the actions of individual classic hallucinogens.

Functional selectivity of hallucinogenic phenethylamine and phenylisopropylamine derivatives at human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors.

2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT)(2A/2C) agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A(2) (PLA(2))] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA(2) and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT(2A) or 5-HT(2C) receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT(2C) receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT(2A) receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT(2C) receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT(2C) receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA(2)-specific at the 5-HT(2A) receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT(2A) receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.

[Antibacterial constituents against Helicobacter pylori of Brazilian medicinal plant, Pariparoba].

Four known compounds have been isolated from the aerial parts of the Brazilian medicinal plant Pariparoba (Pothomorphe umbellata). They were an alkaloid, a flavone, a dihydrocalcone, and a steroid. The chemical structures were established to be N-benzoylmescaline, wogonin, uvangoletin, and beta-sitosterol glucoside using spectral methods. Among these compounds, the main component N-benzoylmescaline showed significant antibacterial activity against Helicobacter pylori.

The mescaline or strychnine spikes as a tool for physiological and pharmacological studies.

The all-or-nothing spikes elicited by antidromic, afferent, or direct electrical stimulation of a cortical area treated with mescaline or strychnine were studied. These potentials are most probably originated in nonsynaptic dentritic membranes and their changes in amplitude and latency can be an index of the excitability of these structures. Several factors are considered as sources of error when measurements of such parameters are made to follow their changes in different experimental conditions. When these sources of error can be eliminated, the frequency, amplitude and latency of those spikes can be taken as an index of the variations in cortical excitability under some physiological conditions. Another use of these giant potentials can be for the study of humoral and pharmacological agents.

A depressant cortical reaction induced by afferent stimulation.

A depressant reaction of the electrocortical activity of the brain cortex is described. The changes consist in decrease in the amplitude and frequency of the basal waves of the electrocorticogram together with the appearance of slow waves similar to those of the sleep state. The results are more clear upon the dendritic action potentials induced by the topical application of strychnine or mescaline. They include a rise in the threshold to the electrical stimulation applied to elicit these potentials together with a lengthening of their latencies. The depressant effects were obtained by low threshold vagal, carotid sinus, low threshold sciatic and tactile afferent stimulation. Similar depressant effects were produced by serotonin (5-HT) topically applied. The effects of afferent stimulation were reduced in magnitude by an intracisternal injection of 5,6-dihydroxytryptamine. A serotonergic mechanism acting in a diffuse, humoral, way is postulated. The methodological importance of studying the strychnine or mescaline spikes is emphasized.

Effect of peyote on human chromosomes. Cytogenetic study of the Huichol Indians of Northern Mexico.

Fify-seven Huichol Indians with a lifelong individual history and a 1,600-year cultural tradition of ingestion of peyote, a mescaline-containing cactus possessing hallucinogenic properties, were compared with 50 Huichol Indian controls and ten laboratory controls for effects on lymphocyte chromosomes. The frequency of abnormalities in the experimental and control groups did not differ significantly. Our results indicate that multigenerational ingestion of peyote is not associated with abnormalities in lymphocyte chromosomes.

Studies on the mechanisms of learning. IV. Ontogeny of calcium channels in the rat's cortex.

The sensitivity of some electrocortical potentials of rats to topically applied tetrodotoxin (TTX), manganese, lanthanum, calcium, mescaline and strychnine was followed from the age of 6 to 20 days and compared with that of adult animals. Sensitivity to TTX was relatively greater in the younger rats. In contrast, the blocking effect of Mn2+ or La3+ was small initially but increased with age. Similarly, the ability of mescaline or strychnine to give rise to giant spikes (dendritic action potentials) increased with maturation of the brain cortex. Finally, an increase in external calcium concentration depressed cortical potentials in the younger animals and had the usual increase of the mescaline or strychnine spikes in the older rats. It is concluded that the formation of calcium channels in dendritic membranes is part of the maturation process of cortical neurons and possibly related to the learning mechanisms. The depressant action of high external calcium during the first days of life was ascribed to an unspecific reduction in membrane permeability.

On the role of catecholamines in the humoral modulation of the electrocortical activity in the cat.

By using the mescaline or the strychnine spikes as indicators of electrocortical activity it was found that they are increased in size by some catecholamines topically applied. These spikes showed late and long-lasting changes after somatic, as well as after autonomic afferent stimulation. The latter induced by cyanide, light asphyxia, intravenous injections of adrenaline or noradrenaline, and after a small dose of 6-hydroxydopamine. After a dose of this last substance, high enough to deplete the catecholamines of the brain, the late increase in amplitude of the cortical potentials observed following afferent stimulation disappeared leaving a long lasting reduction in that amplitude. The hypothesis is presented that the noradrenaline liberated by the adrenergic nerve fibers reaching the upper layers of the cortex acts on the nonsynaptic dendritic membranes modulating their activity in a humoral-like way. The pattern of this facilitating effect has a different temporal course and is longer lasting than that which is to be expectec only by the arrival of impulses at the cortex during the persistence of the neuronal activation induced by the information input to the CNS.