Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala.

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) catalyse the hydrolysis of the endocannabinoids anandamide and 2-arachidonoyl glycerol. We investigated their ultrastructural distribution in brain areas where the localization and effects of cannabinoid receptor activation are known. In the hippocampus, FAAH was present in somata and dendrites of principal cells, but not in interneurons. It was located mostly on the membrane surface of intracellular organelles known to store Ca(2+) (e.g. mitochondria, smooth endoplasmic reticulum), less frequently on the somatic or dendritic plasma membrane. MGL immunoreactivity was found in axon terminals of granule cells, CA3 pyramidal cells and some interneurons. In the cerebellum, Purkinje cells and their dendrites are intensively immunoreactive for FAAH, together with a sparse axon plexus at the border of the Purkinje cell/granule cell layers. Immunostaining for MGL was complementary, the axons in the molecular layer were intensively labelled leaving the Purkinje cell dendrites blank. FAAH distribution in the amygdala was similar to that of the CB(1) cannabinoid receptor: evident signal in neuronal somata and proximal dendrites in the basolateral nucleus, and hardly any labelling in the central nucleus. MGL staining was restricted to axons in the neuropil, with similar relative signal intensities seen for FAAH in different nuclei. Thus, FAAH is primarily a postsynaptic enzyme, whereas MGL is presynaptic. FAAH is associated with membranes of cytoplasmic organelles. The differential compartmentalization of the two enzymes suggests that anandamide and 2-AG signalling may subserve functional roles that are spatially segregated at least at the stage of metabolism.

The endocannabinoid system as a target for therapeutic drugs.

Cannabinoid receptors, the molecular targets of the cannabis constituent Delta9-tetrahydrocannabinol, are present throughout the body and are normally bound by a family of endogenous lipids - the endocannabinoids. Release of endocannabinoids is stimulated in a receptor-dependent manner by neurotransmitters and requires the enzymatic cleavage of phospholipid precursors present in the membranes of neurons and other cells. Once released, the endocannabinoids activate cannabinoid receptors on nearby cells and are rapidly inactivated by transport and subsequent enzymatic hydrolysis. These compounds might act near their site of synthesis to serve a variety of regulatory functions, some of which are now beginning to be understood. Recent advances in the biochemistry and pharmacology of the endocannabinoid system in relation to the opportunities that this system offers for the development of novel therapeutic agents will be discussed.

Medicinal plants for the treatment of urogenital tract pathologies according to Dioscorides' De Materia Medica.

The De Materia Medica of the Greek Dioscorides reports about 200 plants used for the treatment of pathologies of the urogenital tract during the 1st century AD. On the basis of explicit and implicit affirmations by Dioscorides, a theoretical system concerning the specific properties of these plants has been attempted. Comparison of the species reported by Dioscorides and Pliny the Elder for renal affections does not support the thesis of a close relationship between De Materia Medica and the Naturalis Historia.

Eicosanoids in synaptic transmission.

Arachidonic acid is released from membrane phospholipids in a receptor-dependent manner when neurons or glial cells are stimulated with neurotransmitters, hormones, or growth factors. The released fatty acid can be metabolized in brain tissue by three enzymatic pathways--cyclooxygenase, lipoxygenase, and cytochrome P450--giving rise to a series of biologically active products, the eicosanoids. Intracellular actions of these lipids include regulation of membrane ion channels, protein kinases, and ion pumps, thus suggesting a role as neuronal second messengers. In addition, the eicosanoids may be released into the extracellular space and interact with high affinity, G protein-coupled receptors on neurons and glial cells. Acting through these two distinct and complementary modes of action, the eicosanoids may participate in several forms of neuromodulation and synaptic plasticity.

A study in Renaissance psychotropic plant ointments.

Various historical sources from the Renaissance--including transcripts of trials for witchcraft, writings on demonology and textbooks of pharmaceutical botany--describe vegetal ointments prepared by women accused of witchcraft and endowed with marked psychoactive properties. Here, we examine the botanical composition and the possible pharmacological actions of these ointments. The results of our study suggest that recipes for narcotic and mind-altering salves were known to Renaissance folk healers, and were in part distinct from homologous preparations of educated medicine. In addition, our study reveals an unexpected connection of these vegetal psychotropes with archaic chtonic beliefs, confirming the tight association between rituals and cults entered on the Underworld and the image of the Medieval witch.

Dopamine activation of the arachidonic acid cascade as a basis for D1/D2 receptor synergism.

Understanding the actions of the neurotransmitter dopamine in the brain is important in view of its roles in neuropsychiatric illnesses. Dopamine D1 receptors, which stimulate both adenylyl cyclase and phospholipase C, and D2 receptors, which inhibit them, can nevertheless act synergistically to produce many electrophysiological and behavioral responses. Because this functional synergism can occur at the level of single neurons, another, as yet unidentified, signalling pathway activated by dopamine has been hypothesized. We report here that in Chinese hamster ovary (CHO) cells transfected with the D2 receptor complementary DNA, D2 agonists potently enhanced arachidonic acid release, provided that such release has been initiated by stimulating constitutive purinergic receptors or by increasing intracellular Ca2+. In CHO cells expressed D1 receptors, D1 agonists exert no such effect. When D1 and D2 receptors are coexpressed, however, activation of both subtypes results in a marked synergistic potentiation of arachidonic acid release. The numerous actions of arachidonic acid and its metabolites in neuronal signal transduction suggest that facilitation of its release may be implicated in dopaminergic responses, such as feedback inhibition mediated by D2 autoreceptors, and may constitute a molecular basis for D1/D2 receptor synergism.