THC

links: Drugs reference:

• A Proteomic View of Cellular and Molecular Effects of Cannabis 11-8-2021

THC ((-)-trans-Δ9-Tetrahydrocannabinol) #

• Partial agonist of CB1 (25.1nM Ki), CB2 (35.2nM Ki), as well as other Endocannabinoid receptors like:
  • ‘Orphan receptors’:
    • GPR18 (0.96nM Ki)
      • (N-Arachidonyl glycine receptor (indeed that’s a ligand, a metabolite of Anandamide) (but guess what it may not even an agonist))
      • Regulates intraocular pressure. Chinese eyes?
      • Resolvin (metabolite of DHA D2 is an agonist. Have I not heard about PUFAs and intraocular pressure?
        • GPR18 ‘resolves’ inflammatory-responses.
    • GPR55 (8.1nM Ki) (G13 G-protein coupled.)
      • Forms heteromers with CB2
    • Maybe GPR119 (endogenous ligand is Oleoylethanolamine but also binds is anandamide etc.)
      • Expressed predominantly in the pancreas and GI; activation reduces food intake and weight gain.
    • TRPV1/2, TRPA1
• When cannabis is decarboxylated, tetrahydrocannabinolic acid is converted into THC.
• When THC is taken orally, it is metabolized into 11-hydroxy-THC (then into 11-nor-9carboxy-THC), which are glucuronidated and excreted into the urine.
• Blocking both LTP and LTD makes sense why it’s used for escapism, no?
• PPAR-γ agonist.
• Δ9-Tetrahydrocannabinol Disrupts Estrogen-Signaling through Up-Regulation of Estrogen Receptor β
  • Suppresses Estradiol-induced MCF-7 cell proliferation. **Inhibits E2-liganded ERα activation. Upregulates ERβ.
• Δ9-THC-caused synaptic and memory impairments are mediated through COX-2 signaling
  • Mediated by the βγ of CB1.
  • Ablation of COX-2 also eliminates Δ9-THC-impaired hippocampal long-term synaptic plasticity, spatial, and fear memories.
    • I’ve heard of problems regarding STAT3 though.
• Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway
  • Supersensitive coupling of 5-HT2A toward inhibitory Gαi/o/etc. G proteins was observed, without alteration in canonical Gq signaling.
• Dissociation of the Pharmacological Effects of THC by mTOR Blockade
  • Acute anxiogenic and amnesic-like effects were prevented by subchronic mTOR inhibition. But hypothermia, anxiolysis, etc.
  • a clear tolerance to THC-induced anxiolysis, hypothermia, hypolocomotion, and antinociception was observed after chronic treatment, but not to its anxiogenic- and amnesic-like effects.
• Constitutional isomer (trivial knowledge tbh lol) of Progesterone: $\ce{C21H30O2}$.
• The Role of Cannabinoids in Neuroanatomic Alterations in Cannabis Users (2016)
• Cannabinoid modulation of hippocampal long-term memory is mediated by mTOR signaling
  • THC → GABAergic inhibition → NMDA signalling (!) → mTOR aberrant protein synthesis
  • THC long-term memory deficits were mediated by CB1Rs expressed on GABAergic interneurons through a glutamatergic mechanism, as both the amnesic-like effects and p70S6K phosphorylation were reduced in GABA-CB1R knockout mice and by NMDA blockade.
• Hyper-priming in cannabis users: a naturalistic study of the effects of cannabis on semantic memory function
  • Finding connections between unrelated concepts is due to ‘hyper-priming’ causing ‘fast and loose’ patterns of spreading activity.
• Bayesian causal network modeling suggests adolescent cannabis use accelerates prefrontal cortical thinning

Opioid #

• Cannabis-Induced Hypodopaminergic Anhedonia and Cognitive Decline in Humans: Embracing Putative Induction of Dopamine Homeostasis
  • it is possible to induce ‘dopamine homeostasis,’ that is, restore dopamine function with dopamine upregulation with the proposed compound and normalize behavior in chronic cannabis users with cannabis-induced hypodopaminergic anhedonia (depression) and cognitive decline
  • I believe they’re referring to ‘Pro-Dopamine Regulator’ (KB220(Z)), which is an Enkephalinase inhibitor. As well as screening for risk alleles, and balancing dysfunctional dopamine with pro-dopamine reward genes - and they actually cite DAT1, D2, D4, and COMT.
• Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism (Tanda 1997)
  • Increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2.
  • SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of THC but not those of heroin. Systemic naloxone, or naloxonazine (selective μ-1 antagonist) infusion into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopaine transmission.
• [Cannabinoid receptor and WIN 55 212‐2‐stimulated [35S]‐GTPγS binding in the brain of mu‐, delta‐ and kappa‐opioid receptor knockout mice (Latimer 1987)]: The efficacy of CB1 receptor activation by the cannabinoid agonist WIN 55 212-2 was dramatically reduced in the caudate-putamen of MOR knockout animals
• Antagonism of the Kappa Opioid Receptor Attenuates THC-Induced Place Aversions in Adult Male Sprague-Dawley Rats
• Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice
  • Acute effects and physical dependence were not modified in single deletion of μ-opioid receptor, δ-opioid receptor, or κ-opioid receptor.
  • Antinociception and hypolocomotion induced by acute THC administration remained unaffected, whereas the hypothermic effect was slightly attenuated in these double knockout mice.
  • During chronic THC treatment, knockout mice developed slower tolerance to the hypothermic effect, but the development of tolerance to antinociceptive and hypolocomotor effects was unchanged.
  • The rewarding properties of THC, measured in the conditioned place preference paradigm, were reduced in knockout mice.
  • Interestingly, the somatic manifestations of THC withdrawal were also significantly attenuated in mutant mice, suggesting that a cooperative action of MOR and DOR is required for the entire expression of THC dependence.

Neurotransmitters #

I’d say it’s contentious.

• [Marijuana and Cholinergic Dynamics (Cheney 1981)]
  • Modertate doses reduce acetylcholine release from the cat cortex, and reduces the rate of biosynthesis in the hypothalamic and striatal slices.
• Increases total brain Acetylcholine levels R R R; inhibits AChE
  • Inhibitory Effects of Cannabinoids on Acetylcholinesterase and Butyrylcholinesterase Enzyme Activities
• Pre-treatment with D1 antagonist (barely) reduced THC-induced ACh release in PFCx and hippocampus. THC has been shown to increase DA release in Nucleus Accumbens via μ-Opioid Receptor-mediated mechanism in the VTA R
• Increases Pregnenolone synthesis via stimulation of CB1 (Gi/o), with it acting as an inhibitor reducing THC’s effects. R
  • Related: Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone
• Delta(9)-tetrahydrocannabinol decreases extracellular GABA and increases extracellular glutamate and dopamine levels in the rat prefrontal cortex: an in vivo microdialysis study wtf?
  • Delta(9)-THC (1 mg/kg, i.v.) significantly increased extracellular dopamine and glutamate levels and decreased GABA levels. These effects were prevented by the cannabinoid antagonist SR141716A

• Repeated exposure to Δ9-tetrahydrocannabinol reduces prefrontal cortical dopamine metabolism in the rat
• The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study
• Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Δ9-THC exposure-impaired hippocampal synaptic plasticity
• Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity
• Deficits in striatal dopamine release in cannabis dependence
• D21 formation of course:
  • Δ-Tetrahydrocannabinol Increases Dopamine D1-D2 Receptor Heteromer and Elicits Phenotypic Reprogramming in Adult Primate Striatal Neurons BUT CBD attenuated most of this.
  • Daily THC and withdrawal increase dopamine D1-D2 receptor heteromer to mediate anhedonia and anxiogenic-like behavior through a dynorphin and kappa opioid receptor mechanism
  • Δ-Tetrahydrocannabinol Increases Dopamine D1-D2 Receptor Heteromer and Elicits Phenotypic Reprogramming in Adult Primate Striatal Neurons
• Cannabis-Induced Hypodopaminergic Anhedonia and Cognitive Decline in Humans: Embracing Putative Induction of Dopamine Homeostasis

Prenatal #

• Prenatal THC exposure raises kynurenic acid levels in the prefrontal cortex of adult rats
• [Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects (Jiang et al 2005)] wtf?
• Prenatal marijuana exposure and neonatal outcomes in Jamaica: an ethnographic study
  • The neonates of heavy-marijuana-using mothers had better scores on autonomic stability, quality of alertness, irritability, and self-regulation and were judged to be more rewarding for caregivers.

Other compounds #

If I read research I’ll make separate pages.

• HHC: more clear-headed; less anxiety and less psychoactive. More relaxing.
• Δ8 is basically just weaker.
• Δ10
• THCV (exists as Δ8/Δ9-THCV): reduces Default Mode Network activation. Blocks CB1.
  • The only ones I’ve seen also come with other compounds. Ones with CBD exist but eh.
  • https://www.3chi.com/product/thcv-isolate/
  • The phytocannabinoid, Δ9-tetrahydrocannabivarin, can act through 5-HT1A receptors to produce antipsychotic effects