Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions.

BACKGROUND: Mescaline (3,4,5-trimethoxyphenethylamine), mainly found in the Peyote cactus (Lophophora williamsii), is one of the oldest known hallucinogenic agents that influence human and animal behavior, but its psychoactive mechanisms remain poorly understood. OBJECTIVES: This article aims to fully review pharmacokinetics and pharmacodynamics of mescaline, focusing on the in vivo and in vitro metabolic profile of the drug and its implications for the variability of response. METHODS: Mescaline pharmacokinetic and pharmacodynamic aspects were searched in books and in PubMed (U.S. National Library of Medicine) without a limiting period. Biological effects of other compounds found in peyote were also reviewed. RESULTS: Although its illicit administration is less common, in comparison with cocaine and Cannabis, it has been extensively described in adolescents and young adults, and licit consumption often occurs in religious and therapeutic rituals practiced by the Native American Church. Its pharmacodynamic mechanisms of action are primarily attributed to the interaction with the serotonergic 5-HT2A-C receptors, and therefore clinical effects are similar to those elicited by other psychoactive substances, such as lysergic acid diethylamide (LSD) and psilocybin, which include euphoria, hallucinations, depersonalization and psychoses. Moreover, as a phenethylamine derivative, signs and symptoms are consistent with a sympathomimetic effect. Mescaline is mainly metabolized into trimethoxyphenylacetic acid by oxidative deamination but several minor metabolites with possible clinical and forensic repercussions have also been reported. CONCLUSION: Most reports concerning mescaline were presented in a complete absence of exposure confirmation, since toxicological analysis is not widely available. Addiction and dependence are practically absent and it is clear that most intoxications appear to be mild and are unlikely to produce lifethreatening symptoms, which favors the contemporary interest in the therapeutic potential of the drugs of the class.

The phenomenology of the psychotic break and Huxley's trip: substance use and the onset of psychosis.

BACKGROUND: While considerable research attention has been devoted to the causal relationship between substance use and psychosis, the phenomenology of the association between the two has largely been ignored. This is a significant shortcoming, because it blinds researchers to the possibility that there may be elements of the subjective experience of substance use and psychosis that contribute to their apparent relationship in empirical studies. SAMPLING AND METHODS: The current paper examines the phenomenology of the onset of psychosis and the phenomenology of substance intoxication through consideration of two texts: Sass's account of the phenomenology of psychosis onset and Huxley's account of the experience of hallucinogenic intoxication. Sass's account of psychosis onset includes four components: Unreality, Fragmentation, Mere Being, and Apophany. RESULTS: The analysis reveals significant parallels - and also some differences - between this account and the phenomenology of substance intoxication. CONCLUSIONS: We discuss the implications of this for the causal relationship between psychosis and substance use and suggest several ways of understanding the overlapping phenomenologies. This includes the suggestion of a shared factor, perhaps best described as psychotic-like experience, which seems to involve a breakdown of the sign-referent relationship and relationship with the common-sense, practical world. However, in the onset of psychosis, this breakdown is primarily experienced as a sense of alienation from self and world, whereas in the hallucinogenic state a sense of mystical union and revelation seems predominant. Further research may extend this analysis by looking at experiences with other drugs, particularly cannabis, and by examining the phenomenology of psychotic disorder beyond the first episode.

Mescaline effects on rat behavior and its time profile in serum and brain tissue after a single subcutaneous dose.

RATIONALE: Mescaline is a nonselective serotonin receptor agonist. It has relatively delayed onset of action and prolonged duration. Mescaline attenuates various behavioral parameters in rats; however, no information is available about its pharmacokinetics in rats and its relation to the behavioral changes produced by the drug. OBJECTIVES: The present study evaluates the spontaneous locomotor activity and sensorimotor gating in relation to mescaline concentrations in the serum and the brain of rats MATERIALS AND METHODS: Behavioral changes induced by mescaline [10, 20, and 100 mg/kg subcutaneously (s.c.)] were evaluated in an open-field test and testing of the prepulse inhibition of acoustic startle reaction (PPI) 15 and 60 min after drug administration. The time disposition of mescaline 20 mg/kg s.c. in rat serum and brain homogenates was analyzed by gas chromatography-mass spectrometry. RESULTS: Mescaline produced significant inhibitory effects on locomotion in low doses and a biphasic effect with the highest dose. In the PPI test, only when tested 60 min after drug administration, all doses of mescaline disrupted PPI. Besides the experimental protocol, we have observed that approximately 50% of animals receiving 100 mg/kg died within 12 h post-injection. The serum levels of mescaline rapidly increased within 30 min and subsequently quickly decreased; however, the brain concentrations reached a maximum 1 h after administration and remained high for an additional 60 min. CONCLUSIONS: Mescaline had a delayed onset of the main behavioral changes in rats compared to other hallucinogens. Behavioral changes correlated with the pharmacokinetics of the drug.

DPP IV inhibitor blocks mescaline-induced scratching and amphetamine-induced hyperactivity in mice.

Dipeptidyl peptidase IV (DPP IV) is a ubiquitous membrane-bound enzyme that cleaves the two N-terminal amino acids from peptides with a proline or alanine residue in the second position from the amino end. Potential substrates for DPP IV include several neuropeptides, suggesting a role for DPP IV in neurological processes. We have developed a potent DPP IV inhibitor (IC50 = 30 nM), 1-(2-amino-3-methyl-butyryl)-azetidine-2-carbonitrile (AMAC), which has shown efficacy in two established models of psychosis: mescaline-induced scratching and amphetamine-induced hyperactivity. In the mescaline-induced scratching model, AMAC treatment before mescaline administration reduced the number of scratching paroxysms by 68% (P < 0.01). The compound showed a dose-dependent effect, inhibiting significantly at 6, 20 and 60 mg/kg (37%, 39% and 68%, respectively). In the amphetamine-induced hyperactivity model, 50 and 60 mg/kg AMAC, given before injection of amphetamine, significantly reduced hyper-locomotion by 65% and 76%, respectively. Additionally, AMAC showed no significant activity in binding assays for 20 receptors thought to be involved in the pathology of schizophrenia, including dopamine, serotonin and glutamate. A structurally similar analog, 1-(2-dimethylamino-3-methyl-butyryl)-azetidine-2-carbonitrile (DAMAC), that does not inhibit DPP IV, was inactive in both models. Taken together, these data suggest that the antipsychotic effects of AMAC are the result of DPP IV inhibition.

Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research.

The psychological, neuropsychological, and neurometabolic effects of the hallucinogenic agent mescaline were investigated in 12 normal men who were volunteers. Mescaline produced an acute psychotic state 3 1/2-4 hr after drug intake, as measured by the Brief Psychiatric Rating Scale (BPRS) and Paranoid Depression Scale (PDS). The Assessment of Altered States of Consciousness (APZ) questionnaire revealed specific effects of mescaline in the visual system. Neuropsychological effects were studied with a face/nonface decision task with known right-hemisphere advantage, in which mescaline induced a decrease of functioning of the right hemisphere. In functional brain imaging using single photon emission computed tomography (SPECT), mescaline produced a "hyperfrontal" pattern with an emphasis on the right hemisphere, which was correlated with mescaline-induced psychotic psychopathology. Our findings question the validity of the concept of hypofrontality as an explanation for schizophrenic symptomatology. The study of psychoactive substances under controlled laboratory conditions has the methodological advantage of intraindividual control, and hence, minimal variability of data.

Mescaline-induced motor impairment in rats, assessed by two different methods.

Motor impairment, especially ataxia, is often mentioned as a 'side effect' of doses of psychoactive drugs which depress animal behaviour; it is difficult to determine it accurately from visual observation, but relatively few attempts have been made to measure it objectively and quantitatively. Mescaline, in moderate to large doses, can induce biphasic--depressant followed by stimulant--effects on learnt and other performance of laboratory rodents. Motor impairment, using three doses, was accordingly measured during the depressant phase by two methods. An 'ataxia' test, involving analyses of footprints, showed few irregularities of gait splay due to mescaline, but the drug markedly reduced the length of steps ('stride') in a dose-related manner. In a 'tilt plane' test for general motor control, the animals' ability to cling to a tilted plane decreased with 25 mg/kg mescaline, at 30 and 40 minutes after administration. Deficits of this kind can be relevant to interpreting drug actions on forms of behaviour which involve movements for responding, and they also have interesting potential in their own right.

Teratogenic effects of mescaline, epinephrine, and norepinephrine in the hamster.

Mescaline was administered orally at doses of 16 and 32 mg/kg on the seventh through tenth days of gestation to pregnant cream-strain hamsters. This treatment resulted in a dose-dependent effect on reproductive success and skeletal ossification. The effect of mescaline on reproductive success included an increased number of resorptions resulting in a decreased litter size. The 32 mg/kg dose of mescaline caused 48.8% resorptions, while 16 mg/kg and control animals had 12.0% and 6.4% resorptions, respectively. Litter size was decreased from 12.0 pups in controls to 10.3 (16 mg/kg) and 6.5 (32 mg/kg) pups per litter in treated groups. No gross abnormalities were observed at necropsy; there was, however, a dose-dependent increased delay in the ossification of the skull, sternum, and metatarsals. Both epinephrine and norepinephrine caused a decrease in reproductive success when administered at 500 micrograms/kg. Epinephrine appeared to cause a trend toward preimplantation wastage as indicated by an increased corpora lutea to implantation site ratio (from 1.3-1.9). Norepinephrine, however, caused an increased number of resorptions (29.1% in controls). Both norepinephrine and epinephrine produced similar delays in ossification.

Congenital malformations induced by mescaline, lysergic acid diethylamide, and bromolysergic acid in the hamster.

Malformations of the brain, spinal cord, liver, and other viscera; body edema; and localized hemorrhages were found in fetal hamsters from mothers injected subcutaneously with a single dose of mescaline, lysergic acid diethylamide, or 2-bromo-D lysergic acid diethylamide on the 8th day of pregnancy. In addition, all three drugs produced an increase in the percentages of small fetuses per litter, of resorptions, and of fetal mortality.