Journal of Addictive Behaviors,Therapy & RehabilitationISSN: 2324-9005

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Research Article, J Addict Behav Ther Rehabil Vol: 5 Issue: 3

Cannabis (Marijuana):Psychoactive Properties, Addiction, Therapeutic Uses, and Toxicity

Sumanasekera WK* and Spio K
Sullivan University College of Pharmacy, USA
Corresponding author : Sumanasekera WK, Ph.D
Sullivan University College of Pharmacy, 2100 Gardiner lane, Louisville KY 40205, USA
Tel: 502-413-8954
E-mail: [email protected]
Received: June 15, 2016 Accepted: October 19, 2016 Published: October 26, 2016
Citation: Sumanasekera WK, Spio K (2016) Cannabis (Marijuana): Psychoactive Properties, Addiction, Therapeutic Uses, and Toxicity. J Addict Behav Ther Rehabil 5:3. doi: 10.4172/2324-9005.1000156

Abstract

Cannabis (Marijuana):Psychoactive Properties, Addiction, Therapeutic Uses, and Toxicity

Background and Objectives: To analyze the existing literature on cannabis (marijuana) under several sub topics; history of use, addiction, mechanism of action, therapeutic uses, and adverse effects. Methods: A comprehensive literature search was conducted. Data sources include original research articles, systematic reviews and meta- analysis, and web-based references such as Drug strategy monographs and Merck Index. Data bases such as PubMed and Cinhal was used. References were from 1979 -2016.

Hypothesis: Based on the available literature it can be hypothesized that despite the addictive properties and adverse effects, marijuana has a therapeutic potential and should be used with caution. Results: The available literature on cannabis smoke was discussed under five major categories, which are history of use, addiction, mechanism of action, therapeutic uses, and adverse effects.

Discussion and Conclusions: Marijuana (preparations of the hemp plant, cannabis sativa), is usually consumed as a smoke. It is an addictive compound that has been consumed for medical ailments for generations. The mechanism of action of cannabis was not known until the recent discovery of the endocannabinoid system. Endocannabinoids are released from the post-synaptic neurons and act on the pre-synaptic neurons. ?-9 tetrahydrocannabinol (THC), the psychoactive component present in Cannabis behaves similar to endocannabinoids. In addition to psychoactive modulations, cannabis consumption leads to cognitive impairments. Despite its’ medicinal and recreational value, due to its’ addictive properties cannabis consumption has been banned by several countries. In US, recreational and therapeutic use of cannabis is recently allowed in some states.

Scientific Significance: Despite the psych activity associated with cannabis consumption, it can be used therapeutically for many diseases including epilepsy and to alleviate chronic neuropathic pain associated with many sicknesses. Cannabis also possesses anti-cancer properties. However, strict laws should be enforced to avoid its’ abuse while allowing its’ medicinal use.

Keywords: Addiction; Anti-cancer; Therapeutics; Toxicity; Psychoactive; Inhibitory neurotransmitters

Keywords

Addiction; Anti-cancer; Therapeutics; Toxicity; Psychoactive; Inhibitory neurotransmitters

Introduction

Cannabis (marijuana) is a derivative from the hemp plant and a very addictive constituent. Cannabis leaves can be combusted and consumed as smoke. Cannabis consumption leads to psychoactive behaviors that can lead to addiction. It is the most commonly used psychoactive substance which is under international control [1]. In 1964 Δ-9 tetrahydrocannabinol (THC) was identified to be the psychoactive constituent of marijuana [2]. Chronic use of smoked Marijuana can lead to symptoms of obstructive lung disease [3].
Marijuana is still illegal in many countries. Cannabis causes mind-altering effects and it is derived from the plant Cannabis sativa [4]. Beside marijuana, cannabis is also known as ganja, grass, hashish, Indian hemp pot, reefer and weed among many others. THC is the mind-altering component present in marijuana [2]. The cannabinoids are compounds structurally similar to THC [5]. Its preparations are used as psychotic drug and in many instances it is consumed for its mental and physical effects. In other words, it is used recreationally or as medicinal drug.
Though marijuana’s therapeutic potential was obvious as seen by the effects it caused on patients, many countries, including the United States hesitated to accept its’ therapeutic benefits for a long period. In 2004 UN estimated that about 4% of the world’s population (approximately 162 million people) used cannabis annually and about 0.6% (22.5 million) on a daily basis. The possession, preparation, sale, distribution and use of cannabis became illegal in most parts of the world in the early 20th century. Based on the UN’s report, cannabis is the most used illegal drug in the world [1].
Marijuana was categorized under schedule 1 drug, which is one of the most hazardous drugs, by the Federal Drug Enforcement Administration (DEA) [6]. However, recently medical cannabis has been approved by many US states due to the obvious benefits seen in patients. Europe has taken the lead in Legalization of medical marijuana and many states of US are following the same path. The abuse potential and the toxicity of cannabis lead to the slow legalization process of medical marijuana. The objective of this paper is to review the available literature on the addiction, mechanism of action, therapeutic use and toxicity of cannabis with the goal of broadening the understanding of medical cannabis.

Methods

A comprehensive literature search was conducted on the history of cannabis use in the US, Its properties including psychoactive characteristics, mechanism of action, addiction, therapeutic use, and the unwanted side effects and toxicities. Data sources include original research articles, systematic reviews and meta- analysis, and online references such as Drug strategy monographs and Merck Index. The available literature from 1979-2016 on cannabis smoke was discussed under five major categories.

Results and Discussion

History of cannabis use in the US
In 1850, Marijuana was added to US Pharmacopeia and was used widely for medical ailments [6]. However, from 1906 onwards cannabis was classified as a toxic substance, which leads to prevention of its use in 1920s. In the US, cannabis was regulated drug in many states, including 35 states that adopted the Uniform State Narcotic Drug Act [7]. Marihuana Tax Act of 1937 was the first national regulation [8] and this act enforced a tax of $1 per ounce of marijuana for medicinal use and $100 per ounce for nonmedical use. During that time physicians were mandated to pay a special levy for prescribing marijuana [9].
In 1942, marijuana was detached from the U.S. Pharmacopoeia due to its toxicity related concerns [7]. In 1951, based on the Boggs act, cannabis was included with the narcotic drugs and its use was banned in US for all commitments except for research until recently. In 1970, marijuana was classified as a schedule I drug, which are usually highly toxic drugs that lack any medicinal value in the United States. Some other schedule I drugs include heroin, and LSD. However, in US Cannabis was given to patients on a case-by-case basis under the Compassionate Use Investigational New Drug program established in 1978 [10]. In 1976, the first case of legal marijuana use was recognized by the US federal government. However, it took two decades (till 1996) to legalize the medical marijuana use and California was the first state to legalize marijuana for medical use [6].
As of July 2014, 23 states and the District of Columbia legally allow cannabis for personal medical use. Rules surrounding the use of medical cannabis (medical marijuana) vary by state. However, even in these states consuming marijuana for non- medical purpose continues to be a felony under Federal law in United States [1] since it is a Schedule 1 drug under the Controlled Substances Act [5].
Medical and recreational cannabis is becoming more prevalent in many states in the United States-a movement driven by the legalization of herbal cannabis in some states. Many proponents for the use of cannabis foresee a day when cannabis comes under the same restrictions as tobacco, while those against its legalization continue to tout cannabis as a “gateway” drug that leads to the inevitable use of “harder” substances like methamphetamine and cocaine.
Addiction
Addiction usually starts with what is named marijuana use disorder. Recent data indicates that 30% of cannabis users may have marijuana use disorder [11]. These individual expresses withdrawal symptoms in absence of the drug. At this stage the brain might have adapted to large amount of drug by decreasing production of and sensitivity to its own endocannabinoid neurotransmitters [12]. This disorder becomes addiction when the individual cannot stop using marijuana even though it interferes with many aspects of that individual’s life.
Among individuals who have ever used cannabis, the proportion who goes on to develop dependence is about 9% [13]. All things being equal, one might say that the rate of dependence is lower than other drugs of abuse and addiction like cocaine, heroin and some prescribed drugs. However, it is also fair to say that the high prevalence of cannabis use across the population makes it more significant. In 2014, marijuana use rose from 4.1 percent to 9.5 percent of the U.S. adult population [14].
Several factors including its’ calming effect / attenuation of aggression [15], euphoric feeling [16], and pain relief ability [17,18,19] might have led to its’ heavy consumption leading to the addiction. Regardless of knowing the negative consequences of marijuana and other drugs of abuse, people who are addicted constantly make the decision to use the drug. Neuronal processes underlying the drug use is one of the under investigated areas of research. Bedi et al. has recently conducted a behavioral study on cannabis use. Participants were given a choice to take the offer to purchase cannabis or decline the offer, and their brains were analyzed via functional magnetic resonance imaging (fMRI). It has been concluded that several area of the brain including posterior parietal regions and dorsal striatum are involved in the decision to smoke cannabis [20].
Marijuana use is prevalent in psychiatric patients [21,22]; a known risk factor for schizophrenia [23,24], and it is abused in patients with bipolar disorder [21,25,26]. However, according to some cohort studies, these patients have started the cannabis use prior to the onset of bipolar disorder, suggesting cannabis might play a role in causing bipolar disorder [22,27,28]. There is also evidence that cannabis use is linked with higher suicide risk and severe mood symptoms in patients with bipolar disorder [22,24,29-31]. However, a recent study suggests the ability of cannabis to lower the clinical outcomes of the bipolar spectrum disorder as measured by the remission rate [32]. The remission rate of the bipolar spectrum disorder was lowest in the concurrent cigarette smoke and cannabis users [32].
Withdrawal from cannabis may lead to symptoms like irritability and sleeping complications, decreased appetite, cravings, and various forms of physical discomfort [33]. Marijuana addiction seems to be very similar to other substance abuse disorders and most users experience withdrawal symptoms upon cessation [34].
Mechanism of action
Understanding the mechanism of action of cannabis is crucial as it helps to understand the toxicities associated with cannabis. Cannabinoids, which are C21 compounds, originate from three sources: (1) phytocannabinoids are plant derived compounds; (2) endocannabinoids are neurotransmitters formed in the brain and CNS, and (3) synthetic cannabinoids are man-made structural analogous to phytocannabinoids or endocannabinoids [5]. Mechanism of action of all three types of cannabis is similar. Numerous chemicals and cannabinoids, which include THC, cannabidiol (CBD), are present in the cannabis plant [2,35]. Other components present in the plant [36] are illustrated in Tables 1 and 2. While Table 1 illustrates psychoactive components present in cannabis, Table 2 shows non psycho active components. While THC is the primary psychoactive compound, a non-psychoactive CBD is the second cannabinoid [37]. THC was isolated in 1964, however its’ mechanism of action and endocannabinoid system of the body was not investigated till 1990s [38].
Table 1: Structures and characteristics of psychoactive cannabinoids. This table is adopted from a figure from “Montana Biotech, Cannabinoid Facts: THC, CBD, CBN, CBC, THCV, CBG and Other Unique Phyto Cannabinoids”.
Table 2: Structures and characteristics of non-psychoactive cannabinoids. This table is adopted from a figure from “Montana Biotech, Cannabinoid Facts: THC, CBD, CBN, CBC, THCV, CBG and Other Unique Phyto Cannabinoids”.
The mechanism of action of Cannabis is depicted in the Figure 1, which is based on the information derived from Yamamoto and Takada [39]. Endocannabinoids are produced by the post synaptic neurons due to post-synaptic depolarization and these released endocannabinoids act on the pre-synaptic neurons. This phenomenon is called retrograde signaling. Released endocannabinoids such as 2 arachidonoyl glycerol (2-AG) and anandamide exert its’ effects via binding to cannabinoid receptors in pre-synaptic neurons and cause suppression of both excitatory and inhibitory neurotransmitter release from pre-synaptic neurons [40]. The cannabinoid receptor is a G protein coupled receptor and Cannabinoid receptor mediated signaling involves the second messenger, cAMP production followed by calcium influx in the pre synaptic neurons of CNS (Figure 1) leading to the modulation of excitatory / inhibitory neurotransmitter release [39].
Figure 1: Ligands, receptors, neurotransmitters, second messengers, and channels involved in cannabis induced signaling.
Cannabinoid receptors are present in many cell types of the CNS and many peripheral tissues and organs of humans. Those receptors can be occupied by both endocannabinoids produced by the body as well as exogenous cannabinoids such as THC from the cannabis plant (Marijuana). The cannabinoid receptors are called CB1 and CB2 receptors and cannabinoid receptors and endocannabinoids produced by the body that bind to these receptors constitute the endocannabinoid system [41]. It should be noted that the known mechanism of action of cannabinoids is mostly centered on THC and other cannabinoids that binds to known cannabinoid receptors.
THC, the active component of cannabis, behaves similar to the endogenous cannabinoids [17]. THC binds to the cannabinoid CB1 receptors on pre-synaptic nerve terminals in the CNS leading to attenuation of excitatory and inhibitory neurotransmitter release resulting in the inhibition of adenylate cyclase enzyme and several channels (Figure 1). THC binding to CB1 receptors also activates MAP kinase pathway. All these signaling effects lead to the ecstatic feelings associated with cannabis use [42] as well as its’ therapeutic potential [40].
Marijuana also causes anticholinergic effects, which is known to be accountable for the cognitive deficits due to cannabis consumption. Many hormone levels including growth hormone are affected by marijuana use. Activation of the CB receptors may cause several effects including euphoria, anxiety, muscle relaxation, hunger, and pain reduction [39].
Therapeutic use
Since the discovery of endocannabinoid system, there has been intense study on what the beneficial uses of cannabis are. Studies on these cannabis-based medications have led to the approval of the medications such as Dronabinol (synthetic THC), Nabilone (a synthetic derivative of THC), Nabiximols (Combination of cannabidiol and THC), and cannabis extract in several countries around the world [43]. Medical cannabis users have reported that they prefer the tablets and capsules over mouth-spray or vaporizer as the delivery mode [44]. The reason behind this could be the prolonged half-life of oral cannabis compared to other forms resulting in longer psychoactive effects. In addition, oral cannabis gets metabolized in the liver forming 11- hydroxyl- THC, which is more psychoactive than Δ9-THC [18].
Neuropathic pain and chronic non-cancer pain
It is effective in treating pain caused by neuropathy and has been used to treat fibromyalgia and rheumatoid arthritis. According to reviews and Meta analyses by Sanchez et al. [45] and Andrea et al. [46] on cannabis use, it has been concluded that medical cannabis was effective in reducing neuropathic pain [19,47], and chronic non cancer pain [47]. The study by Carter et al., 2011 advocates for prescribing cannabis in place of opioids for neuropathic pain because it reduces the morbidity and mortality rates associated with prescribing pain medications [17]. However, it should be noted that another study in 2015 reported limited evidence that medical cannabis is effective for neuropathic pain when combined with analgesics [48].
Although cannabis can be used therapeutically to relieve neuropathic pain, due to its’ addiction and adverse effects manifested via central nervous system, some studies suggest targeting peripheral cannabinoid system as opposed to cannabis consumption orally or as a smoke [49]. The usage of cannabis to treat the pain associated with chronic diseases has increased recently in US as several states are able to access it via legalization of marijuana use [49].
HIV and AIDS
Some studies have shown that medical cannabis can help manage the symptoms of HIV/AIDS [50]. Others have also shown that medical cannabis help improve appetite, muscle pain level, nausea, anxiety, depression, skin tingling, combating weight loss, and muscle breakdowns [50,51]. A study in 2012 discovered that marijuana-like compounds can block the spread of HIV virus during the infection’s late stages [52]. It is also reported that marijuana users experience significant muscle mass loss [53] and consume large amount of food [51]. A clinical trial was done to assess the impact of smoked marijuana on neuropathic pain in HIV using double-blind, placebo-controlled, crossover trial of analgesia. The results suggest that cannabinoid therapy may be an effective option for pain relief in patients with medically intractable pain due to HIV-associated Distal Sensory Predominant Polyneuropathy (DSPN) [54].
Cancer
Medical marijuana is effective in attenuating cancer growth and metastasis in various cancer types. Activation of CB1 receptor s by cannabinoids leads to attenuation of high-affinity nerve growth factor (Trk), prolactin (PRL) receptors, and the breast cancer gene BRCA1 via cAMP-PKA / MAPK / Raf-ERK signaling pathways [55]. THC also declined the levels of cyclin dependent kinase 2 (cdk2), which controls the entrance of cells to G1 phase of the cell cycle, leading to cell cycle arrest and apoptosis [56].
According to few reports, cannabis possesses anti-carcinogenic potential. In a study where experimental mice were inserted with ErbB2 (tyrosine kinase receptor)-driven metastatic breast cancer cells, THC treatment reported to reduce tumor growth, metastasis, cell proliferation, and angiogenesis [56]. Based on a report by Yamamoto and Takada, cannabinoid induced cAMP-PKA / Raf-ERK signaling resulted in inhibition of prostate cancer cell proliferation and induced cell cycle arrest and cancer cell apoptosis [39]. In addition, medical cannabis can be used in the treatment of chemotherapy induced nausea and vomiting [57]. However, limited studies exist comparing its antiemetic effects with other prescription antiemetic drugs. Oncology patients can be benefited by medical cannabis since it serves as an appetite enhancer. However, the results from current trials need to be further verified due to limited evidence [58]. Cannabis can also be used to relieve pain associated with cancer [18,19].
Treatment resistant epilepsy
Cannabis induced attenuation of seizures were evident from animal studies, as mice who lack CB1 receptor were presented more severe seizures compared to the wild type control mice [40]. The anti-convulsive ability of CBD and its’ derivatives were first reported in 1975 using mice models [59]. Based on another report that utilized experimental rats as the model, marijuana and its constituent’s exhibited anti-seizure effects and reduced seizure-related death [60]. However, few animal studies show pro-convulsive activity of cannabis [43] possibly via CB2 receptor mediated signaling [61].
According to limited human studies, cannabis seems to be a hopeful treatment [62]. Both THC and CBD possess anti-convulsive properties [63]. The therapeutic potential of Marijuana in treating treatment resistant epilepsy (RE) was evident by few studies [64,65]. Usual treatment options for epilepsy were barbiturates, benzodiazepines, and other potent anti-seizure drugs. However, these drugs are less effective or not effective and not only hinder patients from their normal activities but also can cause epilepsy-related death [40]. Despite the accessibility of many anti-seizure drugs, 30% of epileptic patients still have seizure due to the development of resistance to those drugs [66]. Therefore, in some states of the US Marijuana is considered and used as potential alternative therapy for TRE [67].
Based on the studies mentioned above [64,65], patients suffering from grand mal seizures reported that they can prevent their seizures completely by inhaling marijuana. People suffered from partial seizures have reported that marijuana also controls their symptoms and keep them alert [60]. Marijuana has been reported to be safe and effective in treatment-resistant epilepsies (TRE), including Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS) in children [64,65]. However, Marijuana use is illegal in some countries as well as in some states of the United States. Therefore, some parents are sometimes struggling to access cannabis to treat their children, who suffers from tragic epilepsy syndromes [68].
Recently, cannabis gained more publicity as a potential unconventional therapy for TRE, which affects about 30% of epilepsy cases. The exact mechanism of Cannabis induced mitigation of epilepsy is yet to be revealed. Cannabidiol (CBD), the major non-psycho active component present in marijuana may play a role in attenuating seizures [67].
While both CBD and the entire-plant cannabis contribute to attenuate seizures, due to non-psychoactive characteristic of CBD it can serve as a better therapeutic option for seizures [40]. Now high CBD / Low THC cannabis products are available and currently use in TRE including childhood epilepsy [69]. Therapeutic potential of cannabis as an anticonvulsant drug has been not studied well. However, patients suffering from epilepsy are constantly noticing the efficacy of cannabis in attenuating their symptoms. Although many studies support the anti-convulsive properties of Cannabis, patient responsiveness to marijuana may vary and in some patients Marijuana may aggravate the symptoms [70].
Multiple sclerosis (MS) and Amyotrophic lateral sclerosis (ALS)
Cannabis can be used to treat multiple sclerosis [43]. Nabiximols, a combination spray composed of cannabidiol and THC, is currently in use for muscle relaxation / to increase spasticity in multiple sclerosis patients. Patients consume oral cannabis to alleviate the pain associated with multiple sclerosis. However, the effectiveness of smoked cannabis is questionable [71]. Pre-clinical evidence suggests that cannabis can be used as disease modifying agent as well as to manage symptoms of ALS, a disease characterized by the death of the motor neurons [72].
Other disorders
Marijuana can also be utilized as a therapeutic option for many other diseases including Gastro intestinal disorders such as nausea, vomiting, inflammatory bowel syndrome (IBS) and Crohn’s disease [73]. Recently, Cannabis gained attention as a treatment option for neuropsychiatric disorders including anxiety disorders and obsessive compulsive disorder [74]. In addition, Cannabis possesses anti-oxidant properties and cause anti-inflammatory effects [72]. Non psychoactive CBD shows positive therapeutic value in ischemic stroke and other chronic diseases, including Parkinson’s disease [75]. Many other uses of cannabis are yet to be revealed.
Adverse effects of cannabis
Acute cannabis toxicity results in difficulty of coordination, decreased muscle strength, decreased hand steadiness, postural hypotension, lethargy, decreased concentration, attenuated reaction time, slurred speech, and conjunctival inflammation. Although acute toxicity is benign in the average adult, children are more susceptible to cannabis toxicity. A 250-1000 mg ingestion of hashish (up to 20% THC concentration) can result in apnea, bradycardia, cyanosis, or hypertonia in children [76]. The clearance pathways for cannabis were feces (about 65%) and urine (about 20%) and cannabis and hydroxylated and carboxylated metabolites of cannabis were eliminated from the body within five days [77]. Cannabis metabolites present in urine were glucuronic acid conjugates, which include THCCOOH, Δ9-THC, and 11-OH-THC. While THCCOOH was the primary metabolite in urine, 11-OH-THC was the major metabolite in feces [78].
Based on Merck Index, the LD50 (the dose that causes the death of 50% of animals) of THC is 42 mg/kg for rats who inhaled cannabis. There was no experimental indication to conclude a lethal dose of cannabis in humans. Extrapolation data from the animal studies proposes that the ratio between amounts of cannabis needed to produce a fatal overdose to the amounts of cannabis needed to saturate cannabinoid receptors and cause intoxication was estimated to be 40,000:1 [79].
If higher concentrations of cannabis are consumed, unwanted toxicity may occur regardless of its high margin of safety. According to Schaffer Library of Drug Policy, some of the cannabis-induced toxic reactions include tachycardia, increased tremor, CNS and respiratory depression, which can be life threatening with severe overdose [80]. However, the risk of fatal overdose is rare because people tend to stop consuming cannabis after they reach mind altering effects. People can unintentionally get exposed to cannabis smoke via second hand smoke [81].
While CBD in cannabis shows psycho protection, THC in cannabis leads to unwanted health risks such as triggering psychotic disorders, including schizophrenia possibly via affecting many mechanisms including dopaminergic signaling in the brain [82-86]. Anomalies in the cannabinoid system have been reported in the brains of schizophrenic patients [82]. Other health effects of long term or heavy cannabis use include memory impairment [87], depri’ved educational consequences, cognitive deficiency with low IQ, and changed brain development [84]. Compared to non- use controls and short term users, Long-term Marijuana users show attenuated memory and attention, as demonstrated by tests and tasks designed to access memory and attention [88]. In addition to impaired motor functions, cannabis use cause difficulty to control emotions and diminished abilities of several functions including decision making and problem solving [89].
Cognition related adverse effects are strongly correlated with the initial cannabis use as a child or in teen years when the brain development takes place [84], and frequent cannabis users may develop tolerance, which leads to diminished cognitive deficiency [34]. Although cannabis use is associated with cognitive deficiency in general population, in schizophrenic population the association between cannabis use and cognitive function is contradictory. In patients with schizophrenia compared to non-cannabis user patients, early psychotic patients who use cannabis showed increased cognitive functions as measured by memory- based tests and executive functions [90].
A brain MRI study, which investigated the correlation between cannabis use and the brain white matter integrity, has revealed that the cannabis use has altered the normal age related brain development [91]. According to another brain MRI study, compared to non -users, cannabis users who exposed to THC shows 11% reduction in hippocampal volume [92], which can be overcome by CBD or long-term abstinence. According to a Voxel-based morphometry study to assess the association between cannabis use and brain morphology changes, heavy cannabis users showed decreased gray matter volume in amygdala and the hippocampus [93]. According to Cousijn et al. Heavy cannabis use was also associated with changes in white matter volume of several areas of the brain [93]. However, Tzilos et al.’s brain MRI study, which utilized 22 long-term cannabis users, contradicts with this finding. Tzilos et al. reported that there is no association between brain white matter, gray matter, or hippocampal volume with long-term cannabis use [94]. The inconsistency could be due to many reasons including the differences in imaging methodology. Further studies in this area will be needed to resolve the discrepancy among these studies.
In addition, compared to age, gender, and IQ matched control group, the brain of the cannabis users demonstrated higher connectivity between different areas of the brain that involved in coordinating behavioral control. This is a compensatory mechanism of the brain, which occurred to meet the needs of cognitive control demands in Marijuana uses [95].

Conclusions

Marijuana (psycho active preparations of the hemp plant, cannabis sativa), which usually consumed as a smoke, is an addictive compound that has been consumed for medical ailments for generations. However, due to its psychoactive properties, cannabis addiction became inevitable. In addition to the addictive properties, cannabis cause adverse effects such as cognitive impairment, psychosis, and abnormal brain development. Marijuana can be used to treat vast array of disorders including treatment resistant epilepsy. Cannabis causes its’ effects via cannabinoid receptor mediated retrograde signaling.
In conclusion, regardless of the toxicity and psychoactive behaviors associated with cannabis consumption, therapeutic value of cannabis can’t be ignored. Recent changes in cannabis regulation laws allowed its’ medicinal and recreational use in some states. However, due to its’ psychoactive characteristic, people may tend to abuse cannabis. Therefore strict rules must be enforced to avoid cannabis abuse, while allowing its’ medicinal use. Cannabis can be used to treat vast array of illnesses. However, the safety, tolerability, and efficacy of cannabis –based therapy needs to be evaluated. Currently pharmaceutical quality herbal cannabis production and evaluating their efficacy and safety is underway in Europe as well as in the United States.

Acknowledgments

We would like to acknowledge Dr. William Nethery for editing the manuscript. We thank Drs. Tanya Nguyen and Nu Nguyen for their help with the literature search.

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