Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction.

https://link.springer.com/content/pdf/10.1007%2Fs13311-015-0377-3.pdf

Molecular Targets of Cannabidiol in Neurological Disorders

Hormesis: U-shaped dose responses and their centrality in toxicology

The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid-dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.

/pdf/the-effects-of-d9-tetrahydrocannabinol-on-the-dopamine-3t2wyltk7t.pdf

The effects of Δ9-tetrahydrocannabinol on the dopamine system.

The present article represents a comprehensive effort to assess the hypothesis that hormesis is a highly generalizable biological phenomenon independent of environmental stressor, biological endpoint, and experimental model system. The evaluative methodology and complementary approaches employed to assess this question are (1) evolutionary biology-based theoretical paradigm; (2) evaluation of > 20,000 toxicology articles using a priori entry and evaluative criteria; (3) evaluation of 17 large-scale studies each providing data on numerous agents tested in the same experimental model by the same research team; (4) the assimilation of experimental pharmacological data on 24 receptor systems in which biphasic dose responses have been established reproducibly along with hormetic mechanism elucidation; and (5) assessment of the original hormesis database with 1600 dose-response relationships demonstrating evidence consistent with the hormesis hypothesis. The complementary approaches for assessing hormesis provided strong support for its credibility as a central biological theory based on its high frequency of occurrence and quantitative features of expression within microbe, plant, and invertebrate and vertebrate animal systems. The findings suggest that hormetic effects represent evolutionary-based adaptive responses to environmentally induced disruptions in homeostasis. Such adaptive responses, which are incorporated into organismal integrative physiological systems and now clarified at the mechanistic level for more than two dozen receptor systems, provide a cogent basis for the application of hormetic mechanisms in the elucidation of fundamental evolutionary-based biological processes and in the development of novel clinical modalities.

Hormesis: a generalizable and unifying hypothesis.

In vitro effects of delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-tetrahydrocannabinol (delta 8-THC), cannabinol (CBN) and cannabidiol (CBD) have been studied on the uptake and release of 3H-labeled dopamine (DA) and norepinephrine (NE) in the synaptosomal preparation of rat brain corpus striatum and hypothalamus. The uptake of both DA and NE in these two regions was stimulated at low concentrations of delta 9-THC (1 x 10(-7) and 2 x 10(-7) M) and delta 8-THC (5 x 10(-9) and 1 x 10(-8) M), whereas at higher concentrations (1 x 10(-5) and 1 x 10(-4) M) both delta 9-THC and its delta 8-isomer inhibited the uptake of DA and NE. Similarly, the release of DA and NE from the preloaded synaptosomes of these two brain regions were inhibited at low concentrations of delta 9-THC (1 x 10(-7) M) and delta 8-THC (1 x 10(-8) M) and stimulated at high concentrations of both isomers (1 x 10(-5) and 1 x 10(-4) M). High concentrations of both CBN and CBD were needed to produce only an inhibitory effect on the uptake and the stimulation on the release of DA and NE in synaptosomes of the two brain regions. No significant effect was found at lower concentrations of CBN and CBD. These results demonstrate that 1) delta 9- and delta 8-THC, but not CBN and CBD, produce a biphasic effect on the uptake and release of DA and NE in the corpus striatum and hypothalamic regions of brain and 2) delta 8-THC is more potent than delta 9-THC on both uptake and release of DA and NE in these two brain regions.

Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes.

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Effects of cannabinoids on catecholamine uptake and release in hypothalamic and striatal synaptosomes.