Furthermore, in the presence of 200 μ m guanilylimidodiphosphate, the binding of [ 3 H]domperidone to the high-affinity site (at D2High receptors) was completely abolished. All the dopamine D2High receptors had converted to their D2Low state in the presence of the guanine nucleotide.
Independently, the Cheng–Prusoff equation (Cheng and Prusoff 11 ) was also used to derive the dissociation constants (Ki values) of the compound from the concentration that inhibited 50% of the high-affinity component (IC50%) or 50% of the low-affinity component for [ 3 H]domperidone, as indicated in the results. The form of the Cheng–Prusoff equation used was Ki=IC50%/(1+C*/Kd), where C* was the final concentration of the radioligand and Kd was the dissociation constant of [ 3 H]domperidone (Kd=0.5 n m ), as determined directly by the saturation binding of [ 3 H]domperidone (that is, Scatchard plot) to the striatal homogenate. Reagents and compounds were obtained from commercial sources (Sigma-Aldrich, St. Louis, MO, USA).
Cannabidiol/[ 3 H]domperidone competition
The present data for cannabidiol may help explain some effects of cannabidiol that has actions similar to atypical antipsychotic drugs. 17, 18, 19
In contrast to the reproducible biphasic pattern of cannabidiol competition versus the binding of [ 3 H]domperidone, there was no such biphasic competition when cannabidiol competed against the binding of [ 3 H]raclopride (data not shown). In fact, cannabidiol inhibited the binding of [ 3 H]raclopride with only a single dissociation constant of 4900 n m at the dopamine D2Low receptors (with an IC50% concentration of 9000 n m ). Such a phenomenon was also previously seen with dopamine, which competed in a biphasic manner versus [ 3 H]domperidone but in a monophasic manner at D2Low receptors when using [ 3 H]raclopride. 14
Materials and Methods
The data in Figure 1 clearly show that cannabidiol inhibited the binding of [ 3 H]domperidone in two phases, corresponding to dopamine D2High and D2Low dopamine receptors. This biphasic pattern only occurs with dopamine agonists, as consistently found with hallucinogens 15 and the commonly used anti-Parkinson agonists. 16
Products of plant-derived cannabis are not well evaluated on the basis of traditional medicines, which led to an increase in uncertainty regarding its aptitude in human health . While, it is well understood from these findings that there are many synthetic forms of cannabis that are easily accessible with prescriptions, but the various cannabis plant products obtained naturally differ in the concentrations of THC and CBD which makes the effects of exposure unpredictable .
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.
Cannabis is a known illicit drug that has been used for many decades. There are above 100 cannabinoids reported to be present, out of which THC is the causative incompetent cannabinoid that causes DA insult; whereas, CBD is a positively featured cannabinoid with antipsychotic effect. Behind these findings, the presence of other cannabinoids of cannabis is not yet isolated or introduced that could explain their possible effects on brain DA manifestations. This review highlights the evidence showing that THC exerts its detrimental effects on the DA system [19, 39, 40, 48]. The various research work and studies demonstrated that acute administration of THC elevated DA release and nerve activity which are region-specific and understanding their functional significance is the basic need. The available preclinical evidence suggested that the administration of chronic THC induces long-term complications on the DA system. There is a need for further studies on the use of cannabis in association with other drugs like nicotine and alcohol when administered together. There is also a need to understand the activities of other cannabinoids of Cannabis sativa, their role in the moderation of THC-induced DAergic alterations. Human PET studies have executed reports on blunted DA synthesis in cannabis users in contrast to non-users, the precise mechanisms underlying this process is not yet clear.
Individuals may be influenced by an addiction arrest through various biological and sociological factors. This may induce vulnerability towards initial use in addition to the positive and negative reinforcement that follows. This vulnerability is further complicated with a comorbid psychiatric disorder and withdrawal of the same is followed by self-medication. The evidence highlighted in this study revealed the subversive effects of recreational cannabis rather than therapeutics. Evaluation and analysis of related findings is a measure to disseminate accurate information to the people so that individuals can resolve and make precocious choices on their use.
Cannabis in Medicinal Implementation
Recent evidence suggested the antipsychotic effect of CBD as a promising potential antipsychotic treatment. In preclinical models of schizophrenia induced by psychometric drugs, CBD is found to reduce its detrimental effects by its neuropharmacological profile. As mentioned, CBD is found to be more effective than haloperidol and analogous to clozapine in attenuating ketamine-induced hyperlocomotion . In experimental mice and rats, CBD has been reported to converse MK-801-induced sensorimotor gating deficits  and social withdrawal respectively . In 2012, Leweke et al., documented in a recent clinical trial that, CBD possesses antipsychotic properties which reduce psychotic symptoms with significantly fewer side-effects . However, the mechanisms underlying the antipsychotic effect of CBD is still unknown. Considerably, molecular evidence on schizophrenia explains disturbances in signaling pathways along with DA receptor function. These signaling pathways include the Wnt signal transduction pathway, Akt, GSK-3, and catenin. Most eminently, both typical and atypical medicaments can initiate these pathways [85,86,87].
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.
Over the last decade, in North America, there has been an increased interest in the use of medical cannabis. It is estimated that about 3.5 million people in the USA are purposely using medical cannabis legally, and is recorded for a total worth of USD $ 6.7 billion are endowed in North America on legal marijuana in 2016 . Health care of Canada approved the Canadian residents to purchase medical marijuana with prescriptions, which boosted its use from 30,537 in 2015 to near 100,000 in 2016 . Medical cannabis assists the use of its components in the varied extent of medical conditions, remarkably in the field of pain management  and multiple sclerosis . Numerous synthetic cannabinoids are useful in medicinal purposes and are already been produced viz. dronabinol and nabilone, which, in some ways, mimic the effects of THC. They are licensed by many countries including the US, Netherland, Germany, Austria for the treatment of weight loss in patients suffering from nausea, vomiting, and AIDS . In comparison to other herbal remedies, the prepared content of non-medicinal CBD, as declared, is often inaccurate [111, 112], and these products periodically may exceed the legal limit of THC . Moreover, when compared to the clinical trials , the amount of CBD in these products is found to be much lower [114, 115]. There are some products composed of cannabis that were already available in the medicinal ground before its rescheduling in 2018. Sativex, derived from cannabis, is an oral spray that contains both THC and CBD in a 1:1 ratio. It is licensed in 29 countries including Canada and the UK and is used for the treatment of multiple sclerosis spasms. However, a meta-analysis suggested that its effectiveness may be inadequate and restricted . Because of its weak and insufficient effectiveness, it is not recommended by the UK’s National Institute for Health and Care Excellence (NICE) . Additionally, a cannabis-derived oral solution named Epidiolex was licensed by the US Food and Drug Administration in 2018 for seizure medicaments in two rare and severe forms of childhood epilepsy—Lennox–Gaustat syndrome and Dravet syndrome .
Stages of drug addiction: binge/intoxication stage, withdrawal/negative affect stage and preoccupation/anticipation stage
The first study on CBD induced anxiolytic and antipsychotic effects was demonstrated in the 1970s and 1980s and was later studied in humans executing promising results . In addition to anxiety and psychotic effects, basic and clinical research on other therapeutic contributions of CBD was conducted. Moreover, synthetic analogs of CBD with efficacious potentiality have recently been developed recommended for patients with compromised health . CBD was first isolated from cannabis extracts by Adams and his co-workers in the year 1940 . In the early 1970s, several studies reported that CBD was incompetent to imitate the effects of cannabis, which led to hypothesize that; CBD would be a non-functioning cannabinoid. However, it was also speculated that CBD, with other cannabinoids, could interfere with the THC effects [73, 74]. These studies indicated the pharmacological activities of CBD exhibiting a broad spectrum of gesture .