Molecular Pathways of the Therapeutic Effects of Ayahuasca, a Botanical Psychedelic and Potential Rapid-Acting Antidepressant.

Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for ß-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca's therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca's components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.

Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia.

Increasing evidence suggests that the tetracycline antibiotic minocycline has neuroprotective effects and is a potential treatment for schizophrenia. However, the mechanisms of action of minocycline in the CNS remain elusive. The aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12months of a randomized double-blind, placebo-controlled clinical trial of minocycline add-on treatment. This study included 24 outpatients with recent-onset schizophrenia randomized for 12months of adjuvant treatment with minocycline (200mg/d) or placebo. MRI (1.5T) and [(99m)Tc]-ECD SPECT brain scans were performed at the end of the 12-month of trial. Between-condition comparisons of SPECT and MRI brain images were performed using statistical parametric mapping and analyzed by voxel-based morphometry (VBM). Minocycline adjuvant treatment significantly reduced positive and negative symptoms when compared with placebo. The VBM analysis of MRI scans showed that the patients in the placebo group had significant lower gray matter volumes in the midposterior cingulate cortex and in the precentral gyrus in comparison with the patients in the minocycline group. In addition, a decreased ECD uptake in the minocycline condition was observed in fronto-temporal areas. These results suggest that minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period.

The MAO inhibitor phenelzine can improve functional outcomes in mice with established clinical signs in experimental autoimmune encephalomyelitis (EAE).

Many symptoms in multiple sclerosis (MS) can be related to changes in the levels of key neurotransmitters. These neurotransmitters have a direct role in the maintenance of neurons and also have immunomodulatory properties. Previously we have shown that when treatment began prior to the onset of clinical signs, daily treatment with the monoamine oxidase (MAO) inhibitor phenelzine (PLZ), which also elevates CNS levels of GABA, lead to substantial behavioral improvements in the experimental autoimmune encephalomyelitis (EAE), the animal model for MS. To determine whether PLZ could have beneficial effects in an already established disease state, we conducted experiments in which PLZ treatment only began when mice with EAE exhibited the first clinical signs of the disease. Using this more clinically relevant treatment approach, we find that PLZ treatment can reduce the severity of clinical signs and improve exploratory behaviors for the duration of the experiment in mice with EAE. Treatment with PLZ did not affect the infiltration of CD4+ T-cells into the spinal cord nor did it reduce the degree of reactive gliosis as measured by Iba1 immunostaining. Beginning PLZ treatment after the start of clinical signs did however lead to significantly better 5-HT innervation density in the ventral horn of the spinal cord and also resulted in higher levels of GABA, dopamine and norepinephrine in the brain and spinal cord. These results indicate that even in an established EAE disease state, PLZ can have clinical benefits. These benefits likely derive from PLZ's ability to normalize the innervation to ventral horn motor neuron pools as well as the elevations in GABA and biogenic amines that have been shown to have anti-inflammatory properties.

The antidepressant phenelzine enhances memory in the double Y-maze and increases GABA levels in the hippocampus and frontal cortex of rats.

Subchronic treatment with a non-competitive glutamate NMDA-receptor antagonist (e.g., MK-801, phencyclidine) or social isolation (SI) from weaning (age 21 days) to adulthood (age 56 days) produces deficits similar to some positive and negative symptoms of schizophrenia. Down-regulation of GABA-ergic neurons has been demonstrated in people with schizophrenia and treatment with GABA-ergic compounds (including benzodiazepines, valproate) has shown some favorable outcomes. We hypothesized that subchronic MK-801 (0.5 mg/kg 2 times daily for 7 days), post-weaning SI or the two in combination will alter activity in a novel environment and memory in the double Y-maze (a test with a spatial discrimination and spatial alternation component) and that treatment with phenelzine (PLZ), a monoamine oxidase (MAO)-inhibiting antidepressant that also produces a rapid increase in brain levels of GABA, will improve memory. SI rats (n=18) showed increased locomotor activity when exposed to a novel environment but no deficits in the double Y-maze and the combination of SI plus subchronic MK-801 did not alter these effects. Delays did not affect performance in the spatial discrimination component of the Y-maze and decreased performance in the alternation component for saline rats but not MK-801 rats. Treatment with PLZ improved performance in both components of the Y-maze in a dose-dependent manner. Neurochemical analyses confirmed that PLZ increased GABA levels in the brain and changes in levels of dopamine, serotonin and their metabolites were consistent with inhibition of MAO. It was concluded that PLZ does not specifically augment memory in SI or subchronic MK-801-treated rats.

N-Propynyl analogs of beta-phenylethylidenehydrazines: synthesis and evaluation of effects on glycine, GABA, and monoamine oxidase.

A group of beta-phenylethylidenehydrazines possessing a variety of substituents (Me, OMe, Cl, F, and CF(3)) at the ortho-, meta-, or para-positions of the phenyl ring, in conjunction with either a N-bis-(2-propynyl) or a N-mono-(2-propynyl) moiety, were synthesized and compared to the novel neuroprotective drug beta-phenylethylidenehydrazine (PEH) with regard to their ability to inhibit the enzymes GABA-transaminase (GABA-T) and monoamine oxidase (MAO)-A and -B in vitro in brain tissue. Two of the analogs synthesized (mono- and bis-N-propynylPEH) were also studied exvivo in rats to compare their effects to those of PEH with regard to ability to inhibit GABA-T and MAO and to change brain levels of several important amino acids. Unlike PEH, none of the new drugs inhibited GABA-T in vitro at 10 or 100 microM, and all of the drugs (including PEH) were poor inhibitors (at 10 microM) of MAO-A and -B invitro. The two analogs studied exvivo inhibited GABA-T to a lesser extent than PEH, unlike PEH that did not elevate brain levels of GABA, and inhibited MAO-A and -B more potently than PEH. Interestingly, unlike PEH, the two analogs caused marked increases in brain levels of glycine; because of the current interest in drugs that increase glycine availability in the brain as potential antipsychotic drugs, these two analogs now warrant further investigation.

Design and biological evaluation of phenyl-substituted analogs of beta-phenylethylidenehydrazine.

Beta-Phenylethylidenehydrazine (PEH) has been demonstrated previously to be an inhibitor of gamma-aminobutyric acid transaminase (GABA-T) and to cause a marked increase in rat brain levels of GABA, a major neurotransmitter. A group of PEH analogs, possessing a variety of substituents (Me, OMe, Cl, F, and CF3) at the 2-, 3-, and 4-positions of the phenyl ring, were synthesized for evaluation as inhibitors of GABA-T. The details of the synthesis and chemical characterization of the analogs are described. Preliminary in vitro screening for GABA-T inhibition showed that all the analogs possessed activity against this enzyme, although substitution of CF3 at the 2- and 4-positions caused reduced activity. One of the drugs, 4-fluoro-beta-phenylethylidenehydrazine, was investigated further ex vivo, where it was shown to inhibit GABA-T, elevate brain levels of GABA, and decrease levels of glutamine, similar to the profile observed previously for PEH.