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Abstract
Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction, and intoxication. Some research into those harms will be reviewed here and misgivings about the use of Pregnenolone, to treat cannabis addiction and intoxication explained. Pregnenolone considered the inactive precursor of all steroid hormones, has recently been shown to protect the brain from Cannabis intoxication. The major active ingredient of Cannabis sativa (marijuana), Δ9-tetrahydrocannabinol (THC) enhances Pregnenolone synthesis in the brain via stimulation of the type-1 cannabinoid (CB1) receptor. This steroid has been shown to inhibit the activity of the CB1 receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee et al., incorrectly suggest that blocking CB1 receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. In this hypothesis, we caution the scientific community that, other CB1 receptor blockers, such as, Rimonabant (SR141718) have been pulled off the market in Europe. In addition, CB1 receptor blockers were rejected by the FDA due to mood changes including suicide ideation. Blocking CB1 receptors would result in reduced neuronal release of Dopamine by disinhibition of GABA signaling. Long-term blockade of cannabinoid receptors could occur with raising Pregnenolone brain levels, may induce a hypodopaminergic state, and lead to aberrant substance and non-substance (behavioral) addictions.
Highlights
Pregnenolone considered the inactive precursor of all steroid hormones, has recently been shown to protect the brain from Cannabis intoxication
Longterm blockade of cannabinoid receptors could occur with raising Pregnenolone brain levels, may induce a hypodopaminergic state, and lead to aberrant substance and nonsubstance addictions
Substance Use Disorder (SUD) is a subset of Reward Deficiency Syndrome (RDS) a framework based on a known hypodopaminergic trait further impacted by environmental elements [1]
Summary
Substance Use Disorder (SUD) is a subset of Reward Deficiency Syndrome (RDS) a framework based on a known hypodopaminergic trait (genetic) further impacted by environmental elements (epigenetic) [1]. We pointed out that by doing so raising Kynurenic acid will reduce neuronal release of dopamine at mesolimbic sites [15] Along these lines, we are cognizant that potentially in the short-term the therapeutic approach of blocking the euphoric effects of cannabinoids could be useful in terms of extinction and potential amelioration of THC-induced psychosis intoxication in infants and children. Volkow’s group showed the profound effects of drugs of abuse like chronic cocaine that induces imbalance between D1 and D2 receptor signaling leading to dopaminergic deficiency [18] This D1/D2 imbalence has been underscored by the surprising finding of Willuhn et al, showing that when dopamine levels fall in the brain Ventral Medial Striatum (VMS), cocaine self-administration escalates in rats. The dopamine release effect of the sulfated Pregnenolone seems to be incongruent and unresolved relative to their current hypotheses
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