It really was safer in the 1960’s…no, not that (although that was safer, too) …I am referring to the THC:CDB ratios in marijuana grown then vs now.
American College of Neuropsychopharmacology (ACNP) 56th Annual Meeting: Poster Session II, December 5, 2017
T234. Repeated Delta-9-Tetrahydrocannabinol (THC) of Marijuana Upregulates DCC mRNA Expression in Prefrontal Cortex, but THC Combined With Cannabidiol (CBD) Does Not: Relevance to Psychiatric Symptoms Associated With Long Term Marijuana Use?
Bertha Madras*, Jack Bergman, Stephen Kohut, Susan George, Yasmin Hurd, Zhicheng Lin
Harvard Medical School, Belmont, Massachusetts, United States
Background: Regular heavy marijuana use in susceptible populations is associated with heightened risks for marijuana (cannabis) use disorder, memory impairment, and less frequently, psychiatric disorders, including schizophrenia, bipolar disorder, depression, social anxiety, and exacerbation of psychiatric symptoms. Of the 100 or more cannabinoids in the marijuana plant, THC is the most abundant cannabinoid followed by cannabidiol (CBD). Selective breeding has greatly increased the concentration of THC and reduced CBD levels in current marijuana products. THC is psychoactive, addictive, psychotomimetic and anxiogenic, whereas CBD does not engender these pharmacological effects and reportedly has anti-psychotic, anxiolytic, and anti-seizure therapeutic potential. With increasing evidence for a causal relationship between long-term potent marijuana use and psychiatric symptoms, we focused on an axonal guidance molecule, DCC, that conceivably mediates some of the adverse actions of marijuana based on research showing that: (a) heavy marijuana users exhibit reduced dopamine release, self-report blunted reward (less “high”), heightened negative responses (anxiety, restlessness) following a dopaminergic challenge, (b) aberrant prefrontal cortical dopamine signaling is implicated in psychosis; (c) the netrin-1 receptor DCC drives prefrontal cortex maturation by guiding dopamine circuit formation; (d) decreased DCC expression in mice increases dopamine innervation and improves specific behaviors, whereas exaggerated DCC expression is associated with major depression disorders in humans and behavioral anomalies in rodents; (f) GWAS association studies implicate the dcc gene in schizophrenia. We previously reported that dcc was upregulated in rats treated repeatedly with THC. Our present goals were to determine whether THC administered repeatedly to adult monkeys altered dcc and dopamine receptor mRNA expression in brain regions and whether CBD modulated the effects of THC.
Methods: Adult rhesus monkeys (Macaca mulatta) were treated for 24 days with escalating doses of THC, or THC combined with CBD, or vehicle control (n=3/group). THC was administered during 24 total study days in a range of doses 0.1-3.2 mg/kg, i.m.) and brains were harvested on day 25. THC + CBD were administered for 24 total study days for THC (doses ranging from 0.1-3.2 mg/kg. i/m/) and CBD (days 6-24; doses ranging from 1-3 mg/kg i.m.), with brain harvest on day 25. Gene expression levels were measured following mRNA isolation from cerebellum, frontal cortex, hippocampus, and striatum, and cDNA synthesized. Expression of the selected genes were measured using real-time PCR using species-specific, intron-spanning when possible primers and probes. Data were analyzed and normalized to beta actin (ACTB) as a housekeeping gene. The average fold change values with standard error were analyzed for statistical significance, using a two-tailed, paired t-test in Excel.
Results: In nonhuman primates treated daily with THC for 24 days, dcc and the D1 dopamine receptor gene were upregulated in prefrontal cortex. CBD, if administered together with THC to nonhuman primates for 19 days, prevented THC up-regulation of dcc and D1 dopamine receptor genes in prefrontal cortex of nonhuman primates.
Conclusions: These exciting discoveries reveal that THC increased mRNA expression of the dcc gene, which encodes DCC, a receptor implicated in guiding formation of dopamine circuitry in prefrontal cortex. Conceivably THC modulates dopamine circuitry and function in the prefrontal cortex via DCC, with relevance to psychiatric and other adverse symptoms associated with chronic, frequent marijuana use. Cannabidiol effectively attenuated dcc up-regulation by THC, indicating that CBD can modulate THC-induced molecular adaptations. Although the mechanisms underlying THC and CBD effects on dcc remain unknown, we postulate that repeated exposure to marijuana containing a high THC:CBD ratio upregulates DCC in human prefrontal cortex, conceivably contributing to the emergence of adverse effects associated with heavy use marijuana. Others have reported overexpression of dcc in major depressive disorder in humans and behavioral anomalies in rodents. Current strains of marijuana have been bred to produce high THC:CBD ratios. Our results are relevant to candidate cannabinoid therapeutics and to regulatory oversight of the ratio of THC:CBD in strains of marketed marijuana.
Keywords: Marijuana, D1 Dopamine Receptors, Psychosis, Major Depression Disorder, THC