Δ 9‑Tetrahydrocannabinol Toxicity and Validation of Cannabidiol on Brain Dopamine Levels : An Assessment on Cannabis Duplicity
Swapnali Chetia · Gaurab Borah
Natural Products and Bioprospecting, 2020, 10, 285–296
doi : 10.1007/s13659-020-00263-z
Δ9-tetrahydrocannabinol (THC) of cannabis is the main psychoactive component which is a global significant concern to human health. Evaluation on THC reported its drastic effect on the brain dopaminergic (DAergic) system stimulating mesolimbic DA containing neurons thereby increasing the level of striatal DA. Cannabidiol (CBD), with its anxiolytic and anti-psychotic property, is potent to ameliorate the THC-induced DAergic variations. Legal authorization of cannabis use and its analogs in most countries led to a drastic dispute in the elicitation of cannabis products. With a recent increase in cannabis-induced disorder rates, the present review highlighted the detrimental effects of THC and the effects of CBD on THC induced alterations in DA synthesis and release. Alongside the reported data, uses of cannabis as a therapeutic medium in a number of health complications are also being briefly reviewed. These evaluated reports led to an anticipation of additional research contradictory to the findings of THC and CBD activity in the brain DAergic system and their medical implementations as therapeutics.
Keywords : Cannabis : Tetrahydrocannabinol, Cannabidiol, Dopamine, Medicinal uses
Cannabis, commonly called marijuana, is a psychoactive and one of the most illicit recreational drugs around the world [1, 2], extracted from Cannabis sativa. With a precise estimation, as reported in 2017, there are about 188 million cannabis users in the world, rating the world’s population at approximately 3.8% . Cannabis possesses antioxidant properties which may also contribute to other therapeutic aspects like anticonvulsant, anti-inflammatory, and neuroprotection, other than its detrimental effects . Acute and chronic use of cannabis can influence CNS and PNS through several complications which include hyperemesis syndrome, impaired coordination, and performance, anxiety, psychotic disorders, suicidal tendencies, cannabis withdrawal symptoms, neurocognitive impairment, cardiovascular, respiratory, Cerebro-peripheral vascular diseases [1, 5], bullous lung disease, pneumothorax, desquamated interstitial disease, pneumopericardium, pneumomediastinum, and brown pigmented macrophages .
Apart from the virtue of medicinal properties, recent studies on chronic cannabis inhalation reported the intimation of cerebrovascular diseases  although the underlying mechanisms have not been strongly established yet. Numerous neurological disorders have been observed in discrete studies on cannabis exposure viz. cognitive dysfunction, behavioral complications, memory/attention deficiency, structural and functional variations in the brain [8–11]. About 100 cannabinoids are being reported to date , out of which Δ9- tetrahydrocannabinol (THC) (Fig. 1) and cannabidiol (CBD) (Fig. 2) are the principal
components that are actively involved in brain DAergic alterations. THC is one of the major and principal psychoactive constituents of cannabis . In contrast, CBD is an anxiolytic and antipsychotic cannabinoid compound that may help in inhibiting the effects of THC and other negative effects effectuated due to cannabis exposure [14–16].
The psychoactive properties of THC are responsible for cannabis addictive potential and alterations in brain dopaminergic (DAergic) functions. Acute THC administration has been reported to elicit striatal dopamine (DA) release in animals  and humans [18–20].
1.1 Cannabis Addiction
Drug or cannabis addiction is a compulsive drug intake disorder, embodied due to loss of control over drug intake limitation and when prevented, emerges a negative emotional state . THC is the principal causative cannabinoid responsible for cannabis addiction due to its psychoactive properties and associated effects on brain DAergic function.
Koob and Volkow  described three stages of drug addiction that confer major alterations in neurocircuits. The three stages are—(a) the binge/intoxication stage generated by changes in basal ganglia characterized by excess impulsivity and irresistibility to drug usage despite the detrimental
effects associated with it, (b) the withdrawal/negative affect stage driven by changes in the extended amygdala involving stria terminalis that implies reward cognition due to the loss of motivations towards non-drug rewards, (c) the preoccupation/anticipation stage driven by alterations in the prefrontal cortex (PFC) involving disrupted GABAergic and glutamatergic activity (Fig. 3).
In the intoxication stage, the mesocorticolimbic DAergic reward pathway of the brain is hyperactivated followed by positive reinforcement of the rewarding effects of drugs. Impairment in incentive salience is a characteristic feature of the intoxication stage in which initial exposure to a drug intimating signaling contexts are exaggeratedly assigned with high rewarding properties. This lead to a conditioned evoke of DA release. Incentive salience dysfunction drives DA signals to perpetuate impulse of the drug upon exposure to conditioned-cues.
Following the intoxication stage, the withdrawal stage is triggered by adversary process responses following an overdosing interlude. These adversary process retaliations are marked by neurobiological within and between-system changes that direct motivation loss towards non-drug rewards and impaired emotion regulation. Within-system neuroconversions encompass dorsal striatum and the nucleus accumbens (NAc) with reduced DAergic signaling, resulting in elevation of reward thresholds for non drug promoters, promoting depression. Between-system neuroadaptations embrace neurochemical dysfunction induced stress responses such as elevated extrication of corticotrophin- releasing factor (CRF) in the amygdala inclusive of HPA-axis dysfunction. These reverberates distinguishing symptoms specifically chronic irritability, anxiety-like responses, malaise, and dysphoria.
The preoccupation stage is involved in rehabilitationinduced abusive substance ensuing abstention. In this prolonged abstinence, effectuated constrain over craving and impulsivity is a vital strategy interposed by the PFC. This stage is marked by self-regulation, decision making, inhibitory control, and functional memory influenced through aberrant signaling between PFC and brain. This in turn might suspend the activity of GABAergic and glutamatergic exploitation. Proprietarily, this renders surplus salience incrimination of drug-induced cues, reduction in responsiveness-induced non-drug signaling intensifiers, and reduces maladaptive behavior inhibition activity.
2 Cannabis and Dopamine
Vulnerability to DA-enhancing substances of abuse is analogous to impaired striatal DA transmission [22, 23]. Studies in chronic cannabis users (CD) with co-morbid psychotic symptoms unveiled a reduction in DA synthesis  and mitigate the release of stress-induced DA . This exhibits an inconsistent effect of reduced DA release in chronic cannabis users without psychotic symptoms.