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The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

Biotech R & D Institute, University of the West Indies, Mona 99999, Jamaica
Vilotos Pharmaceuticals Inc., Baltimore, MD 21202, USA
Flavocure Biotech Inc., Baltimore, MD 21202, USA
Department of Medicine, University of Maryland Medical School, Baltimore, MD 21202, USA
Brigham and Women’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(17), 9472;
Original submission received: 22 July 2021 / Revised: 23 August 2021 / Accepted: 26 August 2021 / Published: 31 August 2021
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)


The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems. In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development. The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases. This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.

1. Introduction

1.1. History

The Endocannabinoid System (ECS) is a complex molecular/biological system discovered in 1988 by scientists Allyn Howlett and W.A. Devane [1,2]. The word “Endocannabinoid” was first coined after the discovery of membrane receptors for Δ9-tetrahydrocannabinol (Δ9-THC or simply “THC”) in 1988 [3]. The ECS plays critical roles in multiple physiological processes such as homeostasis, anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development [4,5,6].
In recent years, there has been increasing interest in the role of the ECS in health and disease processes, and its components have been implicated as an emerging target of pharmacotherapy for a wide range of diseases including, but not limited to, general pain, headache, migraine, glaucoma, mood and anxiety disorders, obesity/metabolic syndrome, osteoporosis, neuromotor, neuropsychological and neurodegenerative diseases, respiratory diseases such as asthma, cardiovascular diseases such as stroke, atherosclerosis, myocardial infarction, metabolic disorders, arrhythmias, and hypertension [7,8,9].
Due to the involvement of the ECS in multiple pathophysiological processes, it offers promising opportunities for the development of novel cannabinoids-based therapeutic drugs that may be designed to target different components and/or cell-signalling pathways of the ECS, which may ultimately be of therapeutic benefit.
Cannabimimetic drugs such as small-molecule cannabinoid receptor agonists and antagonists may be designed to target the ECS and its enzymes and either enhance the bioactivity or activation of endocannabinoids or inhibit their inactivation [3,10]. On the same tangent, blockade of cannabinoid receptor-type 1 (CB1R) has been shown to reduce body weight, activation of extracerebral cannabinoid receptors has been shown to alleviate pain, and inhibition of endocannabinoid degradation has been implicated in the modulation of pain and anxiety [11].

1.2. Components of the ECS

The ECS has increasingly become a favourable target for the treatment of various diseases as many of its components are distributed widely throughout the body and take part in cell-signalling pathways involved in the pathophysiology of many types of diseases.
The components (proteins) of the ECS include receptors, their ligands, and enzymes responsible for their biosynthesis and degradation/deactivation and are widely distributed throughout mammalian tissues and cells [12]. Components of the ECS include: (1) the three main receptor classes that cannabinoids interact with (i) G-Coupled Protein Receptors (GPCRs) (e.g., CB1R and Cannabinoid-receptor type 1 (CB2R)) and which share 44% overall homology [13], (ii) Ligand-sensitive ion channels (e.g., Transient Receptor Potential Vanilloid 1—TRPV1). TRPV1 is also activated by chemical agents, physical stimuli, capsaicin, and ions, and (iii) Nuclear receptors (e.g., PPARs) [14,15]; (2) the endogenous ligands anandamide or N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG); and (3) the endocannabinoid metabolic enzymes responsible for endocannabinoid synthesis and degradation such as diacylglycerol lipase isozymes α and β, fatty acid amide hydrolase, monoacylglycerol lipase, and N-acylphosphatidylethanolamine-selective phospholipase D [3,16]. Refer to Table 1 for components of the ECS.

2. The ECS as a Therapeutic Target

In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. It’s important physiological and pathophysiological roles offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that, genetically or pharmacologically, modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS—beneficial in a number of diseases.

2.1. Mood and Anxiety Disorders

Anxiety is the body’s natural survival response to harm or dangerous situations, and is characterized by increased responsiveness, defensiveness, and vigilance. Neuropsychiatric/anxiety-related disorders include Panic Disorder (PD), Social Anxiety Disorder (SAD), Generalized Anxiety Disorder (GAD), Post Traumatic Stress Disorder (PTSD), and Obsessive-Compulsive Disorder (OCD) [31]). Globally, these anxiety-related disorders are the most prevalent of any mental disorder. As a result, they are of great social and economic burden. Currently available anxiolytic and anti-depressant agents have limited response rates, limited tolerability, and unfavourable side-effect profiles, thus, cannabinoids may be promising novel alternative therapeutic agents to traditional anxiolytics and anti-depressants.
Activation of the cannabinoid 1 receptor (CB1R) mediates natural rewards (such as social interaction, sexual intercourse, and delicious food) and drug rewards (desirable effects) [32]. As such, the CB1R may be a promising, novel drug target for the treatment of mood and anxiety disorders. It is via this receptor that Δ9-THC produces the desirable effects on an individual’s mental health, however fleeting. The ECS also potentially modulates synaptic transmission of neurotransmitters, such as mesocorticolimbic dopamine, acetycholine, glutamate, opiate peptides, and GABA, which play significant roles in the control of our emotions and behaviours [33]. The CB1R is densely populated in the brain, in areas responsible for the mediation of reward, such as the amygdala, hippocampus, and orbitofrontal cortex [34,35] and, thus, the ECS also plays a role in “emotional metastasis” [32,33]. On the same tangent, single nucleotide polymorphisms (a type of mutation) in the cannabinoid receptor 1 (CNR1) gene that that encodes the CB1R has been linked to depression [36,37], nicotine dependence [38], alcohol dependence [39], and possibly other substance-use disorders that are the result of mood and anxiety disorders.
Cannabidiol (CBD) was first observed to be anxiolytic when it was shown to reverse Δ9-THC’s psychotic and anxiogenic effects, via a CB1R-independent mechanism [40]. There is strong preclinical evidence that supports CBD’s great potential as an anxiolytic, panicolytic, and anti-compulsive agent. Pre-clinical and animal studies have shown that CBD’s activity decreased condition fear, mitigated the adverse effects of chronic stress, decreases autonomic arousal, prevents fear reconsolidation, and promotes fear extinction [31]. CBD is postulated to regulate fear and anxiety through interaction with the serotonin 5-HT1A, the TRPV-1 receptor, and, to a lesser extent, CB1R [31]. CB1R activation results in anxiolytic effects and plays a role in regulating/preventing fear and preventing chronic stress. CB1R seems to mediate the anti-compulsive activity of CBD [31]. Activation of the serotonin 5-HT1A receptor (5-HT1AR) by CBD has been implicated in the regulation of fear and prevention chronic stress [31]. Another proposed mechanism of action by which CBD may produce anxiolytic effects is by upregulating hippocampal AEA, an endogenous cannabinoid with anxiolytic properties [41].
A 2011 preliminary study by Bergamaschi and colleagues investigated the effect of a single dose of CBD on subjects undertaking a simulation public speaking test (SPST). A total of 24 patients with Social Anxiety Disorder (SAD), who were never treated prior, received a single 600 mg dose of CBD before the SPS test. There was an improvement in speech performance, a reduction in anxiety, cognitive impairment, and alert anticipatory speech [42].
In murine models, CBD was able to reduce the depression induced by the Forced Swimming Test (FST), tests of conditioned fear, conflict tests, and restraint stress tests [31]. The mechanism of action is suggested to be by activation of the 5-HT1A receptor. It has also been postulated that CBD increases brain-derived neurotropic factor (BDNF), thereby reducing depression [43]. The BDNF protein is responsible for neurogenesis (formation of nerve cells), and the growth, maintenance, and survival of nerve cells.

2.2. Pain Management

Pain is a symptom of many diseases. Both anecdotal and scientific evidence support the use of C. sativa L. and its secondary metabolite for overall pain management, and is effective even against chronic pain—both as a stand-alone drug and as an adjuvant, and there is record of the use of C. sativa L. in pain management in Chinese pharmacopoeia—some 5000 years ago.
More recently, the ECS has been implicated in the management of pain as cannabinoids have been shown to target components of the ECS [44] such as the CB1R, CB2R, non-CB1R/CB2R cannabinoid G protein-coupled receptor (GPCR) 55 (GPR55) [45], GPCR 18 (GPR18) aka N-arachidonoyl glycine (NAGly) receptor [46], opioid/serotonin (5-HT) receptors [47,48,49], TRPV1 [50,51], and PPARα and γ [15]. Additionally, it is notable that, in a murine model, the GPR55 receptor modulates the proinflammatory cytokines IL-4, IL-10, IFN gamma, and GM-CSF, thereby mitigating hyperalgesia [45].
Antagonists of CB2R have been reported to demonstrate antinociceptive properties in models of inflammatory and nociceptive pain [52]. One mechanism of action is possibly by inhibition of AEA metabolism; another possibility is via modulation of peroxisome proliferator-activated receptor α agonists, TRPV1 antagonists, and/or α2-adrenoceptor modulators [52]. In some cases, this is accomplished via activation of opioid system/enhancement of μ-opioid receptor agonists [52]. On the same tangent, cannabinoid and opioids, and cannabinoids and non-steroidal anti-inflammatory drugs (NSAIDs), have been shown to act synergistically [52]. Current evidence suggests that CBD, in particular, may have therapeutic benefits in treating Rheumatoid arthritis, Fibromyalgia, arthritis, chronic back pain, chronic abdominal pain due to surgery, and chronic pancreatitis, headache, and facial pain.
Studies in murine models of arthritic pain have also shown great promise [53]. In one animal model, cannabinoids were shown to inhibit neuropathic nociception caused by traumatic nerve injury, disease, and toxic insults [54]. In yet another animal model, cannabinoids demonstrated therapeutic efficacy against thermal pain, noxious pain, post-operative pain, cancer pain, and spinal cord injury-related pain [55]. On the same tangent, the endocannabinoid AEA demonstrated antinociceptive properties at the spinal level [50].
In general, C. sativa L., and its secondary metabolites thereof, may be a safer, non-addictive alternative to opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and most painkillers. This has contributed to CBD’s growing popularity, particularly in professional sports and cancer-management. Furthermore, CBD is well-tolerated across wide dose ranges.
CBD could be particularly useful in cases where chronic cancer pain is refractory to treatment with traditional analgesics. A 2018 review article/meta-analysis by Vučković and colleagues explored scientific studies conducted between 1975 and March 2018 to examine CBD’s therapeutic applicability in treating cancer-associated pain, fibromyalgia, and neuropathic pain, and concluded that the current scientific evidence supports the use medical cannabis in pain management [44]. There are many components to the many different types of pain. Vučković and colleagues, 2018, also postulate a number of possible mechanisms of action of CBD-induced analgesia [44]. These include the reduction in inflammation, activation of some pain inhibition pathways, inhibition of neuropeptide and neurotransmitter release, and/or regulation of neuron excitability (particularly in the case of neuropathic pain).
In the present day, Nabiximols (Sativex®), a synthetic cannabinoid oromucosal spray, has been approved in some European countries and in Canada for the treatment of cancer-related pain. It is also used for spasticity and neuropathic pain in patients with Multiple Sclerosis.
Components of the ECS are also expressed in migraine-related structures [56] and, as such, the ECS may also be a target for the treatment of migraines. Refer to Table 2 for a list of synthetic cannabinoids and their therapeutic window for pain.

2.3. Cannabinoids as an Alternative to Opioids

Opioid overdose (OOD) is a worldwide crisis, primarily due to over-prescription of opioids for the management of chronic pain, and also to the illicit drug market. Opioid overdose accounts for approximately 69,000 deaths worldwide, whereas some 15 million people are addicted [59].
An opioid (narcotic) is a class of drugs manufactured synthetically or from the opium plant. The mechanism of action is by binding to opioid receptors (G protein-coupled) located primarily in the central and peripheral nervous system and the gastrointestinal system. Ligands, the endogenous opioids that bind to said receptors, include endorphins, endomorphins, enkephalins, and dynorphins. These receptors mediate analgesia and nociception, and are typically used as pain relievers and anaesthetics. Other uses are to suppress diarrhoea and coughing, and to relieve shortness of breath. This class of drugs include heroin and synthetic opioids such as Fentanyl (Actiq®, Duragesic®, Fentora®, Abstral®, and Onsolis®), codeine, Hydrocodone (Hysingla® and Zohydro ER®), Hydrocodone/acetaminophen (Lorcet®, Lortab®, Norco®, and Vicodin®), Hydromorphone (Dilaudid® and Exalgo®), Meperidine (Demerol®), Methadone (Dolophine® and Methadose®), Morphine (Kadian®, MS Contin®, and Morphabond®), Oxycodone (OxyContin®, and Oxaydo®), Oxycodone and Acetaminophen (Percocet® and Roxicet®), and Oxycodone and naloxone. Fentanyl is 50 to 100 times more potent than morphine [60]. Side effects of opioid abuse include nausea, respiratory depression, sedation, euphoria, constipation, urinary retention, and itchiness. Side effects of opioid overdose include pinpoint pupils, drowsiness, cyanosis, slow breathing, loss of consciousness, and even death.
The analgesic effects of C. sativa L. and its secondary metabolites have made them promising tools in combatting the opioid crisis. This if further confirmed by the presence of cannabinoid receptors in peripheral, spinal, and supraspinal neurons associated with modulation of nociceptive signalling [61,62,63,64,65] and the implication of ECS in opiate dependence withdrawal [48]. In a sample of 4,840,562 persons, the legalization of medical cannabis directly correlated with lower chances of opioid use [66].
A preliminary cohort study reported a clinically and statistically significant relationship between enrolment in a New Mexico Medical Cannabis Program (MCP) and pain reduction, opioid prescription cessation (no prescription of opioid medication within the last 3 months), reduction in daily intravenous (IV) injection of opioid medications, reduced hospitalization due to prescription opioid medications (POMs) [67], reduced health care costs [67], and improvements of overall quality of life, social life, concentration, and activity levels [68]. A 41% opioid dose reduction (ODR) was also achieved using medical cannabis in cancer and rheumatological patients [69].
An association was also found between a reduction in opioid related deaths in Colorado and the legalization of recreational cannabis in Colorado (increasing access to medical cannabis via dispensaries) [70,71,72,73]. Another found a direct relationship between the implementation of medical cannabis access laws and the reduction in the probability a provider prescribes any opioids net of any offsetting effects, the total number of patients receiving opioids and total days’ supply of opioids prescribed [74]. Other studies suggest that the implementation of more flexible medical and adult-use marijuana laws may directly correlate with a reduction in opioid overdose death rates [75,76] and lower opioid prescribing rates (5.88% and 6.38% lower, respectively) [77].
A 2020 study by Blake explored the prescription rates of opioids in 19 states where medical cannabis is legal [78]. Results of this study show that, in these states, opioid prescriptions decreased. In another study, the decreased opioid use (in persons aged 18–55—Medicare/Medicade populations) was only associated with the implementation of a medical cannabis law (as opposed to a recreational cannabis law) [73,79]. On the same tangent, a 2019 study by Flexon and colleagues report no relationship between medicinal cannabis legislation and opioid misuse [80]. In another study, medical cannabis access and use directly correlated with and increased rate of cessation of injection of opioids [81]. Cannabis may also have a safer side-effect profile, lower abuse potential, and may even be used to treat some side effects of opioid use such as nausea [82].
At this point, it is suggested that cannabinoid-based analgesics may be used as an adjuvant, rather than an alternative form of therapy, and may even produce a synergistic result when used in combination with opioid analgesics [83,84,85]. A 2019 study by Capano and colleagues evaluated the effects of CBD hemp extract on opioid use and quality of life in a prospective cohort study in patients suffering from chronic pain. Patients given a CBD-rich extract were able to significantly improve their quality of life, and significantly reduce, or completely cease, the use of opioids [86]. No positive correlation between frequent cannabis use and frequent opioid use (whether illicit or prescribed) for pain was reported in this study.
On a different tangent, in contrast to opioids, the primary analgesic used to treat cancer-induced bone pain (CIBP) caused by malignant cancers such as breast cancer that tend to invade bone, peripherally restricted CB1R agonists such as 4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (PrNMI), have demonstrated significant alleviation of CIBP [87].

2.4. Inflammation

Inflammation may accompany many diseases, including many types of cancers, asthma, and autoimmune disorders such as rheumatoid arthritis, hepatitis, colitis, multiple sclerosis, and common dermatologic conditions. Cannabinoids, in general, are very potent anti-inflammatory agents. Endocannabinoids, such as AEA and 2-AG, and phytocannabinoids, such as Δ9-THC and CBD, have demonstrated anti-inflammatory and immune-suppressive properties via CB1R and CB2R [88]. Cannabinoids have demonstrated the ability to downregulate cytokine and chemokine production and, in doing so, are able to suppress inflammatory responses [88]. As such, both endocannabinoids and phytocannabinoids may be promising tools in the treatment of inflammatory disorders.
It has been postulated that CBD binds to an adenosine A2A receptor, and decreases inflammation by way of inhibition of adenosine uptake. This has been confirmed in murine models. In another murine model, CBD was able to mitigate LPS-induced inflammation through said A2A receptors. CBD also had the same effect on inflammation in animal models for multiple sclerosis. In yet another murine model, CBD, by way of the TRPV-1 receptor, was able to reduce the levels of pro-inflammatory cytokines (eotaxin1, IL-2, IL-6, IL-12, IL-17, TNF-α, IFC-c, and MCP-1) [89]. AEA is also implicated in the treatment of inflammation [90].
It has also been postulated that CBD is a functional antagonist to the GPR55 receptor [91]. Via inhibition of GPR55 receptor activity, CBD may mediate levels of inflammation by controlling the release of pro-inflammatory cytokines IL-12 and TNF-α [92]. Additionally, by binding to and blocking the GPR55 receptor, CBD may exhibit analgesic effects in neuropathic pain, and anti-inflammatory activity in Inflammatory Bowel Disease [92].
CBD interacts with the PPAR-y receptor to mitigate beta-amyloid (Aβ)-induced neuroinflammation [92]. Through said receptor, CBD also promotes neurogenesis in the hippocampus. The anti-inflammatory actions of CBD were also reported in murine models of Type 1 Diabetic Cardiomyopathy, Pneumococcal meningitis, Colitis, Alzheimer’s, and Inflammatory Bowel Syndrome [92]. In murine models, CBD also has the ability to decrease Reactive Oxygen Species (ROS), thereby inhibiting inflammation [92]. The extent to which these results in murine models may be applied to humans requires further study.

2.5. Cardiovascular Disorders

Studies have shown that cannabinoids, including CBD, have a cardioprotective role—preventing heart damage, reducing the risks thereof, and maintaining a “healthy” heart and vasculature [93]. Cannabinoids have also shown promise against arrhythmias, atherosclerosis, and stroke [94,95]. Studies also show that cannabinoids may lower the risk of cardiovascular diseases, heart attack (myocardial infarction), and injury as a result of reduced/restricted blood flow (ischaemia) [93]. CBD and other cannabinoids have also been shown to cause relaxation of the blood vessel walls (vasorelaxation) [93]. It is suggested that CBD decreases blood pressure, attenuates atherosclerosis, and increases the available nitric oxide by way of PPARy antagonism [93]. Nitric oxide is a neurotransmitter and blood vessel relaxant, that improves blood circulation, reduces blood pressure, regulates heart rate, prevents clogged arteries, regulates contractility of the heart and vascular tone, prevents adhesion of cells to the endothelium, and prevents the formation of blood clots by inhibiting platelet activation. As an anxiolytic agent, CBD mitigates the cardiovascular response when we become anxious or stressed.
Proposed mechanisms of action by which CBD exerts its activity on the cardiovascular system are by TRPV channel activation, nuclear factor-kB (NFκB), and map kinase (MAPK) pathways [93]. AEA also activates TRPV1, and is implicated in the treatment of cardiovascular disorders [90]. Other cannabinoids may act by way of CB1R activation. CBD is also shown to prevent hypotension by inducing arteriolar and venular vasodilation [93].

2.5.1. Diabetes

Diabetes is a metabolic disease characterized by high blood-sugar levels and is a significant risk factor for cardiovascular diseases (CVD) such as stroke, blood vessel disease, and coronary artery disease, as it damages the nerves and the blood vessels of the heart/cardiovascular system and possibly other organs, such as the eyes and kidney [96,97]. The hormone responsible for the regulation of blood glucose is insulin. In Type 1 diabetes, an autoimmune disease, the pancreatic cells that make insulin are attacked and destroyed by the individual’s own immune system. In Type 2 diabetes, the individual becomes resistant to insulin and, as a result, there is an accumulation of sugar in the blood [98].
Both CBD and Δ9-tetrahydrocannabivarin (Δ9-THCV) a non-psychoactive cannabinoid, have been shown to play a role in lipid and glucose metabolism in animal models, and may be opportunities for glycaemic control in the case of patients with type 2 diabetes mellitus (T2DM) [99]. The CB1R has also been implicated as a therapeutic target for the treatment of T2DM, as the ECS has demonstrated a role in insulin resistance characteristic of T2DM [100]. Δ9-THCV has been implicated in the clinical management of type 2 diabetes as it has demonstrated the ability to decrease appetite, up-regulate energy metabolism, and increase satiety [101].
CBD also seems to have therapeutic activity against endothelial dysfunction [93]. The endothelium is a layer of single-celled tissue which lines organs, in this case the heart. Endothelial dysfunction is characterized by inflammation, blood clotting (thrombosis), and impaired vasodilation. High glucose intake, as in cases of diabetes, is a cause of endothelial dysfunction. Another proposed mechanism of action of CBD on diabetes is through the upkeeping of the blood–retinal barrier. Disruption of the blood–retinal barrier is characteristic of diabetes [93].

2.5.2. Stroke

The wide distribution of the components of the ECS makes it a promising target in the treatment of CNS diseases/neurological disorders such as strokes [7]. A stroke is a type of cardiovascular disease that is characterized by brain damage and other possible signs and symptoms such as severe headache, loss of coordination, dizziness, confusion, blurred vision and even temporary blindness, slurred speech, and numbness/paralysis of face or limbs [102]. Strokes are the result of a lack of oxygen and nutrients to the brain due to interruption or restriction of blood supply to brain [102]. Types of strokes include: (1) ischemic stroke due to a blocked artery, and (2) haemorrhagic stroke due to a leaking or burst blood vessel [102].
Δ9-THC has demonstrated positive effects on brain oxygenation and increased hemodynamic blood flow to the prefrontal cortex, and may possibly be beneficial in the treatment of (frontal lobe) strokes [103]. The anti-spastic properties of CBD may also be beneficial for patients with post-stroke spasticity [103].
In in vivo and in vitro animal models, CBD plays a neuroprotective role in the pathophysiology of ischaemic stroke–the most common type of stroke—characterized by blockage of blood vessels in the brain by blood clots. Studies show that CBD increases cerebral blood flow (CBF), thereby reducing the risk of ischaemic strokes [93]. HU-211 has also demonstrated therapeutic promise against CNS diseases [104].
Another proposed mechanism of action of CBD on CBF is through antagonism of the serotonin (5HT3) receptor (5-HT1AR) [93]. CBD facilitates 5-HT1AR signalling in animal models. Yet, another proposed mechanism of action of CBD on strokes is through the upkeeping of the blood–brain barrier [93]. Disruption of the blood–brain barrier is one proposed cause of ischaemic stroke.
An increased infarct size is characteristic of heart attacks (myocardial infarction). Studies have shown that CBD reduces infarct size by reducing inflammation [93,105,106]. There is also evidence that CBD influences blood cell function, including promoting the survival and migration of white blood cells, mediating programmed cell deaths, and regulating platelet aggregation [93].

2.6. Cancer

Cannabinoids have demonstrated well established analgesic, antinauseant, antidepressant, antiemetic, anti-nociceptive, and orexigenic properties and, as a result, they have been studied and utilized in the treatment of cancer patients receiving chemotherapy or radiotherapy, and in AIDS/HIV patients [107,108,109,110]. In addition to the well-established palliative properties that Δ9-THC and CBD exert on cancer-related symptomology, several phyto-, endo-, and synthetic cannabinoids all exert their anti-cancer properties via several different proposed mechanisms of action including, but not limited to: induction of apoptosis, autophagy and cell-cycle arrest, inhibition of cancer cell migration, metastasis, angiogenesis, neovascularization, adhesion, and/or invasion [111,112,113,114,115,116,117]. These properties are likely attributed to their role in endocannabinoid signalling pathways involved in cancer processes such as the MEK-extracellular signal-regulated kinase signalling cascade, and the adenylyl cyclase, cyclic AMP-protein kinase-A pathway [113,118]. Ultimately, the use of cannabinoids to target the ECS-signalling involved in the pathogenesis of these cancers, is a very promising target that is currently being given increasing attention in the medical landscape.
Multiple studies also confirm the direct correlation between the upregulation of said cannabinoid receptors, endocannabinoid metabolic enzymes, and endogenous ligands in cancerous tissue [119,120,121,122,123,124,125].]. Signalling between cancer cells is also shown to be mediated by cannabinoids [119]. One study suggests that the ECS may play a role in tumour suppression [126]. Multiple studies have also demonstrated the apoptotic, anti-metastatic, anti-angiogenic, anti-inflammatory properties of cannabinoid and non-cannabinoid secondary metabolites of C. sativa L. This suggests that cannabinoid-based therapeutics may be promising in the treatment of many different types of cancers, in addition to the aforementioned diseases.
Cannabinoids such as AEA, Met-F-AEA, 2-AG, Δ9-THC, CBD, CBDA, HU120, WIN-552122, JWH-133, AME121, and R-(+)-MET have all demonstrated anti-cancer properties in various cancer models such as breast-, lung-, prostate-, testicular-, gastric-, skin-, colon-, bone cancers, and glioblastomas, lymphomas, leukaemias, and neuroblastomas. Mechanisms of action of these cannabinoids in these cancers range from induction of apoptosis and cell cycle arrest, inhibition of DNA synthesis, inhibition of various signalling pathways such as the PI3K/AKT/mTOR/AMPK or the EGF/EGFR, inhibition of angiogenesis, inhibition of tumour growth, tumour regression, and inhibition of metastasis.

3. Neurological/Neurodegenerative Diseases

Neurodegenerative diseases are characterized by inflammation and dysregulation of the function of neurons, and in some cases death, resulting from an ongoing/progressive degeneration of neurons [127]. This category of diseases includes amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, Huntington’s, Batten disease, fatal familial insomnia, and, by some hypotheses, schizophrenia. These diseases are incurable, but cannabinoids have been shown to provide relief to some symptoms associated with said diseases. Cannabinoids are known to play a role in the modulation of inflammation (neuroinflammation), along with providing and enhancing neuroprotection [95,127,128]. In addition, cannabinoids such as CBD have shown analgesic, anxiolytic, and immunosuppressive properties that may help to combat certain neurological disorders [129].
Cannabinoids have been implicated in the modulation of adult neurogenesis in the hippocampus and the lateral ventricles [130,131]. Chronic treatment of the synthetic cannabinoid HU-210 has been shown to enhance the survival and proliferation of cells in murine models of hippocampal neurogenesis while exerting anxiolytic and anti-depressant properties [132]. Other synthetic cannabinoids, such as JWH-133, AM1241, JWH-056, AM251, WIN55,212-2, and URB597, have also demonstrated pro-neurogenic properties [130]. Neurogenesis is the process by which neural stem cells (NSCs) produce neurons (nerve cells). Neurogenesis in the hippocampus influences our capacity to learn and retain memory. Neuroplasticity is the brains capacity for synaptogenesis, which is the structural change/re-wiring of said connections between neurons. Studies show that schizophrenia and other psychiatric disorders physically alter the brain, as characterized by a reduction in the volume of the hippocampus, along with other areas [40]. This is typically as a result of an inhibition of neurogenesis in the hippocampus.
In one study, prolonged CBD administration demonstrated a neuroprotective role against neuroanatomical alterations in the hippocampus, hippocampal volume loss, and even ameliorated brain damage [133]. In murine models, CBD promoted hippocampal neurogenesis, synaptic- and dendritic-remodelling, and prevented autophagy, neurogenic disruption, stress-induced anxiogenesis, THC-induced neurotoxicity, oxidative damage/ROS production, and neuronal damage [40].
Cannabinoids may also have potential in the treatment of mood instability associated with neurological disorders, as the ECS has been implicated in pathophysiology of neurological disorders [134]. Although some studies suggest that cannabinoids in general may be promising in the treatment of neurological disorders, others suggest a link between high consumption of recreational cannabis and an increased risk of mental health disorders such as substance dependence—though this is controversial [120,135]. This is, however, likely due to the presence of THC. Further studies are required to clearly elucidate the pro-neurogenic effects of CBD and other cannabinoids in humans.
Scientific evidence suggests that cannabinoids such as Δ9-THC, CBD, WIN55212-2, and CP-55940 may be used to treat various forms of substance abuse such as heroin-, cocaine-, nicotine- and alcohol-abuse and their symptomologies thereof [136].

3.1. Schizophrenia

While some studies suggest that C. sativa L. use may increase the risk of developing psychotic disorders and even worsen prognosis and disease burden, likely due to psychoactive compounds [134,137], others suggest non-psychoactive compounds in the plant may have therapeutic efficacy.
The anti-psychotic, anti-inflammatory, and neuroprotective properties of CBD make it a safer, more tolerable, and promising alternative treatment for psychotic disorders such as schizophrenia [134,138,139]. Δ9-tetrahydrocannabivarin (Δ9-THCV) is another cannabinoid that has gained interest due to its anti-convulsant and non-psychoactive properties [134]. On this same tangent, whole-cannabis extract, or pure Δ9-THC, on the other hand, may be less effective due to the psychoactive properties of Δ9-THC and possibly other psychoactive cannabinoids present in the whole-cannabis extract mixture, and may even increase the risk of psychosis [140,141]. In some studies, CBD has demonstrated the ability to attenuate Δ9-THC-induced psychotic symptoms in healthy patients and symptoms of schizophrenia in schizophrenics [139].
Both SR141716A and CBD have demonstrated antipsychotic properties in dopamine- and glutamate-based models of schizophrenia [142,143,144].

3.2. Epilepsy

Epilepsy is a neurological/central nervous system disorder that is characterized by frequency seizures. Multiple anecdotal and scientific evidence confirm the success of medical cannabis in reducing the frequency of seizure episodes with the use of CBD—this being after the end-of-the-road, i.e., failing therapy with traditional AEDs [145].
In recent years, there has been scientific interest in cannabinoid-based drugs for the treatment of epilepsy, particularly treatment-resistant epilepsy (TRE) and paediatric-onset drug-resistant epilepsy. Phytocannabinoids such as CBD, cannabigerol (CBG), cannabidavarin (CBDV), and Δ9-THCV have demonstrated anti-convulsant properties and may be promising opportunities to develop safer alternatives (and even adjuncts) to traditional antiepileptic drugs (AEDs) [146,147,148]. Of these cannabinoids, Δ9-THC and CBD have been given the most attention for their anti-convulsant properties [149]. CBD, in particular, is of particular interest as it has it circumvents the psychotropic effects resulting from the activation of CB1R [150]. CBD has demonstrated efficacy as an adjunct treatment option in the clinical management of Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) as, in multiple studies, it has reduced the frequency of epileptic seizures [149,151,152,153,154,155].
Charlotte Figi, a SCNIA-confirmed Dravet syndrome patient, is the most famous cases of medical cannabis being used to treat epilepsy—likely as, at one point, she was the youngest medical marijuana patient, and this caused of a lot of controversy [156]. Charlotte Figi began having seizures at the age of 3 months [156]. By the age of 5 years, she was having up to 300 generalized chronic-tonic seizures (GCTs) seizures per week (50/day), and facing a failing therapy of a cocktail of antiepileptic drugs and a ketogenic diet [156]. She had to be fed through a tube, had motor impairment and cognitive delay and, as a result, had to be assisted with every activity.
Charlotte began receiving sublingual doses of C. sativa L. plant extract—starting with low doses (2 mg CBD/lb per day) and increasing up to 4 mg CBD/lb per day [156]. This extract, made from the Charlotte’s Web strain, had 0.3% Δ9-THC, sufficient to avoid psychosis, and high content of CBD. Twenty months later, Charlotte’s seizures were reduced by 90% to 2–3 per month, and she could now walk, talk, and do activities unassisted [156]. Upon the success of her treatment with CBD, Charlotte no longer had to take the antiepileptic drug Clobazam®. The preparation also began to improve her autistic behaviour. A reduction in dosages of this preparation resulted in a return of seizures, clearly indicating that the preparation had therapeutic effects.
In 2018, Epidiolex® became the first and currently the only US Food and Drug Administration (FDA)-approved plant-derived CBD-based pharmaceutical preparation developed for the treatment of Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS).

4. Autoimmune Diseases

Immune system disorders are the result of dysregulation (hypo- or hyper-activity) of the immune system. In particular, autoimmune disorders are characterized by hyperactivity (overactivity) of the immune system, resulting in the production of antibodies that attack the body’s own tissues instead of invading pathogens. Autoimmune disorders include autoimmune encephalitis, chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain–Barré syndrome, Grave’s disease, Hashimoto’s thyroiditis, multiple sclerosis, inflammatory bowel disease (IBD) (e.g., Chron’s disease and ulcerative colitis), systemic lupus erythematosus (SLE), rheumatoid arthritis, myasthenia gravis, vasculitis, type-1 diabetes mellitus, psoriasis, and scleroderma.
The ECS has been implicated in immunoregulation as endocannabinoids, synthetic cannabinoids (such as Ajulemic acid and JWH-015, SR144528, and WIN55,212-12), and phytocannabinoids (such as Δ9-THC and CBD) have demonstrated immunosuppressive properties, primarily by way of apoptosis [88]. The ECS is suggested to have therapeutic implications in a number of autoimmune (and neurological) diseases as components (CB1R and CB2R) of the ECS have been expressed in microglial cells [157] and distributed throughout the central nervous system (brain and spinal cord) [158].
To reiterate, the CB1R is densely populated in areas of the brain responsible for learning and memory, coordination, movement, regulation of hormones, sensory perception, reward and emotions, and body temperature [159]. On the other hand, CB2R are primarily expressed in the cells of the immune system [159]. This is further confirmed by the immunosuppressive properties of some cannabinoids [160], and the inhibition of production of proinflammatory cytokines [160,161], likely acting through the CB2R [162]. Both types of receptors are implicated in the modulation of neurotransmitter and cytokine release [160]. Through interaction with CB1R and CB2R, cannabinoids demonstrate the ability to induce apoptosis of T cells and macrophages [160].
CB1R and CB2R are expressed in microglial cells at low and high levels, respectively, with the distribution and expression of CB2R is suggested to modulate microglial activity [159]. Microglial cells are morphologically, phenotypically, and functionally related to macrophages [159].
In “resting” macrophages, CB2R is not detected [159]. Elevated levels of expression of CB2R directly correlating to the conversion of microglial cells into a either a “primed” state, where the cells function in chemotaxis, or a “responsive” state, in which these cells carry out antigen processing [159]. In a fully activated state, CB2 is expressed at very low levels in macrophages [159]. In addition to primed and activated macrophages, inflammatory macrophages also express the highest levels of CB2R [159]. This means that cannabinoids may only have a window during which to carry out their therapeutic function [159]. CB1R is only expressed in very low levels in microglia [159].
2-arachidonylglycerol, an endocannabinoid, interacts with CB2R to stimulate a chemotactic response, whereas in vivo and in vitro, the exogenous cannabinoids Δ9-THC and CP55940 interact with CB2R to inhibited microglia from a chemotactic response to Acanthamoeba culbertsoni, an opportunistic pathogen responsible for Granulomatous Amoebic Encephalitis [159].
The pro-inflammatory properties of cannabinoids have implicated them as possible treatments for inflammation associated with autoimmune diseases such as type 1 diabetes mellitus, multiple sclerosis, and neuropathic pain [160].

4.1. Blood–Brain Barrier (BBB) (Also Referred to as the “Blood–Spinal Cord Barrier” (BSCB))

The blood–brain barrier (BBB) is where peripheral blood circulation (and components/chemicals in the blood, thereof), meet the anatomical structures of the brain (central nervous system) [163]. It is essentially a border or defensive barrier between the CNS and circulating blood [163]. Blood vessels play a critical role in delivering oxygen and nutrients to the tissues and organs of the body, maintaining hormone signalling among tissues, removing metabolic waste and carbon dioxide from said tissues, and general neuroprotection [164,165]. Blood vessels of the central nervous system (CNS) make up the blood–brain barrier and regulate CNS homeostasis, the movement of cells, ions, and molecules between the blood and the brain [164]. In maintaining CNS homeostasis, the BBB confers neuroprotection from pathogens and toxic chemicals circulating in the blood.
Dysregulation of the BBB has been implicated in the pathogenesis of neurological autoimmune diseases such as antiphospholipid syndrome with neurological involvement [166,167,168], chronic inflammatory demyelinating polyneuropathy (CIDP) [169], Guillain–Barré syndrome (GBS) [170,171,172], Alzheimer’s disease [173], multiple sclerosis (MS) [174], and neuromyelitis optica [175,176,177].
The endocannainoid system has been implicated in the modulation of the blood–brain barrier [178], and may likely be a potential target for the treatment and/or clinical management of neurological or psychiatric diseases such as schizophrenia and epilepsy [179]. Both AEA and 2-AG have been shown to regulate (decrease) the permeability in in vivo and in vitro models of ischaemia/reperfusion, chronic head injury, and multiple sclerosis [178,180,181]. In another study, CBD was shown to enhance brain-targeting capacity, that is, the passage of lipid nanocapsules across the BBB in both in vivo and in vitro models of BBB, and thus may be an opportunity for novel CNS drugs [182].
CB1R and CB2R may provide neuroprotection via protection from processes that damage the BBB such as inflammation (CB2R-mediated), excitotoxicity (CB1R-mediated), and cell death (CB1R-mediated) and oxidative stress [165]. In addition to these neuroprotective effects, CB1R and CB2R have both demonstrated the ability to restore the BBB and even improve BBB integrity, thus further conferring protection against neurological or psychiatric diseases [165]. One mechanism of action by which endocannabinoid receptors confer protection of the BBB is via Aβ-efflux across the BBB [165]. The medical significance of this is that deposition of Aβ, and an inability to clear such depositions, is implicated in Alzheimer’s disease [183]. This is due to a dysregulation of the BBB and the inability of Aβ to be transported across the BBB [183]. This 2013 study by Bachmeier and colleagues also investigated and demonstrated the role of the ECS in transporting Aβ across the BBB, clearing of Aβ across the BBB, reducing deposition of Aβ in the AD brain, and improving cognitive behaviour in animal models of Alzheimer’s disease [183].

4.2. Multiple Sclerosis

Growing scientific and anecdotal evidence suggests that cannabinoids such as Δ9-THC demonstrate therapeutic effects against symptoms of multiple sclerosis such as neuropathic pain and spasticity [184,185]. Sativex®, an FDA approved synthetic cannabinoid (a combination of Δ9-THC and CBD) is an oromucosal spray made from whole-plant cannabis extract that has demonstrated efficacy in the treatment of moderate to severe symptoms of multiple sclerosis (MS) without adverse side-effects, potential of drug tolerance, or potential for abuse or misuse [186,187,188,189]. It is proposed that Sativex improves MS symptomology by significantly reducing spinal excitability and increasing intracortical inhibition [190]. Another study proposes that Sativex is even more effective at improving MS spasticity than first line antispasticity treatment alone [191].
In animal models of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS), cannabinoids were shown to mediate EAE suppression via CB1R expressed by neurons [192]. Inflammation associated with EAE was also shown to be controlled by CB2R expressed by encephalitogenic T cells [192]. T-cells deficient in CB2R exacerbated the clinical course of EAE by increasing the production and proliferation of inflammatory cytokines [192]. In addition, these T-cell were resistant to apoptosis [192]. This CB2R activity was confirmed in a study by Stipe and colleagues who investigated the effect of a dinucleotide polymorphism in a human gene on endocannabinoid-induced inhibition of T lymphocyte proliferation [162]. The CB2R cDNA 188–189 AA → GG polymorphism is the result of arginine replacing glutamate at amino acid position 63 [162], and the rate of polymorphism is reported to be increased in autoimmune diseases [162]. In conclusion, variation in the gene that encoded CB2R is suggested to put an individual at increased risk for autoimmunity [162].

4.3. Rheumatoid Arthritis

Immunomodulatory, immunosuppressive, and analgesic properties make cannabinoids promising therapeutic agents in the management of rheumatoid arthritis [193,194,195]. The CB2R is reported to be a target for RA therapy, as suggested by increased expression in synovial tissues from the rheumatoid joints [196]. JWH133, a selective CB2R agonist inhibited the production of the inflammatory mediators interleukin (IL)-6, matrix metalloproteinase-3 (MMP-3), and chemokine (C-C motif) ligand 2 (CCL2) by tumour necrosis factor-α-stimulated fibroblast-like synoviocytes (FLS) derived from the rheumatoid joints [196]. JWH133 also inhibited the osteoclastogenesis of peripheral blood monocytes, which also occurs in RA [196,197]. In a murine model of RA, another cannabinoid receptor 2 agonist JWH-015 demonstrated inhibition of pro-inflammatory cytokine interleukin-1β-induced inflammation in rheumatoid arthritis synovial fibroblasts partly via a glucocorticoid receptor [198].

4.4. Disturbances of the Bowel and Inflammatory Bowel Disease (IDB)

Inflammatory Bowel Disease (IDB) describes two conditions, Chron’s disease and ulcerative colitis, which are characterized by chronic inflammation of the gastrointestinal (GI) tract. Whereas ulcerative colitis is characterized by ulcers and inflammation and the colon and rectum, Chron’s disease may affect any area of the GI tract from mouth to anus, though most often the small intestines, which become inflamed [199,200,201].
In traditional Indian, Chinese, and African medicine, C. sativa L. was used regularly for disorders of the GI tract and of the bowel, and is still of interest in the treatment of such diseases. CBD, in particular, has shown therapeutic potential in the management of IDB.
Components of the ECS are distributed, though differentially, in colonic tissue (epithelium, lamina propria, smooth muscle, and enteric plexi) [202], as revealed by Western blot and immunocytochemistry. CB1R are distributed throughout the enteric nervous system (ENS) [203] and the gut-brain axis (GBA), a communication network between the brain and the gut [204,205]. This suggests that disorders of the gastrointestinal (GI) tract may be treated with drugs that target said CB1R and cannabinoid signalling in the ENS [203,206].
The ECS has been implicated in gastrointestinal physiology and homeostasis, and in the pathogenesis of Inflammatory Bowel Disease as confirmed by anecdotal data, studies in humans, epidemiologic data, murine models of colitis [206,207], and other pathophysiological conditions [208,209,210,211]. Refer to Table 3 for a list of uses and properties of cannabinoids for bowel disorders.
Multiple anecdotal evidence confirms the therapeutic properties of medical cannabis against abdominal cramps, diarrhoea [228,229], and anorexia [219]. Other disturbances and inflammatory disorders of the bowel [219,230,231,232], such emesis, anorexia, diabetic gastroparesis [233], colitis [234], and colon cancer [235].
There is increasing interest in the use of medical cannabis (and its cannabinoids, particularly Δ9-THC, CBD, and CBG) as an alternative to opioids in the treatment of IBD, due to its safer side-effect profile and lower chance of dependency and mortality [212].
In addition to Chron’s disease, the ECS may also be a promising therapeutic target for the treatment of functional bowel diseases such as irritable bowel syndrome and secretion- and motility-related disorders of the GI tract [209]. The ECS may also play a protective role against colonic inflammation [208]. It is, however, unclear whether the mechanisms of cannabinoids against IBD is through inhibition of an inflammation pathway or via masking of IBD symptoms [207]. In a murine model, the ECS provides GI tract protection from inflammation and excessive enteric and gastric secretions [209]. On the tangent of murine models of colitis, two novel ligands, CB13 and AM841, may be used by the cannabinoid system in the pathogenesis of inflammatory bowel diseases [206].
To reiterate, CB2R are primarily expressed in the cells of the immune system [159] and may play a role in mucosal immunity [210]. This is further confirmed by the immunosuppressive properties of some cannabinoids [160], and the inhibition of production of proinflammatory cytokines [160,161], likely acting through the CB2R [162]. This suggests a possible role of the CB2R in regulation of inflammation of the GI tract, including colitis-associated inflammation [202].
The ECS is proposed to play an immunomodulatory role in gastrointestinal inflammatory disorders [210]. The distribution of CB2R in the GI tract suggests that it may also play a role in limiting visceral sensitivity and pain and in the regulation of gastrointestinal propulsion [211]. Methanandamide (MAEA), a non-hydrolysable AEA analog is reported to have effects on the mucosal proinflammatory response, by downregulating the pro-inflammatory cytokines interferon-γ and tumour necrosis factor-α [236]. Inflamed IBD mucosa expressed significantly lower levels of the endocannabinoid AEA [236].
In a study by Storr and colleagues, it is reported that drugs that targeted blocked degradation of the ECS, including the expression fatty acid amide hydrolase (FAAH), may be promising candidates for drugs used to treat IBD [24,25].
In a separate study by Storr and colleagues, CB2R-deficient murine models of trinitrobenzene sulfonic acid (TNBS)-induced colitis were administered intraperitoneal injections of the CB2R agonists JWH133, AM1241, or the CB2R antagonist AM630 [234]. After a 3-day treatment, AM630 demonstrated complete exacerbation of colitis, while JWH133 or AM1241 significantly reduced colitis [234]. In a separate study, Storr and colleagues also reported that drugs that targeted blocked degradation of the ECS, including the expression fatty acid amide hydrolase (FAAH), may be promising candidates for drugs used to treat IBD [24,25].
On the other hand, CB1R are widely distributed within the GI tract, particularly in sensory terminals of vagal and spinal neurons and neurons of the enteric nervous system [209]. It has been reported that CB1R plays a role in the modulation of multiple GI tract functions such as gastric secretion and emptying, and intestinal motility [209]. It should also be noted that an increased expression of CB1R directly correlated with Croton oil-induced intestinal inflammation in a murine model of inflammation [235]. Wright and colleagues also report that cannabinoids demonstrated the ability to enhance epithelial wound closure via interaction with the CB1R [210]. The CB2R, though less present and not yet well characterized, is also found in the GI tract. CB2R may also be a promising therapeutic target due to its non-psychoactive nature, and its immunomodulatory function in inflammatory pathways [213].
In a study investigating the effects of the cannabinoid agonists CP 55,940 and cannabinol on intestinal motility, both cannabinoid agonists demonstrated a delay in intestinal motility [235]. Δ9-THC, Δ11-THC, cannabinol, and nabilone (but not CBD) were also reported to have the same effect on intestinal motility (gastrointestinal propulsion/emptying) [237].
Anecdotal evidence and a prospective placebo-controlled study report that medical cannabis has significant therapeutic effects against Chron’s disease [230,238]. Patients with Crohn’s disease who did not respond to treatments with anti–tumour necrosis factor-α agents, immunomodulators or steroids, responded to treatment with 115 mg of Δ9-THC, which significantly mitigated the symptoms of Crohn’s disease, despite its inability to induce remission [220].
CBD, which possesses many of the anti-IBD properties as other cannabinoids, may be more favourable as an anti-IBD drug than Δ9-THC due to its antipsychotic properties [239].

5. Medical Cannabis in Dermatology

The skin is our largest organ, and its primary role is as a first line defence against external agents. All components of the ECS are found in the skin [240], further establishing the role of the ECS in healthy and diseased skin and general homeostasis [241,242]. Dysregulation of these components is implicated in the pathogenesis of several cutaneous disorders [241].
The use of C. sativa L. for skin pathologies has its roots in traditional Chinese medicine where the plant preparations were used as topicals to treat hair loss, skin rashes, ulcers, and wounds [227,243,244,245]. Modern clinical studies also report that cannabinoids demonstrate significant therapeutic effects against skin lesions [246], skin burns [247], and pruritus in several dermatologic diseases such as allergic contact dermatitis, atopic dermatitis, asteatotic eczema, and prurigo nodularis [248]. The Japanese also used C. sativa L. (asashijingan) to treat skin pathologies caused by poisonous bites and intestinal parasites [249,250].
C. sativa L. preparations (powdered leaves) were also used in traditional Arab medicine to treat diseases of the skin such as pityriasis and lichen planus [243,251]. C. sativa L. plant preparations including hemp seed oil have also been traditionally used to treat varicose eczema, acne rosea, and scabies [252].
Inflammatory skin disorders such as acne vulgaris, allergic contact dermatitis, dermatomyositis, psoriasis, and scleroderma are a great disease burden globally, and may greatly impact an individual’s self-esteem, social interactions with others, and general quality of life, particularly if accompanied by pain, pruritus, and permanent scarring [253]. Cannabinoids may also have therapeutic application against asteatotic dermatitis, atopic dermatitis, cutaneous manifestations of systemic sclerosis hidradenitis suppurativa, Kaposi sarcoma, and skin cancer [254]. In a murine model, peripheral administration of 0.01 ng AEA inhibited the induction of, and attenuated, carrageenan-induced hyperalgesia, inhibited capsaicin-induced plasma extravasation, and inhibited inflammation via inhibition of neurosecretion from capsaicin-sensitive primary afferent fibres, all via interaction with CB1R [255]. Cannabinoid receptors are also found in the skin, and play a role in regulating skin growth and maintaining homeostasis of skin cells (melanocytes, keratinocytes, and sebocytes) [256]. Phytocannabinods such as CBD and Cannabigerol (CBG) have been shown to regulate the expression of epidermal differentiation genes (i.e., involucrin, tranglutaminase, and keratins) [257].
The anti-inflammatory properties of some cannabinoids, particularly CBD, suggest that it may have therapeutic application against dermatological inflammatory diseases [258]. Remember that inflammation plays a role in the pathogenesis of many cancers. This, in addition to other anticancer/anti-neoplastic properties of cannabinoids suggest that they may also play a role in regulating, or at least inhibiting skin carcinogenesis [258]. In addition to anti-inflammatory effects, cannabinoids interact with the ECS components of the skin to produce antipruritic, anti-ageing, anti-cancer [259], and antinociceptive effects [260]. Additionally of note is that solar UV radiation is also shown to induce skin inflammation and carcinogenesis via activation of CB1R and CB2R [261]. This was confirmed in a murine model with CB1R and CB2R deficiency which demonstrated significant resistance to UVB-induced inflammation and reduction in UVB-induced skin carcinogenesis [261]. CB1R activated by cannabinoids may also play a role in maintenance of epidermal integrity and permeability [262].
Cannabinoids have also been implicated in the treatment of cutaneous autoimmune diseases such as scleroderma, psoriasis, eczema, and atopic dermatitis. These are discussed in the following sections.

5.1. Acne

Acne is a chronic inflammatory cutaneous disorder and is the most prevalent skin disorder, globally. It is characterized by the clogging of oil glands in the skin by oil and dead skin cells, resulting in the formation of pimples. According to immunologist Dr. Tamas Biro, CBD inhibits lipid synthesis and induces cell death in human sebaceous gland-derived sebocytes and ultimately may be a safer treatment for acne than Accutane, a traditional drug used to treat severe acne [263].
A study by Dobrosi et al. reported that CB2R are expressed in human SZ95 sebocytes, and that the endocannabinoids AEA, and 2-arachidonylglycerol induced upregulation of lipid synthesis, leading to acne. Dobrosi and colleagues also found that inhibiting the said CB2R decreased lipid production in said skin cell line [264]. Thus, drugs that inhibit eCB uptake will increase endocannabinoid levels, resulting in a homeostatic production of sebaceous lipids and an anti-inflammatory response that may be beneficial in treating cutaneous inflammatory conditions and dry skin [265]. In 2014, Oláh and colleagues explored the effects of CBD on human sebaceous gland function and discovered that CBD exerts sebostatic and anti-inflammatory effects on human sebocytes. That is, CBD was shown to have lipostatic action and even decreased sebocyte proliferation. In this same study, CBD was able to inhibit pro-acne agents, such as arachidonic acid (AA), a combination of linoleic acid and testosterone (LA-T), AEA, 2-arachidonylglycerol, that induced excessive lipid synthesis in human sebocytes, leading to acne [266].
Although current scientific is limited, existing evidence suggests that CBD has a positive safety profile in dermatology. Anecdotal evidence also suggests that CBD may also help with anti-aging/wrinkles. This may be attributed to its antioxidant activity. CBD may also help with the natural healing process for open sores caused by dried and cracked skin.

5.2. Psoriasis

Psoriasis is a chronic hyperproliferative, inflammatory skin disease characterized by up-regulation of the keratins K6 and K16 [267]. Psoriasis is also accompanied by increased keratinocyte proliferation and differentiation [268], that is the result of dysregulation of Th1 and Th17 immune cells in the skin, T-cell infiltration, neutrophil infiltration, and activation of dendritic cells and macrophages [243,269]. This suggests that, as cannabinoids regulate Th1 and Th17 immune cells in the skin, the ECS might be a promising therapeutic target for psoriasis [270].
The endocannabinoid AEA, and the CB1R-specific agonist, arachidonoyl-chloro-ethanolamide (ACEA) are also shown to inhibit epidermal differentiation and the proliferation of epidermal keratinocytes (immature skin cells) [267,271] via downregulation of the expression of keratins K6 and K16 in vitro and in vivo [271]. In immortalized human keratinocytes (HaCaT) and normal human epidermal keratinocytes (NHEK), AEA demonstrated inhibition of cornified envelopes, characteristic of keratinocyte differentiation [267]. The anti-inflammatory properties of AEA may also be due to its ability to inhibit cytokines produced by keratinocytes [272].
These immature skin cells are characteristic of psoriasis [267,273]. This mechanism of action is via the activation of the CB1R, which inhibits human hair growth and decreases proliferation of epidermal keratinocytes [267].

5.3. Eczema

Eczema is a skin condition characterized by patches of itchy, cracked, rough, and inflamed skin, typically caused by allergens, microbes, extreme temperatures, hormones, stress, dietary intake, or irritants [274]. The anti-inflammatory, anti-pruritic, anti-itching, pro-neoplastic, moisturizing, and anti-oxidant properties of C. sativa L., particularly CBD, has made medical cannabis a promising and safe alternative to traditional dermatological drugs [259,275,276,277].
In a study by Maghfour and colleagues, researchers investigated the efficacy of topicsal CBD in the treatment of inflammatory skin disorders such as eczema [278]. Using the Patient Oriented Eczema Measure (POEM) and the Quality-of-Life Hand Eczema Questionnaire (QOLHEQ), subjects self-reported a significant reduction in eczema severity, reduction in the psychosocial burden of eczema, reduction in the emotional burden of eczema, decreased itching, and overall improvement of eczema [278].

5.4. Fibrotic Skin Diseases

Systemic scleroderma (simply “sclerosis”/“sclero” = hard; “derma” = skin) is a rare, chronic, autoimmune rheumatic disease characterized by a connective tissue disorder that causes the skin and connective tissues to harden and tighten, and may also affect surrounding muscles, blood vessels, heart, lungs, kidneys, and the digestive tract [279]. A number of factors may cause sclerosis, including an attack of one’s connective tissues by one’s own immune system (“an autoimmune attack”), drugs and certain medications, microbes, and genetics [279]. The endocannabinoid has been implicated in the pathogenesis of dermal fibrosis (scleroderma) [280] via the cannabinoid receptor CB2R. In a CB2R-deficient murine model of bleomycin-induced fibrosis, selective agonists and antagonists of CB2R were administered and evaluated for their effect on the dermal thickness and number of infiltrating leukocytes in lesional skin [280]. In comparison to wildtype mice with CB2R (CB2R(+/+)), mice deficient in CB2R (CB2R(−/−) were more sensitive to bleomycin-induced dermal fibrosis, and demonstrated increased dermal thickness [280]. The CB2R antagonist AM-630 increased dermal thickness and leukocyte infiltration in lesional skin, whereas CB2R agonist JWH-133 reduced leukocyte infiltration and dermal thickening [280].
Δ9-THC is also suggested to have anti-fibrotic events in a murine model via interaction with the CB1R, possibly by medication of leukocyte infiltration [281]. This was confirmed with CB1R-deficient (CB1R(−/−)) mice that demonstrated resistance to/protection from bleomycin-induced dermal fibrosis, with reduced dermal thickening, myofibroblast counts, and hydroxyproline content [281]. On the other hand, ACEA-induced CB1R activation resulted in increased fibrotic thickening to bleomycin and increased leukocyte infiltration [281]. It should be noted that in a TSK-1 mouse model, CB1R knockout (via FAAH inhibition) did not prevent fibrosis [281], and increased levels of cannabinoids were able to induce fibrosis via CB1R [243].
As CBD interacts primarily with the CB2R, CBD may be a good candidate for treatment of sclerosis, while as Δ9-THC interacts with mesenchymal cells and immune cells via CB1R and CB2R, Δ9-THC may be a good candidate for the treatment of systemic sclerosis [281]. The PPARγ receptor may also be a potential target for treating bleomycin-induced scleroderma [242]. VCE-004.8, a non-thiophilic and chemically stable derivative of the CBD quinol and a dual agonist of PPARγ and CB2R, showed promising anti-fibrotic efficacy in a murine model of bleomycin-induced scleroderma, and demonstrated reduction in dermal thickness, reduction in blood vessels collagen accumulation, inhibition of mast cell degranulation, inhibition of macrophage infiltration in the skin, inhibition of TGFβ-induced Col1A2 gene transcription and collagen synthesis, and inhibition of TGFβ–mediated myofibroblast differentiation and wound-healing activity [242]. The expression of many genes linked to fibrosis was also shown to be downregulated by VCE-004.8 [242].
A synthetic cannabinoid, WIN55,212-2, administered 1 mg/kg/day, demonstrated complete prevention of bleomycin-induced scleroderma in a murine model, while also downregulating markers of fibroblast activation such as including α smooth muscle actin and the profibrotic cytokines transforming growth factor (TGF)β, connective tissue growth factor (CTGF) and platelet-derived growth factor (PDGF)-BB [282].

6. Eating Disorders

The ECS has also been implicated in normal appetite control, determination of appetitive value, weight regulation and obesity [283], as confirmed by cannabimimetic drugs that interfere with the ECS and thus influence obesity [284]. Anecdotal evidence has long confirmed that C. sativa L. will likely cause “munchies” after smoking. On the same tangent, Δ9-THC, AEA, and 2-AG have been implicated in appetitive processing [283,285,286,287,288]. It is on this basis that synthetic THC drugs such as Dronabinol® and Nabilone® have been designed to treat chemotherapy-associated nausea and vomiting, and anorexia in cancer (and HIV/AIDS patients) patients.
In rodent models, Δ9-THCV, has been implicated in the clinical management of obesity and it has demonstrated the ability to decrease appetite, up-regulate energy metabolism and increase satiety [101]. SR141716A ((N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-me thyl-1H-pyrazole-3-carboxamide hydrochloride)), a potent and selective antagonist of the brain cannabinoid receptor CB1R, widely expressed in the brain [289], has demonstrated the ability to influence ingestive behaviours [290], and suppress the food intake of a very highly palatable cane-sugar mixture in marmosets [291]. SR141716A has also demonstrated the ability to modulate, by dose, motivation, and locomotor activity (“work”) to consume alcoholic beverages [292]. This implicates SR141716A as a potential to treat alcoholism [292]. Cannabinoid CB1R agonist CP 55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hyd roxypropyl)cyclohexanol) has also been shown to stimulate an appetite for palatable beverages [293].
Implication of the ECS in appetite provides some explanation for the crave (“munchies”) ravenous eating that often accompanies the smoking of the C. sativa L. plant. On the same tangent, Δ9-THC has been reported to have hyperphagic properties; however, this is inhibited by CBD [294].

Anorexia Nervosa

Anorexia is a potentially life-threatening psychological and eating disorder characterized by a distorted perception of body type, body shape/proportion, and body weight that often leads to depression, intense fear of weight gain, self-starvation, and extreme weight loss. A significant number of morbidity cases in cancer patients is often caused by anorexia. Eating disorders may be due to an impairment in endocannabinoid signalling [295] as evidenced by an upregulation of CB1R mRNA in the blood of patients with anorexia nervosa and bulimia nervosa [295], and significant reduction in body weight loss and running wheel activity in an activity-based anorexia (ABA) rodent model after administration of CB1R/CB2R agonist Δ9-THC [296,297] and the synthetic CB1R/CB2R agonist, CP-55,940 [296].
Δ9-THC is a known orexigenic (appetite stimulant), as confirmed by thousands of years of anecdotal evidence and modern-day clinical studies. Increased eating leads to increased rate of weight gain, which ultimately combats cachexia. CBD is also a known orexigenic agent. A 2008 study by Costiniuk and colleagues evaluated and reported the efficacy of oral cannabinoid-containing medications (OCs) for the management of interferon and ribavirin-induced anorexia, nausea, and weight loss in patients with chronic hepatitis C virus [298]. The mechanism of action of antiemetic and antinauseant activity of both Δ9-THC and CBD is unclear, but may be due to a direct effect on gastrointestinal function, central antiemetic properties, and/or psychological changes [237].

7. HIV/AIDS-Related Disorders

CBD is used to alleviate the wasting syndrome associated with HIV and AIDS [299]. It is used as an antiemetic and orexigenic agent (appetite stimulant) and may generally improve the overall quality of life of an HIV/AIDS patient. Both anecdotal and clinical evidence suggest that CBD in HIV/AIDS patients may improve appetite, reduce nausea and vomiting, increase caloric intake, promote weight gain, improve memory and dexterity, improve mood, and mitigate the negative side effects of current anti-retroviral [299] and therapeutic agents. In terms of disease progression (morbidity) and delaying the likelihood death from HIV/AIDS, current studies show that CBD is not effective [299].
Δ9-THC may also be used as an antiemetic and orexigenic agent (appetite stimulant) and may generally improve the overall quality of life of an HIV/AIDS patient, and ultimately alleviate the wasting syndrome associated with HIV and AIDS. Dronabinol®, a synthetic, Δ9-THC product approved by the FDA in 1985, is used to treat anorexia and weight-loss in HIV/AIDS patients.

8. Cannabinoids for the Treatment of Hepatitis B Virus

Liver disease, in general, is a major global health burden. Viral hepatitis is a disease of the liver characterized by liver inflammation and damage as a result of viral infection. Viral hepatitis is commonly caused by one of five hepatotropic viruses (hepatitis A, B, C, D, and E), but may be caused by other viruses such as the herpes simplex virus (HSV), yellow fever virus (YFV), cytomegalovirus (CMV), and Epstein–Barr virus (EBV). Hep A, Hep B, and Hep C are the most common causes of viral hepatitis. Hep A and Hep E are spread by the faecal–oral route, that is, via contaminated food or water. Hep B, Hep C, and Hep D are spread through blood transfusion. There is evidence that these may also be spread sexually.
Hepatitis may also be caused by other types of micro-organisms, including bacteria, fungi, and even parasites, non-infectious agents such as drugs and alcohol, and other metabolic and autoimmune diseases [300]. Hepatitis infections may either be acute (short-term), where the body will be able to resolve the infection, or chronic (long-term), where the body is unable to resolve the infection, resulting in liver failure, liver cirrhosis, and liver cancer.
In a 2017 in vitro study by Lowe and colleagues, CBD was shown to have inhibitory effects against Viral Hepatitis C (HBC) but not Viral Hepatitis B (HBV). In a dose–response assay, at a single concentration of 10 µm, CBD was able to dose-dependently inhibit HCV replication by 86.4% [301]. CBD also seems to have therapeutic efficacy against autoimmune/non-viral hepatitis [301]. CBD shows in vivo activity through its interaction with the CB2R. This interaction inhibits the pathogenesis of autoimmune hepatitis by inducing the apoptosis of thymocytes and splenocytes. This, in turn, inhibits T-cells and macrophages attacking the liver, thereby inhibiting the release of pro-inflammatory cytokines [301].
Myeloid-derived suppressor cells (MDSCs) are responsible for regulating the immune system by suppressing T-cell function and inhibiting liver inflammation. Through interaction TRPV1 receptor, CBD is shown to activate MDSCs, thereby inhibiting inflammation and hepatitis in a murine model [302]. In a concanavalin A model of acute hepatitis in mice, Hegde and colleagues report that CBD was able to reduce ConA-induced inflammation by inhibiting the production and release of various pro-inflammatory cytokines, protecting the mice from acute liver injury [302]. CBD was also shown to mitigate liver fibrosis, a characteristic scarring of healthy liver tissue, that is a result of untreated viral hepatitis. In said study, Lowe and colleagues discovered that CBD inhibited activated hepatic stellate cells (HSCs) that play a role in the development and progression of liver fibrosis.

9. Cannabinoids Used to Modulate the ECS in Cannabinoid-Research

The role of the ECS in the development of various diseases, multiple ECS targets and multiple types of cannabinergic, cannabimimetic, and cannabinoid-based lead-compounds have been established and studied extensively. Refer to Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12 and Table 13 for some types of compounds that may modulate the ECS in the treatment of various disorders and diseases.
Regarding the use of central CB1R agonists [136], examples of CB1R agonists are listed in Table 5 below.
Table 5. Examples of CB1R agonists and their therapeutic windows.
Table 5. Examples of CB1R agonists and their therapeutic windows.
Central CB1R AgonistsBiological Effect(s) and/or Mechanism of ActionReference
i.Δ9-THC (partial agonist)
ii.WIN55,212-2 (also a CB2R agonist)
Decreases the severity of seizures in rodents
Prevents anhedonia in rodents
Anti-cancer properties
iii.ACPA (Arachidonylcyclopropylamide)
Anti-nociceptive in mice
The use of allosteric modulators of CB1R. Examples of CB1R allosteric modulators are listed in Table 6 below.
Table 6. Examples of CB1R allosteric modulators and their therapeutic windows.
Table 6. Examples of CB1R allosteric modulators and their therapeutic windows.
CB1R Allosteric Modulators Biological Effect(s) and/or Mechanism of ActionReference
i.GAT211 (positive allosteric modulators (PAM)(racemic))
Anti-nociceptive/analgesic in models of neuropathic and/or inflammatory pain
ii.GAT228 (R-enantiomer)
May improve Huntington’s disease (HD) symptomology
Reduces corneal inflammation and ocular pain.
iii.GAT229 (S-enantiomer)
May improve Huntington’s disease (HD) symptomology
iv.ORG27569 (negative allosteric modulator (NAM))
Reduces cocaine and methamphetamine seeking behaviour in rat model
Hypophagic, and thus may have use in the treatment of obesity
Peripheral CB1R agonists do not cross the blood–brain barrier (BBB), and are suggested to circumvent the psychotropic effects and other adverse side-effects such as cardiovascular and immune perturbations produced by CB1R activation. Examples of peripheral CB1R agonists (aka peripherally restricted cannabinoid 1 receptor (PRCB)) are listed in Table 7.
Table 7. Examples of peripheral CB1R agonists (aka peripherally restricted cannabinoid 1 receptor (PRCB)) and their therapeutic window.
Table 7. Examples of peripheral CB1R agonists (aka peripherally restricted cannabinoid 1 receptor (PRCB)) and their therapeutic window.
Peripheral CB1R Agonists
(Aka Peripherally Restricted Cannabinoid 1 Receptor (PRCB))
Biological Effect(s) and/or Mechanism of ActionReference
i.4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (“PrNMI” aka 2-“5u”
Anti-allodynic properties (suppresses CIPN* mechanical and cold allodynia in a dose-dependent way). *Chemotherapy-induced peripheral neuropathy (CIPN)
Alleviation of cancer-induced bone pain (CIBP)
Neuropathic pain
ii.4-{2-[(1E)-1-[(4-Methoxynaphthalen-1-yl)methylidene]-1H-inden-3-yl]ethyl}morpholine (2-5j)
Anti-allodynic properties (suppresses mechanical allodynia symptoms
iii.2-5j (2-5j)
Anti-allodynic properties (suppresses mechanical allodynia symptoms
Peripheral CB2R agonist is used to circumvent the psychotropic effects and other adverse side-effects such as cardiovascular and immune perturbations produced by CB1R activation [136]. Examples of peripheral CB2R agonists are listed in Table 8 below.
Table 8. Examples of peripheral CB2R agonists and their therapeutic windows.
Table 8. Examples of peripheral CB2R agonists and their therapeutic windows.
CB2R AgonistsBiological Effect(s) and/or Mechanism of ActionReference
i.AM1241 (University of Connecticut)
Reduction in bone resorption (loss) in NCTC-2472 bone sarcoma cell line
Attenuation of spontaneous and evoked pain in tumour-bearing limb
Reduction in cancer-induced pain
Neuropathic pain
Analgesic in murine model
iii.HU-308 (Hebrew University)
Neuropathic pain
iv.GSK554418AAcute/chronic pain[356]
v.GW842166XInflammatory pain[357]
Suppresses neuropathic pain
Decreased severity in experimental cystitis
Antiallodynic effects in animals on retrovirus infection-induced neuropathic pain
Modulation of HIV-1-associated neurocognitive disorders (HAND)
Antiallodynic effects in animals on retrovirus infection-induced neuropathic pain
Attenuates bone cancer pain
Antiallodynic effects in animals on retrovirus infection-induced neuropathic pain
Alleviates fibrosis in murine model
Anti-proliferative and anti-angiogenic in non-small lung cancer cells (A549) and human umbilical vein endothelial cells.
Cardioprotective against ischemia/reperfusion-induced apoptosis
Reduces neurodegeneration, neuroinflammation, and spatial memory impairment in Alzheimer’s disease model
Regarding the use of CB1R antagonists [136], of note is that side effects of CB1R antagonism may include neuropsychiatric sequalae (e.g., anhedonia and anxiety), pain, hyperalgesia, hypertension, and pro-convulsive effects [136,371]. Examples of CB1R antagonists are listed in Table 9 below.
Table 9. Examples of peripheral CB1R antagonists and their therapeutic windows.
Table 9. Examples of peripheral CB1R antagonists and their therapeutic windows.
CB1R AntagonistsBiological Effect(s) and/or Mechanism of ActionReference
i.SR141716A (Rimonabant)—the first developed CB1R antagonist.
Now discontinued due to unwanted side effects such as depression, anxiety, and suicidal thoughts.
Obesity possibly via inducing loss of appetite or increase in metabolic rate (loss of fat mass) via interaction with corticotropin-releasing hormone (CRH), a known anorexigenic
Rimonabant inhibits CB1R activation which is responsible for lipogenesis
Tobacco addiction
Inhibition of cannabinoid-induced heroin-seeking behaviour in rats

Attenuates mechanical allodynia
Attenuates thermal hyperalgesia
Anti-depressive effects
Improves recognition memory in murine model
Anti-cancer/modulation of tumour growth in mice
iii.SLV-326 (Solvay)
May have anti-obesity, anti-addiction, anti-depressant, and anxiolytic effects
iv.LY320135 (Lilly)
May have anti-obesity, anti-addiction, anti-depressant, and anxiolytic effects
Neutral Antagonists
Prevents opioid addiction (self-administration) in rodent model
Prevents relapse to nicotine-seeking behaviour in rats
Anti-obesity via suppression of appetite
Regulate body weight in rats
vi.O-2654 (Organix)
May have anti-obesity, anti-addiction, anti-depressant, and anxiolytic effects
vii.AM5171 (University of Connecticut)
May have anti-obesity, anti-addiction, anti-depressant, and anxiolytic effects
Examples of endocannabinoid-like compounds (fatty-acid ethanolamides) that interact with receptors outside of CB1R and CB2R [136,383] are listed in Table 10.
Table 10. Endocannabinoid-like compounds (fatty-acid ethanolamides) that interact with receptors outside of CB1R and CB2R.
Table 10. Endocannabinoid-like compounds (fatty-acid ethanolamides) that interact with receptors outside of CB1R and CB2R.
Endocannabinoid-Like Compounds (Fatty-Acid Ethanolamides)Biological Effect(s) and/or Mechanism of ActionReference
i.OEA (an endogenous PPAR-α agonist)
Weight reduction

Via binding to peroxisome proliferators-activate receptor-α (PPAR- α)
ii.Palmitoylethanolamide (PEA)
iii.N-oleoyl-ethanolamide May act as an alternative substrate for FAAH, and in doing so, inhibit the degradation of AEA[383,384]
iv.N-linoleoyl-ethanolamideMay act as an alternative substrate for FAAH, and in doing so, inhibit the degradation of AEA[383,384]
v.N-arachidonoyl-glycineMay act as an alternative substrate for FAAH, and in doing so, inhibit the degradation of AEA[384,385,386]
vi.N-acyl-taurineMay act as an alternative substrate for FAAH, and in doing so, inhibit the degradation of AEA[383,384,387]
vii.N-palmitoyl-ethanolamide Reduced expression of FAAH[384,388]
Synthetic cannabinergic agonists include CP-55940 (Pfizer), HU-210 (Hebrew University), WIN55212-2 (Winthrop), a cannabinoid agonist by Novartis for neuropathic and inflammatory pain treatment, BAY-387271 (Bayer) for stroke, and AM356 [136]. Refer to Table 11 for examples of synthetic cannabinergic agonists.
Table 11. Synthetic cannabinergic agonists.
Table 11. Synthetic cannabinergic agonists.
Synthetic Cannabinergic AgonistsBiological Effect(s) and/or Mechanism Of ActionReference
i.WIN55212-2 (Winthrop)
A mixed R/CB2R agonist.
Penetrates the CNS.
Inhibits heroin-seeking behaviour in rats
Attenuates neurological damage and reduces infarct size in artery occlusion in rats
Reduction in glial damage after hypoxic-ischemic brain injury in preterm lambs
Antinociceptive activity in rat pain models
ii.CP-55940 (Pfizer)
Inhibits heroin-seeking behaviour in rats
iii.URB-597 (aka KDS-4103) (targets FAAH)
Anxiety, cannabis-dependence, and hyperalgesia
iv.PF-04457845 (Pfizer—targets FAAH)Pain disorders (including osteoarthritis) [342]
v.V158866 (Pfizer—targets FAAG)Pain disorders (including osteoarthritis)[6]
Drugs that inhibit the cellular uptake and/metabolism of cannabinoids such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) [184,392] may have benefits against diseases/disorders such as cancer, anxiety, neuropathic path, and inflammatory bowel disease [393]. Examples of drugs that inhibit the cellular uptake and/metabolism of cannabinoids are listed in Table 12.
Table 12. Drugs that inhibit the cellular uptake and/metabolism of cannabinoids such as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).
Table 12. Drugs that inhibit the cellular uptake and/metabolism of cannabinoids such as inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).
Drugs That Inhibit the Cellular Uptake of CannabinoidsMechanism of ActionReference
i.CBD Inhibition of FAAH[394]
ii.LY-2183240Inhibition of FAAH[395]
iii.V-158866 (Vernalis)Inhibition of FAAH[396]
iv.VER-156084 (Vernalis)Inhibition of FAAH[397,398]
v.URB597 (KDS-4103, Kadmus Pharmaceuticals),Inhibition of FAAH[399,400]
vi.PF750 and PF-655Inhibition of FAAH[393]
Examples of drugs that inhibit the deactivation of the ECS [136] or drugs that inhibit endocannabinoid metabolism [57] are listed in Table 13.
Table 13. Drugs that inhibit endocannabinoid metabolism and the deactivation of the ECS.
Table 13. Drugs that inhibit endocannabinoid metabolism and the deactivation of the ECS.
Drugs That Inhibit the DeactivationBiological Effect(s) and/or Mechanism of ActionReference
i.AM404Blocks endocannabinoid transport[136]
ii.OMDM-8Blocks endocannabinoid transport[136]
iii.AM1172 (University of Connecticut/University of California)Blocks endocannabinoid transport[136]
iv.FAAH (fatty acid amide hydrolase)Deactivates/degrades AEA [136]
v.MAGL (monoacylglycerol)Deactivates/degrades 2-AG [136]

10. Conclusions and Future Direction

In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development. The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases (and the dysregulation thereof), all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS—beneficial in the treatment number of diseases. Further studies are required to investigate the molecular mechanisms of action of the ECS-signalling pathways involved in the aforementioned diseases.
The ECS is a complex molecular/biological system of multiple components that also play roles in other systems and physiological processes outside of the ECS. Thus, when targeting and modulating the expression of the ECS components, scientists and drug developers should consider the consequences on other physiological systems, and if the disruption of one component or pathway of the ECS will result in unwanted consequences in other areas of the ECS, and possibly adverse side effects.
The findings of this review suggest that there are multiple cannabinergic secondary metabolites of C. sativa L. that may have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases. These may include single-molecule drugs or whole-plant extracts. Such drugs have already demonstrated promise in palliative care. Now that potential lead compounds from C. sativa L. have been identified, there are several following steps in the drug development process that involve validation of this potential, pre-clinical research, synthesis of the lead compound into an optimal form for delivery into the body, and ultimately clinical research. Other factors, such as benefits, efficacies of these lead compounds, mechanisms of action, risks, adverse effects, drug interactions, toxicities, possible synergies between other compounds, and cellular responses to other cannabinergic, cannabimimetic, and/or cannabinoid-based therapeutic drugs and traditional, mainstay drugs such as chemotherapeutics, should also be investigated.
US Food and Drug Administration (FDA)-approval of such cannabinoid-based pharmaceuticals and substantiated clinical decision-making are strictly dependent upon the elucidation of the aforementioned factors and the generation of more evidence-based data.

Author Contributions

Conceptualization, H.L. and B.S., Writing, review and editing: H.L., B.S., N.T., J.B. and W.N. All authors have read and agreed to the published version of the manuscript.


This research received no external funding.

Institutional Review Board Statement

Not applicable. This study did not involve humans or animals.

Informed Consent Statement

Not applicable. This study did not involve humans or animals.

Data Availability Statement

Data sharing is not applicable to this article. No new data were created or analysed in this study.

Conflicts of Interest

The authors declare no conflict of interest.


2-AG 2-arachidonoylglycerol
AEAN-arachidonoyl ethanolamide
CB1RCannabinoid receptor type 1
CB2RCannabinoid receptor type 2
FDA Food & Drug Administration
NSAIDsNonsteroidal anti-inflammatory drugs
Δ9-THC Δ9-Tetrahydrocannabinol
Δ9-THCA Δ9-tetrahydrocannabinolic acid
ATAnandamide transporter
CBGMCannabigerol Monoethyl Ether
COX2cyclooxygenase subtype 2
ERKExtracellular-regulated kinase
FAAHFatty acid amide hydrolase
GCPRG-Coupled Protein Receptor
PPARγPeroxisome proliferator-activated receptor γ
TRVP1Transient receptor potential vanilloid type 1
MAPMitogen-activated protein kinase
SR141716AN-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride
SR144528N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide
DAGL Diacylglycerol lipase
MAGLMonoacylglycerol lipase
NAPE-PLDN-acetyl-phosphatidyl-ethanolamine-hydrolyzing phospholipase D
FAAHFatty acid amide hydrolase
NAAHN-acylethanolamine acid amide hydrolase
ABHD6Alpha/beta-Hydrolase domain containing 6
ABHD12Alpha/beta-Hydrolase domain containing 12
GABAGamma aminobutyric acid
GPR55G-protein coupled receptor 55
GPR18G-protein coupled receptor 18
GPR119G-protein coupled receptor 119
FABSFatty Acid Binding Protein
HSP70s70 kilodalton heat shock proteins
AMTAnandamide membrane transporter
EMTEndocannabinoid membrane transporter


  1. Kalant, H. Medicinal use of cannabis: History and current status. Pain Res. Manag. 2001, 6, 80–91. [Google Scholar] [CrossRef][Green Version]
  2. Devane, W.A.; Dysarz, F.A., 3rd; Johnson, M.R.; Melvin, L.S.; Howlett, A.C. Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol. 1988, 34, 605–613. [Google Scholar]
  3. Di Marzo, V.; Bifulco, M.; Petrocellis, L. The endocannabinoid system and its therapeutic exploitation. Nat. Rev. Drug Discov. 2004, 3, 771–784. [Google Scholar] [CrossRef]
  4. Aizpurua-Olaizola, O.; Elezgarai, I.; Rico-Barrio, I.; Zarandona, I.; Etxebarria, N.; Usobiaga, A. Targeting the endocannabinoid system: Future therapeutic strategies. Drug Discov. Today 2017, 22, 105–110. [Google Scholar] [CrossRef] [PubMed]
  5. Salzet, M.; Stefano, G.B. The endocannabinoid system in invertebrates. Prostaglandins Leukot. Essent. Fat Acids 2002, 66, 353–361. [Google Scholar] [CrossRef][Green Version]
  6. Battista, N.; Di Tommaso, M.; Bari, M.; Maccarrone, M. The endocannabinoid system: An overview. Front. Behav. Neurosci. 2012, 6, 9. [Google Scholar] [CrossRef] [PubMed][Green Version]
  7. Pacher, P.; Bátkai, S.; Kunos, G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacol. Rev. 2006, 58, 389–462. [Google Scholar] [CrossRef][Green Version]
  8. Eid, B.G. Cannabinoids for Treating Cardiovascular Disorders: Putting Together a Complex Puzzle. J. Microsc. Ultrastruct. 2018, 6, 171–176. [Google Scholar] [CrossRef] [PubMed]
  9. Mendizábal, V.E.; Adler-Graschinsky, E. Cannabinoids as therapeutic agents in cardiovascular disease: A tale of passions and illusions. Br. J. Pharmacol. 2007, 151, 427–440. [Google Scholar] [CrossRef]
  10. Di Marzo, V. Targeting the endocannabinoid system: To enhance or reduce? Nat. Rev. Drug Discov. 2008, 7, 438–455. [Google Scholar] [CrossRef]
  11. Piomelli, D. The endocannabinoid system: A drug discovery perspective. Curr. Opin. Investig. Drugs 2005, 6, 672–679. [Google Scholar] [PubMed]
  12. Di Marzo, V. The endocannabinoid system: Its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation. Pharmacol. Res. 2009, 60, 77–84. [Google Scholar] [CrossRef]
  13. Munro, S.; Thomas, K.L.; Abu-Shaar, M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993, 365, 61–65. [Google Scholar] [CrossRef]
  14. Yang, F.; Zheng, J. Understand spiciness: Mechanism of TRPV1 channel activation by capsaicin. Protein Cell 2017, 8, 169–177. [Google Scholar] [CrossRef] [PubMed][Green Version]
  15. O’Sullivan, S.E. An update on PPAR activation by cannabinoids. Br. J. Pharmacol. 2016, 173, 1899–1910. [Google Scholar] [CrossRef] [PubMed][Green Version]
  16. Dariš, B.; Tancer Verboten, M.; Knez, Ž.; Ferk, P. Cannabinoids in cancer treatment: Therapeutic potential and legislation. Bosn. J. Basic Med. Sci. 2019, 19, 14–23. [Google Scholar] [CrossRef]
  17. Fezza, F.; Bari, M.; Florio, R.; Talamonti, E.; Feole, M.; Maccarrone, M. Endocannabinoids, related compounds and their metabolic routes. Molecules 2014, 19, 17078–17106. [Google Scholar] [CrossRef]
  18. Murataeva, N.; Straiker, A.; Mackie, K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br. J. Pharmacol. 2014, 171, 1379–1391. [Google Scholar] [CrossRef] [PubMed][Green Version]
  19. Maccarrone, M. Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years. Front. Mol. Neurosci. 2017, 10, 166. [Google Scholar] [CrossRef] [PubMed][Green Version]
  20. McHugh, D. GPR18 in microglia: Implications for the CNS and endocannabinoid system signalling. Br. J. Pharmacol. 2012, 167, 1575–1582. [Google Scholar] [CrossRef] [PubMed][Green Version]
  21. Ryberg, E.; Larsson, N.; Sjögren, S.; Hjorth, S.; Hermansson, N.O.; Leonova, J.; Elebring, T.; Nilsson, K.; Drmota, T.; Greasley, P.J. The orphan receptor GPR55 is a novel cannabinoid receptor. Br. J. Pharmacol. 2007, 152, 1092–1101. [Google Scholar] [CrossRef]
  22. Moriconi, A.; Cerbara, I.; Maccarrone, M.; Topai, A. GPR55: Current knowledge and future perspectives of a purported “Type-3” cannabinoid receptor. Curr. Med. Chem. 2010, 17, 1411–1429. [Google Scholar] [CrossRef] [PubMed]
  23. Godlewski, G.; Offertáler, L.; Wagner, J.A.; Kunos, G. Receptors for acylethanolamides-GPR55 and GPR119. Prostaglandins Other Lipid Mediat. 2009, 89, 105–111. [Google Scholar] [CrossRef][Green Version]
  24. Muller, C.; Morales, P.; Reggio, P.H. Cannabinoid Ligands Targeting TRP Channels. Front. Mol. Neurosci. 2019, 11, 487. [Google Scholar] [CrossRef]
  25. Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. Identification of intracellular carriers for the endocannabinoid anandamide. Proc. Natl. Acad. Sci. USA 2009, 106, 6375–6380. [Google Scholar] [CrossRef][Green Version]
  26. Deutsch, D.G. A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs). Front. Pharmacol. 2016, 7, 370. [Google Scholar] [CrossRef] [PubMed]
  27. Oddi, S.; Fezza, F.; Pasquariello, N.; D’Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-Agrò, A.; Maccarrone, M. Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins. Chem. Biol. 2009, 16, 624–632. [Google Scholar] [CrossRef]
  28. Fu, J.; Bottegoni, G.; Sasso, O.; Bertorelli, R.; Rocchia, W.; Masetti, M.; Guijarro, A.; Lodola, A.; Armirotti, A.; Garau, G.; et al. A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat. Neurosci. 2011, 15, 64–69. [Google Scholar] [CrossRef] [PubMed][Green Version]
  29. Nicolussi, S.; Gertsch, J. Endocannabinoid transport revisited. Vitam. Horm. 2015, 98, 441–485. [Google Scholar] [CrossRef]
  30. Chicca, A.; Marazzi, J.; Nicolussi, S.; Gertsch, J. Evidence for bidirectional endocannabinoid transport across cell membranes. J. Biol. Chem. 2012, 287, 34660–34682. [Google Scholar] [CrossRef][Green Version]
  31. Blessing, E.M.; Steenkamp, M.M.; Manzanares, J.; Marmar, C.R. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurother. J. Am. Soc. Exp. Neurother. 2015, 12, 825–836. [Google Scholar] [CrossRef] [PubMed]
  32. Parsons, L.H.; Hurd, Y.L. Endocannabinoid signalling in reward and addiction. Nat. Rev. Neurosci. 2015, 16, 579–594. [Google Scholar] [CrossRef] [PubMed][Green Version]
  33. Stampanoni Bassi, M.; Gilio, L.; Maffei, P.; Dolcetti, E.; Bruno, A.; Buttari, F.; Centonze, D.; Iezzi, E. Exploiting the Multifaceted Effects of Cannabinoids on Mood to Boost Their Therapeutic Use Against Anxiety and Depression. Front. Mol. Neurosci. 2018, 11, 424. [Google Scholar] [CrossRef] [PubMed][Green Version]
  34. Koob, G.F.; Volkow, N.D. Neurocircuitry of addiction. Neuropsychopharmacology 2010, 35, 217–238. [Google Scholar] [CrossRef][Green Version]
  35. Glass, M.; Dragunow, M.; Faull, R.L. Cannabinoid receptors in the human brain: A detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 1997, 77, 299–318. [Google Scholar] [CrossRef]
  36. Barrero, F.J.; Ampuero, I.; Morales, B.; Vives, F.; de Dios Luna Del Castillo, J.; Hoenicka, J.; Yebenes, J.G. Depression in Parkinson’s disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1). Pharmacogenom. J. 2005, 5, 135–141. [Google Scholar] [CrossRef]
  37. Domschke, K.; Dannlowski, U.; Ohrmann, P.; Lawford, B.; Bauer, J.; Kugel, H.; Heindel, W.; Young, R.; Morris, P.; Arolt, V.; et al. Cannabinoid receptor 1 (CNR1) gene: Impact on antidepressant treatment response and emotion processing in major depression. Eur. Neuropsychopharmacol. 2008, 18, 751–759. [Google Scholar] [CrossRef]
  38. Chen, X.; Williamson, V.S.; An, S.-S.; Hettema, J.M.; Aggen, S.H.; Neale, M.C.; Kendler, K.S. Cannabinoid receptor 1 gene association with nicotine dependence. Arch. Gen. Psychiatry 2008, 65, 816–824. [Google Scholar] [CrossRef]
  39. Marcos, M.; Pastor, I.; de la Calle, C.; Barrio-Real, L.; Laso, F.J.; González-Sarmiento, R. Cannabinoid receptor 1 gene is associated with alcohol dependence. Alcohol. Clin. Exp. Res. 2012, 36, 267–271. [Google Scholar] [CrossRef]
  40. Crippa, J.A.; Guimarães, F.S.; Campos, A.C.; Zuardi, A.W. Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age. Front. Immunol. 2018, 9, 2009. [Google Scholar] [CrossRef] [PubMed][Green Version]
  41. Papagianni, E.P.; Stevenson, C.W. Cannabinoid Regulation of Fear and Anxiety: An Update. Curr. Psychiatry Rep. 2019, 21, 38. [Google Scholar] [CrossRef][Green Version]
  42. Bergamaschi, M.M.; Queiroz, R.H.; Chagas, M.H.; de Oliveira, D.C.; De Martinis, B.S.; Kapczinski, F.; Quevedo, J.; Roesler, R.; Schröder, N.; Nardi, A.E.; et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology 2011, 36, 1219–1226. [Google Scholar] [CrossRef]
  43. Porter, B.E.; Jacobson, C. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy. Epilepsy Behav. E B 2013, 29, 574–577. [Google Scholar] [CrossRef][Green Version]
  44. Vučković, S.; Srebro, D.; Vujović, K.S.; Vučetić, Č.; Prostran, M. Cannabinoids and Pain: New Insights From Old Molecules. Front. Pharmacol. 2018, 9, 1259. [Google Scholar] [CrossRef] [PubMed][Green Version]
  45. Staton, P.C.; Hatcher, J.P.; Walker, D.J.; Morrison, A.D.; Shapland, E.M.; Hughes, J.P.; Chong, E.; Mander, P.K.; Green, P.J.; Billinton, A.; et al. The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. Pain 2008, 139, 225–236. [Google Scholar] [CrossRef]
  46. Huang, S.M.; Bisogno, T.; Petros, T.J.; Chang, S.Y.; Zavitsanos, P.A.; Zipkin, R.E.; Sivakumar, R.; Coop, A.; Maeda, D.Y.; De Petrocellis, L.; et al. Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain. J. Biol. Chem. 2001, 276, 42639–42644. [Google Scholar] [CrossRef] [PubMed][Green Version]
  47. Russo, E.B.; Burnett, A.; Hall, B.; Parker, K.K. Agonistic Properties of Cannabidiol at 5-HT1a Receptors. Neurochem. Res. 2005, 30, 1037–1043. [Google Scholar] [CrossRef] [PubMed]
  48. Scavone, J.L.; Sterling, R.C.; Van Bockstaele, E.J. Cannabinoid and opioid interactions: Implications for opiate dependence and withdrawal. Neuroscience 2013, 248, 637–654. [Google Scholar] [CrossRef][Green Version]
  49. De Gregorio, D.; McLaughlin, R.J.; Posa, L.; Ochoa-Sanchez, R.; Enns, J.; Lopez-Canul, M.; Aboud, M.; Maione, S.; Comai, S.; Gobbi, G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain 2019, 160, 136–150. [Google Scholar] [CrossRef] [PubMed]
  50. Horvath, G.; Kekesi, G.; Nagy, E.; Benedek, G. The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level. Pain 2008, 134, 277–284. [Google Scholar] [CrossRef]
  51. Aroke, E.N.; Powell-Roach, K.L.; Jaime-Lara, R.B.; Tesfaye, M.; Roy, A.; Jackson, P.; Joseph, P.V. Taste the Pain: The Role of TRP Channels in Pain and Taste Perception. Int. J. Mol. Sci. 2020, 21, 5929. [Google Scholar] [CrossRef]
  52. Anand, P.; Whiteside, G.; Fowler, C.J.; Hohmann, A.G. Targeting CB2 receptors and the endocannabinoid system for the treatment of pain. Brain Res. Rev. 2009, 60, 255–266. [Google Scholar] [CrossRef] [PubMed][Green Version]
  53. Hammell, D.C.; Zhang, L.P.; Ma, F.; Abshire, S.M.; McIlwrath, S.L.; Stinchcomb, A.L.; Westlund, K.N. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur. J. Pain 2016, 20, 936–948. [Google Scholar] [CrossRef] [PubMed]
  54. Rahn, E.J.; Hohmann, A.G. Cannabinoids as pharmacotherapies for neuropathic pain: From the bench to the bedside. Neurotherapeutics 2009, 6, 713–737. [Google Scholar] [CrossRef]
  55. Shohami, E.; Cohen-Yeshurun, A.; Magid, L.; Algali, M.; Mechoulam, R. Endocannabinoids and traumatic brain injury. Br. J. Pharmacol. 2011, 163, 1402–1410. [Google Scholar] [CrossRef] [PubMed][Green Version]
  56. Leimuranta, P.; Khiroug, L.; Giniatullin, R. Emerging Role of (Endo)Cannabinoids in Migraine. Front. Pharmacol. 2018, 9, 420. [Google Scholar] [CrossRef] [PubMed]
  57. Pertwee, R.G. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol. 2009, 156, 397–411. [Google Scholar] [CrossRef][Green Version]
  58. Yu, T.S.; Cheng, Z.H.; Li, L.Q.; Zhao, R.; Fan, Y.Y.; Du, Y.; Ma, W.X.; Guan, D.W. The cannabinoid receptor type 2 is time-dependently expressed during skeletal muscle wound healing in rats. Int. J. Leg. Med. 2010, 124, 397–404. [Google Scholar] [CrossRef] [PubMed]
  59. Parthvi, R.; Agrawal, A.; Khanijo, S.; Tsegaye, A.; Talwar, A. Acute Opiate Overdose: An Update on Management Strategies in Emergency Department and Critical Care Unit. Am. J. Ther. 2019, 26, e380–e387. [Google Scholar] [CrossRef]
  60. World Health Organization. Opioid Overdose. World Health Organization. 11 March 2021. Available online: (accessed on 5 August 2021).
  61. Lichtman, A.H.; Cook, S.A.; Martin, B.R. Investigation of brain sites mediating cannabinoid-induced antinociception in rats: Evidence supporting periaqueductal gray involvement. J. Pharmacol. Exp. Ther. 1996, 276, 585–593. [Google Scholar]
  62. Luo, C.; Kumamoto, E.; Furue, H.; Chen, J.; Yoshimura, M. Anandamide inhibits excitatory transmission to rat substantia gelatinosa neurones in a manner different from that of capsaicin. Neurosci. Lett. 2002, 321, 17–20. [Google Scholar] [CrossRef]
  63. Morisset, V.; Urban, L. Cannabinoid-induced presynaptic inhibition of glutamatergic EPSCs in substantia gelatinosa neurons of the rat spinal cord. J. Neurophysiol. 2001, 86, 40–48. [Google Scholar] [CrossRef]
  64. Farquhar-Smith, W.P.; Egertová, M.; Bradbury, E.J.; McMahon, S.B.; Rice, A.S.; Elphick, M.R. Cannabinoid CB(1) receptor expression in rat spinal cord. Mol. Cell. Neurosci. 2000, 15, 510–521. [Google Scholar] [CrossRef]
  65. Starowicz, K.; Malek, N.; Przewlocka, B. Cannabinoid receptors and pain. WIREs Membr. Transp. Signal. 2013, 2, 121–132. [Google Scholar] [CrossRef]
  66. Shah, A.; Hayes, C.J.; Lakkad, M.; Martin, B.C. Impact of Medical Marijuana Legalization on Opioid Use, Chronic Opioid Use, and High-risk Opioid Use. J. Gen. Intern. Med. 2019, 34, 1419–1426. [Google Scholar] [CrossRef][Green Version]
  67. Vyas, M.B.; LeBaron, V.T.; Gilson, A.M. The use of cannabis in response to the opioid crisis: A review of the literature. Nurs. Outlook 2018, 66, 56–65. [Google Scholar] [CrossRef]
  68. Vigil, J.M.; Stith, S.S.; Adams, I.M.; Reeve, A.P. Associations between medical cannabis and prescription opioid use in chronic pain patients: A preliminary cohort study. PLoS ONE 2017, 12, e0187795. [Google Scholar] [CrossRef] [PubMed][Green Version]
  69. Bulbul, A.; Mino, E.A.; Khorsand-Sahbaie, M.; Lentkowski, L. Opioid dose reduction and pain control with medical cannabis. J. Clin. Oncol. 2018, 36, 189. [Google Scholar] [CrossRef]
  70. Livingston, M.D.; Barnett, T.E.; Delcher, C.; Wagenaar, A.C. Recreational Cannabis Legalization and Opioid-Related Deaths in Colorado, 2000-2015. Am. J. Public Health 2017, 107, 1827–1829. [Google Scholar] [CrossRef] [PubMed]
  71. Shi, Y.; Liang, D.; Bao, Y.; An, R.; Wallace, M.S.; Grant, I. Recreational marijuana legalization and prescription opioids received by Medicaid enrollees. Drug Alcohol Depend. 2019, 194, 13–19. [Google Scholar] [CrossRef]
  72. Garín, J.; Pohl, R.V.; Smith, R.A. The Effect of Medical Cannabis Dispensaries on Opioid- and Heroin-Overdose Mortality. 19 June 2019. Available online: (accessed on 5 August 2021).
  73. Kropp Lopez, A.K.; Nichols, S.D.; Chung, D.Y.; Kaufman, D.E.; McCall, K.L.; Piper, B.J. Prescription Opioid Distribution after the Legalization of Recreational Marijuana in Colorado. Int. J. Environ. Res. Public Health 2020, 17, 3251. [Google Scholar] [CrossRef]
  74. McMichael, B.J.; Van Horn, R.L.; Viscusi, W.K. The impact of cannabis access laws on opioid prescribing. J. Health Econ. 2020, 69, 102273. [Google Scholar] [CrossRef] [PubMed]
  75. Powell, D.; Pacula, R.L.; Jacobson, M. Do medical marijuana laws reduce addictions and deaths related to pain killers? J. Health Econ. 2018, 58, 29–42. [Google Scholar] [CrossRef][Green Version]
  76. Chihuri, S.; Li, G. State marijuana laws and opioid overdose mortality. Inj. Epidemiol. 2019, 6, 38. [Google Scholar] [CrossRef][Green Version]
  77. Wen, H.; Hockenberry, J.M. Association of Medical and Adult-Use Marijuana Laws With Opioid Prescribing for Medicaid Enrollees. JAMA Intern. Med. 2018, 178, 673–679. [Google Scholar] [CrossRef] [PubMed][Green Version]
  78. Blake, D.K. Can Medical Marijuana be A Solution to The Opioid Epidemic? American Marijuana. 24 March 2020. Available online: (accessed on 7 August 2021).
  79. Raji, M.A.; Kuo, Y.F.; Adhikari, D.; Baillargeon, J.; Goodwin, J.S. Decline in opioid prescribing after federal rescheduling of hydrocodone products. Pharmacoepidemiol. Drug Saf. 2018, 27, 513–519. [Google Scholar] [CrossRef] [PubMed]
  80. Flexon, J.L.; Stolzenberg, L.; D’Alessio, S.J. The effect of cannabis laws on opioid use. Int. J. Drug Policy 2019, 74, 152–159. [Google Scholar] [CrossRef]
  81. Reddon, H.; DeBeck, K.; Socias, M.E.; Lake, S.; Dong, H.; Karamouzian, M.; Hayashi, K.; Kerr, T.; Milloy, M.-J. Frequent Cannabis Use and Cessation of Injection of Opioids, Vancouver, Canada, 2005–2018. Am. J. Public Health 2020, 110, 1553–1560. [Google Scholar] [CrossRef]
  82. Caldera, F.E. Medical cannibus as an alternative for opioids for chronic pain: A case report. SAGE Open Med. Case Rep. 2020, 8, 2050313X20907015. [Google Scholar] [CrossRef][Green Version]
  83. Cichewicz, D.L. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004, 74, 1317–1324. [Google Scholar] [CrossRef]
  84. Ishida, J.H.; Wong, P.O.; Cohen, B.E.; Vali, M.; Steigerwald, S.; Keyhani, S. Substitution of marijuana for opioids in a national survey of US adults. PLoS ONE 2019, 14, e0222577. [Google Scholar] [CrossRef]
  85. Okusanya, B.O.; Asaolu, I.O.; Ehiri, J.E.; Kimaru, L.J.; Okechukwu, A.; Rosales, C. Medical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: A systematic review. Syst. Rev. 2020, 9, 167. [Google Scholar] [CrossRef]
  86. Capano, A.; Weaver, R.; Burkman, E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: A prospective cohort study. Postgrad. Med. 2020, 132, 56–61. [Google Scholar] [CrossRef][Green Version]
  87. Zhang, H.; Lund, D.M.; Ciccone, H.A.; Staatz, W.D.; Ibrahim, M.M.; Largent-Milnes, T.M.; Seltzman, H.H.; Spigelman, I.; Vanderah, T.W. Peripherally restricted cannabinoid 1 receptor agonist as a novel analgesic in cancer-induced bone pain. Pain 2018, 159, 1814–1823. [Google Scholar] [CrossRef] [PubMed]
  88. Nagarkatti, P.; Pandey, R.; Rieder, S.A.; Hegde, V.L.; Nagarkatti, M. Cannabinoids as novel anti-inflammatory drugs. Future Med. Chem. 2009, 1, 1333–1349. [Google Scholar] [CrossRef] [PubMed][Green Version]
  89. Śledziński, P.; Zeyland, J.; Słomski, R.; Nowak, A. The current state and future perspectives of cannabinoids in cancer biology. Cancer Med. 2018, 7, 765–775. [Google Scholar] [CrossRef] [PubMed]
  90. Ross, R.A. Anandamide and vanilloid TRPV1 receptors. Br. J. Pharmacol. 2003, 140, 790–801. [Google Scholar] [CrossRef][Green Version]
  91. Devinsky, O.; Cilio, M.R.; Cross, H.; Fernandez-Ruiz, J.; French, J.; Hill, C.; Katz, R.; Di Marzo, V.; Jutras-Aswad, D.; Notcutt, W.G.; et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 2014, 55, 791–802. [Google Scholar] [CrossRef][Green Version]
  92. Burstein, S. Cannabidiol (CBD) and its analogs: A review of their effects on inflammation. Bioorg. Med. Chem. 2015, 23, 1377–1385. [Google Scholar] [CrossRef] [PubMed]
  93. Stanley, C.P.; Hind, W.H.; O’Sullivan, S.E. Is the cardiovascular system a therapeutic target for cannabidiol? Br. J. Clin. Pharmacol. 2013, 75, 313–322. [Google Scholar] [CrossRef][Green Version]
  94. Kolb, B.; Saber, H.; Fadel, H.; Rajah, G. The endocannabinoid system and stroke: A focused review. Brain Circ. 2019, 5, 1–7. [Google Scholar] [CrossRef]
  95. Fernández-Ruiz, J.; Moro, M.A.; Martínez-Orgado, J. Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications. Neurother. J. Am. Soc. Exp. Neurother. 2015, 12, 793–806. [Google Scholar] [CrossRef] [PubMed][Green Version]
  96. U.S. National Library of Medicine. Diabetes|Type 1 Diabetes|Type 2 Diabetes. MedlinePlus. 27 May 2021. Available online: (accessed on 15 July 2021).
  97. Centers for Disease Control and Prevention. Diabetes and Your Heart. Centers for Disease Control and Prevention. 7 May 2021. Available online: (accessed on 15 July 2021).
  98. Watson, S. Diabetes: Symptoms, Causes, Treatment, Prevention, and More. Healthline. 27 May 2020. Available online: (accessed on 15 July 2021).
  99. Jadoon, K.A.; Ratcliffe, S.H.; Barrett, D.A.; Thomas, E.L.; Stott, C.; Bell, J.D.; O’Sullivan, S.E.; Tan, G.D. Efficacy and Safety of Cannabidiol and Tetrahydrocannabivarin on Glycemic and Lipid Parameters in Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Pilot Study. Diabetes Care 2016, 39, 1777–1786. [Google Scholar] [CrossRef][Green Version]
  100. Jourdan, T.; Godlewski, G.; Cinar, R.; Bertola, A.; Szanda, G.; Liu, J.; Tam, J.; Han, T.; Mukhopadhyay, B.; Skarulis, M.C.; et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat. Med. 2013, 19, 1132–1140. [Google Scholar] [CrossRef] [PubMed][Green Version]
  101. Abioye, A.; Ayodele, O.; Marinkovic, A.; Patidar, R.; Akinwekomi, A.; Sanyaolu, A. Δ9-Tetrahydrocannabivarin (THCV): A commentary on potential therapeutic benefit for the management of obesity and diabetes. J. Cannabis Res. 2020, 2, 6. [Google Scholar] [CrossRef][Green Version]
  102. Mayo Foundation for Medical Education and Research. Stroke. Mayo Clinic. 9 February 2021. Available online: (accessed on 8 March 2021).
  103. Keles, H.O.; Radoman, M.; Pachas, G.N.; Evins, A.E.; Gilman, J.M. Using Functional Near-Infrared Spectroscopy to Measure Effects of Delta 9-Tetrahydrocannabinol on Prefrontal Activity and Working Memory in Cannabis Users. Front. Hum. Neurosci. 2017, 11, 488. [Google Scholar] [CrossRef] [PubMed][Green Version]
  104. Croxford, J.L. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 2003, 17, 179–202. [Google Scholar] [CrossRef]
  105. England, T.J.; Hind, W.H.; Rasid, N.A.; O’Sullivan, S.E. Cannabinoids in experimental stroke: A systematic review and meta-analysis. J. Cereb. Blood Flow Metab. 2015, 35, 348–358. [Google Scholar] [CrossRef] [PubMed][Green Version]
  106. Capettini, L.S.; Savergnini, S.Q.; da Silva, R.F.; Stergiopulos, N.; Santos, R.A.; Mach, F.; Montecucco, F. Update on the role of cannabinoid receptors after ischemic stroke. Mediat. Inflamm. 2012, 2012, 824093. [Google Scholar] [CrossRef] [PubMed][Green Version]
  107. Davis, M.P. Oral nabilone capsules in the treatment of chemotherapy-induced nausea and vomiting and pain. Expert Opin. Investig. Drugs 2008, 17, 85–95. [Google Scholar] [CrossRef] [PubMed]
  108. Navari, R.M. Antiemetic control: Toward a new standard of care for emetogenic chemotherapy. Expert Opin. Pharmacother. 2009, 10, 629–644. [Google Scholar] [CrossRef]
  109. Parker, L.A.; Rock, E.M.; Limebeer, C.L. Regulation of nausea and vomiting by cannabinoids. Br. J. Pharmacol. 2011, 163, 1411–1422. [Google Scholar] [CrossRef][Green Version]
  110. Guindon, J.; Hohmann, A.G. The endocannabinoid system and cancer: Therapeutic implication. Br. J. Pharmacol. 2011, 163, 1447–1463. [Google Scholar] [CrossRef][Green Version]
  111. Ramer, R.; Hinz, B. Cannabinoids as Anticancer Drugs. Adv. Pharmacol. 2017, 80, 397–436. [Google Scholar] [CrossRef]
  112. Massi, P.; Solinas, M.; Cinquina, V.; Parolaro, D. Cannabidiol as potential anticancer drug. Br. J. Clin. Pharmacol. 2013, 75, 303–312. [Google Scholar] [CrossRef] [PubMed][Green Version]
  113. Bifulco, M.; Malfitano, A.M.; Pisanti, S.; Laezza, C. Endocannabinoids in endocrine and related tumours. Endocr. Relat. Cancer 2008, 15, 391–408. [Google Scholar] [CrossRef]
  114. Díaz-Laviada, I. The endocannabinoid system in prostate cancer. Nat. Rev. Urol. 2011, 8, 553–561. [Google Scholar] [CrossRef] [PubMed]
  115. Sarfaraz, S.; Adhami, V.M.; Syed, D.N.; Afaq, F.; Mukhtar, H. Cannabinoids for cancer treatment: Progress and promise. Cancer Res. 2008, 68, 339–342. [Google Scholar] [CrossRef] [PubMed][Green Version]
  116. Solinas, M.; Massi, P.; Cantelmo, A.R.; Cattaneo, M.G.; Cammarota, R.; Bartolini, D.; Cinquina, V.; Valenti, M.; Vicentini, L.M.; Noonan, D.M.; et al. Cannabidiol inhibits angiogenesis by multiple mechanisms. Br. J. Pharmacol. 2012, 167, 1218–1231. [Google Scholar] [CrossRef] [PubMed][Green Version]
  117. Velasco, G.; Sánchez, C.; Guzmán, M. Towards the use of cannabinoids as antitumour agents. Nat. Rev. Cancer 2012, 12, 436–444. [Google Scholar] [CrossRef]
  118. Cridge, B.J.; Rosengren, R.J. Critical appraisal of the potential use of cannabinoids in cancer management. Cancer Manag. Res. 2013, 5, 301–313. [Google Scholar] [CrossRef] [PubMed][Green Version]
  119. Chakravarti, B.; Ravi, J.; Ganju, R.K. Cannabinoids as therapeutic agents in cancer: Current status and future implications. Oncotarget 2014, 5, 5852–5872. [Google Scholar] [CrossRef][Green Version]
  120. Michalski, C.W.; Oti, F.E.; Erkan, M.; Sauliunaite, D.; Bergmann, F.; Pacher, P.; Batkai, S.; Müller, M.W.; Giese, N.A.; Friess, H.; et al. Cannabinoids in pancreatic cancer: Correlation with survival and pain. Int. J. Cancer 2008, 122, 742–750. [Google Scholar] [CrossRef][Green Version]
  121. Zhao, Z.; Yang, J.; Zhao, H.; Fang, X.; Li, H. Cannabinoid receptor 2 is upregulated in melanoma. J. Cancer Res. Ther. 2012, 8, 549–554. [Google Scholar] [CrossRef]
  122. Pérez-Gómez, E.; Andradas, C.; Blasco-Benito, S.; Caffarel, M.M.; García-Taboada, E.; Villa-Morales, M.; Moreno, E.; Hamann, S.; Martín-Villar, E.; Flores, J.M.; et al. Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer. J. Natl. Cancer Inst. 2015, 107, djv077. [Google Scholar] [CrossRef] [PubMed][Green Version]
  123. Sánchez, M.G.; Sánchez, A.M.; Ruiz-Llorente, L.; Díaz-Laviada, I. Enhancement of androgen receptor expression induced by (R)-methanandamide in prostate LNCaP cells. FEBS Lett. 2003, 555, 561–566. [Google Scholar] [CrossRef] [PubMed][Green Version]
  124. Fraguas-Sánchez, A.I.; Martín-Sabroso, C.; Torres-Suárez, A.I. Insights into the effects of the endocannabinoid system in cancer: A review. Br. J. Pharmacol. 2018, 175, 2566–2580. [Google Scholar] [CrossRef] [PubMed][Green Version]
  125. Seltzer, E.S.; Watters, A.K.; MacKenzie, D., Jr.; Granat, L.M.; Zhang, D. Cannabidiol (CBD) as a Promising Anti-Cancer Drug. Cancers 2020, 12, 3203. [Google Scholar] [CrossRef]
  126. Velasco, G.; Sánchez, C.; Guzmán, M. Anticancer mechanisms of cannabinoids. Curr. Oncol. 2016, 23, S23–S32. [Google Scholar] [CrossRef][Green Version]
  127. Kubajewska, I.; Constantinescu, C.S. Cannabinoids and experimental models of multiple sclerosis. Immunobiology 2010, 215, 647–657. [Google Scholar] [CrossRef]
  128. Hayakawa, K.; Mishima, K.; Fujiwara, M. Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke. Pharmaceuticals 2010, 3, 2197–2212. [Google Scholar] [CrossRef]
  129. Choi, S.H.; Mou, Y.; Silva, A.C. Cannabis and Cannabinoid Biology in Stroke. Stroke 2019, 50, 2640–2645. [Google Scholar] [CrossRef] [PubMed]
  130. Prenderville, J.A.; Kelly, Á.M.; Downer, E.J. The role of cannabinoids in adult neurogenesis. Br. J. Pharmacol. 2015, 172, 3950–3963. [Google Scholar] [CrossRef][Green Version]
  131. Palazuelos, J.; Ortega, Z.; Díaz-Alonso, J.; Guzmán, M.; Galve-Roperh, I. CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J. Biol. Chem. 2012, 287, 1198–1209. [Google Scholar] [CrossRef] [PubMed][Green Version]
  132. Jiang, W.; Zhang, Y.; Xiao, L.; Van Cleemput, J.; Ji, S.P.; Bai, G.; Zhang, X. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J. Clin. Investig. 2005, 115, 3104–3116. [Google Scholar] [CrossRef] [PubMed][Green Version]
  133. Beale, C.; Broyd, S.J.; Chye, Y.; Suo, C.; Schira, M.; Galettis, P.; Martin, J.H.; Yücel, M.; Solowij, N. Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users. Cannabis Cannabinoid Res. 2018, 3, 94–107. [Google Scholar] [CrossRef]
  134. Reis, J.; Pereira, G. The Role of Cannabinoids in Schizophrenia: Where Have we Been and Where are we Going? Eur. Psychiatry 2017, 41 (Suppl. 1), S277. [Google Scholar] [CrossRef]
  135. Hamilton, I.; Monaghan, M. Cannabis and Psychosis: Are We any Closer to Understanding the Relationship. Curr. Psychiatry Rep. 2019, 21, 48. [Google Scholar] [CrossRef][Green Version]
  136. Makriyannis, A.; Mechoulam, R.; Piomelli, D. Therapeutic opportunities through modulation of the endocannabinoid system. Neuropharmacology 2005, 48, 1068–1071. [Google Scholar] [CrossRef][Green Version]
  137. Coulston, C.M.; Perdices, M.; Henderson, A.F.; Malhi, G.S. Cannabinoids for the treatment of schizophrenia? A balanced neurochemical framework for both adverse and therapeutic effects of cannabis use. Schizophr. Res. Treat. 2011, 2011, 501726. [Google Scholar] [CrossRef]
  138. Manseau, M.W.; Goff, D.C. Cannabinoids and Schizophrenia: Risks and Therapeutic Potential. Neurother. J. Am. Soc. Exp. NeuroTher. 2015, 12, 816–824. [Google Scholar] [CrossRef] [PubMed]
  139. Bartoli, F.; Riboldi, I.; Bachi, B.; Calabrese, A.; Moretti, F.; Crocamo, C.; Carrà, G. Efficacy of Cannabidiol for Δ-9-Tetrahydrocannabinol-Induced Psychotic Symptoms, Schizophrenia, and Cannabis Use Disorders: A Narrative Review. J. Clin. Med. 2021, 10, 1303. [Google Scholar] [CrossRef]
  140. Murray, R.M.; Quigley, H.; Quattrone, D.; Englund, A.; Di Forti, M. Traditional marijuana, high-potency cannabis and synthetic cannabinoids: Increasing risk for psychosis. World Psychiatry Off. J. World Psychiatr. Assoc. (WPA) 2016, 15, 195–204. [Google Scholar] [CrossRef][Green Version]
  141. Perucca, E. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? J. Epilepsy Res. 2017, 7, 61–76. [Google Scholar] [CrossRef] [PubMed]
  142. Batalla, A.; Janssen, H.; Gangadin, S.S.; Bossong, M.G. The Potential of Cannabidiol as a Treatment for Psychosis and Addiction: Who Benefits Most? A Systematic Review. J. Clin. Med. 2019, 8, 1058. [Google Scholar] [CrossRef][Green Version]
  143. Kopelli, E.; Samara, M.; Siargkas, A.; Goulas, A.; Papazisis, G.; Chourdakis, M. The role of cannabidiol oil in schizophrenia treatment. a systematic review and meta-analysis. Psychiatry Res. 2020, 291, 113246. [Google Scholar] [CrossRef] [PubMed]
  144. McGuire, P.; Robson, P.; Cubala, W.J.; Vasile, D.; Morrison, P.D.; Barron, R.; Taylor, A.; Wright, S. Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Am. J. Psychiatry 2018, 175, 225–231. [Google Scholar] [CrossRef][Green Version]
  145. Lattanzi, S.; Brigo, F.; Trinka, E.; Zaccara, G.; Cagnetti, C.; Del Giovane, C.; Silvestrini, M. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis. Drugs 2018, 78, 1791–1804. [Google Scholar] [CrossRef]
  146. Farrelly, A.M.; Vlachou, S.; Grintzalis, K. Efficacy of Phytocannabinoids in Epilepsy Treatment: Novel Approaches and Recent Advances. Int. J. Environ. Res. Public Health 2021, 18, 3993. [Google Scholar] [CrossRef] [PubMed]
  147. Silvestro, S.; Mammana, S.; Cavalli, E.; Bramanti, P.; Mazzon, E. Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials. Molecules 2019, 24, 1459. [Google Scholar] [CrossRef][Green Version]
  148. Ryan, M. Cannabidiol in epilepsy: The indications and beyond. Ment. Health Clin. 2020, 10, 317–325. [Google Scholar] [CrossRef] [PubMed]
  149. Galan, F.N.; Miller, I. Cannabinoids for the Treatment of Epilepsy: A Review. Curr. Treat. Options Neurol. 2020, 22, 14. [Google Scholar] [CrossRef]
  150. Morano, A.; Fanella, M.; Albini, M.; Cifelli, P.; Palma, E.; Giallonardo, A.T.; Di Bonaventura, C. Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects. Neuropsychiatr. Dis. Treat. 2020, 16, 381–396. [Google Scholar] [CrossRef] [PubMed][Green Version]
  151. Stockings, E.; Zagic, D.; Campbell, G.; Weier, M.; Hall, W.D.; Nielsen, S.; Herkes, G.K.; Farrell, M.; Degenhardt, L. Evidence for cannabis and cannabinoids for epilepsy: A systematic review of controlled and observational evidence. J. Neurol. Neurosurg. Psychiatry 2018, 89, 741–753. [Google Scholar] [CrossRef]
  152. Devinsky, O.; Verducci, C.; Thiele, E.A.; Laux, L.C.; Patel, A.D.; Filloux, F.; Szaflarski, J.P.; Wilfong, A.; Clark, G.D.; Park, Y.D.; et al. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Epilepsy Behav. E B 2018, 86, 131–137. [Google Scholar] [CrossRef][Green Version]
  153. Klein, B.D.; Jacobson, C.A.; Metcalf, C.S.; Smith, M.D.; Wilcox, K.S.; Hampson, A.J.; Kehne, J.H. Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP). Neurochem. Res. 2017, 42, 1939–1948. [Google Scholar] [CrossRef]
  154. Von Wrede, R.; Helmstaedter, C.; Surges, R. Cannabidiol in the Treatment of Epilepsy. Clin. Drug Investig. 2021, 41, 211–220. [Google Scholar] [CrossRef] [PubMed]
  155. Hausman-Kedem, M.; Menascu, S.; Kramer, U. Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents—An observational, longitudinal study. Brain Dev. 2018, 40, 544–551. [Google Scholar] [CrossRef]
  156. Maa, E.; Figi, P. The case for medical marijuana in epilepsy. Epilepsia 2014, 55, 783–786. [Google Scholar] [CrossRef] [PubMed]
  157. Katz, D.; Katz, I.; Porat-Katz, B.S.; Shoenfeld, Y. Medical cannabis: Another piece in the mosaic of autoimmunity? Clin. Pharmacol. Ther. 2017, 101, 230–238. [Google Scholar] [CrossRef]
  158. Ginhoux, F.; Lim, S.; Hoeffel, G.; Low, D.; Huber, T. Origin and differentiation of microglia. Front. Cell. Neurosci. 2013, 7, 45. [Google Scholar] [CrossRef][Green Version]
  159. Cabral, G.A.; Raborn, E.S.; Griffin, L.; Dennis, J.; Marciano-Cabral, F. CB2 receptors in the brain: Role in central immune function. Br. J. Pharmacol. 2008, 153, 240–251. [Google Scholar] [CrossRef][Green Version]
  160. Katchan, V.; David, P.; Shoenfeld, Y. Cannabinoids and autoimmune diseases: A systematic review. Autoimmun. Rev. 2016, 15, 513–528. [Google Scholar] [CrossRef]
  161. Klein, T.W.; Newton, C.A.; Friedman, H. Cannabinoids and the immune system. Pain Res. Manag. 2001, 6, 95–101. [Google Scholar] [CrossRef]
  162. Sipe, J.C.; Arbour, N.; Gerber, A.; Beutler, E. Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: Possible risk for autoimmune disorders. J. Leukoc. Biol. 2005, 78, 231–238. [Google Scholar] [CrossRef] [PubMed]
  163. Suzuki, Y.; Nagai, N.; Umemura, K. A Review of the Mechanisms of Blood-Brain Barrier Permeability by Tissue-Type Plasminogen Activator Treatment for Cerebral Ischemia. Front. Cell. Neurosci. 2016, 10, 2. [Google Scholar] [CrossRef] [PubMed][Green Version]
  164. Daneman, R.; Prat, A. The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 2015, 7, a020412. [Google Scholar] [CrossRef][Green Version]
  165. Vendel, E.; de Lange, E.C.M. Functions of the CB1 and CB2 Receptors in Neuroprotection at the Level of the Blood–Brain Barrier. Neuromol. Med. 2014, 16, 620–642. [Google Scholar] [CrossRef]
  166. Gris, J.C.; Nobile, B.; Bouvier, S. Neuropsychiatric presentations of antiphospholipid antibodies. Thromb. Res. 2015, 135 (Suppl. 1), S56–S59. [Google Scholar] [CrossRef]
  167. Fleetwood, T.; Cantello, R.; Comi, C. Antiphospholipid Syndrome and the Neurologist: From Pathogenesis to Therapy. Front. Neurol. 2018, 9, 1001. [Google Scholar] [CrossRef][Green Version]
  168. Katzav, A.; Shoenfeld, Y.; Chapman, J. The pathogenesis of neural injury in animal models of the antiphospholipid syndrome. Clin. Rev. Allergy Immunol. 2010, 38, 196–200. [Google Scholar] [CrossRef] [PubMed]
  169. Brettschneider, J.; Claus, A.; Kassubek, J.; Tumani, H. Isolated blood-cerebrospinal fluid barrier dysfunction: Prevalence and associated diseases. J. Neurol. 2005, 252, 1067–1073. [Google Scholar] [CrossRef] [PubMed]
  170. Popescu, B.F.; Lucchinetti, C.F. Meningeal and cortical grey matter pathology in multiple sclerosis. BMC Neurol. 2012, 12, 11. [Google Scholar] [CrossRef][Green Version]
  171. Li, S.; Yu, M.; Li, H.; Zhang, H.; Jiang, Y. IL-17 and IL-22 in cerebrospinal fluid and plasma are elevated in Guillain-Barré syndrome. Mediat. Inflamm. 2012, 2012, 260473. [Google Scholar] [CrossRef] [PubMed][Green Version]
  172. Gonzalez-Quevedo, A.; Carriera, R.F.; O’Farrill, Z.L.; Luis, I.S.; Becquer, R.M.; Luis Gonzalez, R.S. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain Barré syndrome. Neurol. India 2009, 57, 288–294. [Google Scholar] [CrossRef] [PubMed][Green Version]
  173. Zhao, Z.; Nelson, A.R.; Betsholtz, C.; Zlokovic, B.V. Establishment and Dysfunction of the Blood-Brain Barrier. Cell 2015, 163, 1064–1078. [Google Scholar] [CrossRef] [PubMed][Green Version]
  174. Alvarez, J.I.; Saint-Laurent, O.; Godschalk, A.; Terouz, S.; Briels, C.; Larouche, S.; Bourbonnière, L.; Larochelle, C.; Prat, A. Focal disturbances in the blood-brain barrier are associated with formation of neuroinflammatory lesions. Neurobiol. Dis. 2015, 74, 14–24. [Google Scholar] [CrossRef]
  175. Aubé, B.; Lévesque, S.A.; Paré, A.; Chamma, É.; Kébir, H.; Gorina, R.; Lécuyer, M.A.; Alvarez, J.I.; De Koninck, Y.; Engelhardt, B.; et al. Neutrophils mediate blood-spinal cord barrier disruption in demyelinating neuroinflammatory diseases. J. Immunol. 2014, 193, 2438–2454. [Google Scholar] [CrossRef][Green Version]
  176. Tomizawa, Y.; Yokoyama, K.; Saiki, S.; Takahashi, T.; Matsuoka, J.; Hattori, N. Blood-brain barrier disruption is more severe in neuromyelitis optica than in multiple sclerosis and correlates with clinical disability. J. Int. Med. Res. 2012, 40, 1483–1491. [Google Scholar] [CrossRef] [PubMed]
  177. Takeshita, Y.; Obermeier, B.; Cotleur, A.C.; Spampinato, S.F.; Shimizu, F.; Yamamoto, E.; Sano, Y.; Kryzer, T.J.; Lennon, V.A.; Kanda, T.; et al. Effects of neuromyelitis optica-IgG at the blood-brain barrier in vitro. Neurol. (R) Neuroimmunol. Neuroinflamm. 2016, 4, e311. [Google Scholar] [CrossRef][Green Version]
  178. Hind, W.H.; Tufarelli, C.; Neophytou, M.; Anderson, S.I.; England, T.J.; O’Sullivan, S.E. Endocannabinoids modulate human blood-brain barrier permeability in vitro. Br. J. Pharmacol. 2015, 172, 3015–3027. [Google Scholar] [CrossRef] [PubMed][Green Version]
  179. Calapai, F.; Cardia, L.; Sorbara, E.E.; Navarra, M.; Gangemi, S.; Calapai, G.; Mannucci, C. Cannabinoids, Blood-Brain Barrier, and Brain Disposition. Pharmaceutics 2020, 12, 265. [Google Scholar] [CrossRef][Green Version]
  180. Panikashvili, D.; Shein, N.A.; Mechoulam, R.; Trembovler, V.; Kohen, R.; Alexandrovich, A.; Shohami, E. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol. Dis. 2006, 22, 257–264. [Google Scholar] [CrossRef] [PubMed]
  181. Mestre, L.; Iñigo, P.M.; Mecha, M.; Correa, F.G.; Hernangómez-Herrero, M.; Loría, F.; Docagne, F.; Borrell, J.; Guaza, C. Anandamide inhibits Theiler’s virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB(1) receptors. J. Neuroinflamm. 2011, 8, 102. [Google Scholar] [CrossRef][Green Version]
  182. Aparicio-Blanco, J.; Romero, I.A.; Male, D.K.; Slowing, K.; García-García, L.; Torres-Suárez, A.I. Cannabidiol Enhances the Passage of Lipid Nanocapsules across the Blood-Brain Barrier Both in Vitro and in Vivo. Mol. Pharm. 2019, 16, 1999–2010. [Google Scholar] [CrossRef]
  183. Bachmeier, C.; Beaulieu-Abdelahad, D.; Mullan, M.; Paris, D. Role of the cannabinoid system in the transit of beta-amyloid across the blood–brain barrier. Mol. Cell. Neurosci. 2013, 56, 255–262. [Google Scholar] [CrossRef]
  184. Pertwee, R.G. Cannabinoids and multiple sclerosis. Pharmacol. Ther. 2002, 95, 165–174. [Google Scholar] [CrossRef]
  185. Barnes, M.P. Sativex: Clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert Opin. Pharmacother. 2006, 7, 607–615. [Google Scholar] [CrossRef]
  186. Giacoppo, S.; Bramanti, P.; Mazzon, E. Sativex in the management of multiple sclerosis-related spasticity: An overview of the last decade of clinical evaluation. Mult. Scler. Relat. Disord. 2017, 17, 22–31. [Google Scholar] [CrossRef] [PubMed]
  187. Flachenecker, P.; Henze, T.; Zettl, U.K. Nabiximols (THC/CBD oromucosal spray, Sativex®) in clinical practice—Results of a multicenter, non-interventional study (MOVE 2) in patients with multiple sclerosis spasticity. Eur. Neurol. 2014, 71, 271–279. [Google Scholar] [CrossRef] [PubMed]
  188. Vermersch, P. Sativex(®) (tetrahydrocannabinol + cannabidiol), an endocannabinoid system modulator: Basic features and main clinical data. Expert Rev. Neurother. 2011, 11 (Suppl. 4), 15–19. [Google Scholar] [CrossRef] [PubMed]
  189. Oreja-Guevara, C. Clinical efficacy and effectiveness of Sativex, a combined cannabinoid medicine, in multiple sclerosis-related spasticity. Expert Rev. Neurother. 2012, 12 (Suppl. 4), 3–8. [Google Scholar] [CrossRef] [PubMed]
  190. Russo, M.; Calabrò, R.S.; Naro, A.; Sessa, E.; Rifici, C.; D’Aleo, G.; Leo, A.; De Luca, R.; Quartarone, A.; Bramanti, P. Sativex in the management of multiple sclerosis-related spasticity: Role of the corticospinal modulation. Neural. Plast. 2015, 2015, 656582. [Google Scholar] [CrossRef][Green Version]
  191. Markovà, J.; Essner, U.; Akmaz, B.; Marinelli, M.; Trompke, C.; Lentschat, A.; Vila, C. Sativex® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: A double-blind, placebo-controlled randomised clinical trial. Int. J. Neurosci. 2019, 129, 119–128. [Google Scholar] [CrossRef]
  192. Maresz, K.; Pryce, G.; Ponomarev, E.D.; Marsicano, G.; Croxford, J.L.; Shriver, L.P.; Ledent, C.; Cheng, X.; Carrier, E.J.; Mann, M.K.; et al. Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells. Nat. Med. 2007, 13, 492–497. [Google Scholar] [CrossRef] [PubMed]
  193. Katz-Talmor, D.; Katz, I.; Porat-Katz, B.S.; Shoenfeld, Y. Cannabinoids for the treatment of rheumatic diseases—Where do we stand? Nat. Rev. Rheumatol. 2018, 14, 488–498. [Google Scholar] [CrossRef]
  194. Sarzi-Puttini, P.; Batticciotto, A.; Atzeni, F.; Bazzichi, L.; Di Franco, M.; Salaffi, F.; Marotto, D.; Ceribelli, A.; Ablin, J.N.; Hauser, W. Medical cannabis and cannabinoids in rheumatology: Where are we now? Expert Rev. Clin. Immunol. 2019, 15, 1019–1032. [Google Scholar] [CrossRef]
  195. Gonen, T.; Amital, H. Cannabis and Cannabinoids in the Treatment of Rheumatic Diseases. Rambam Maimonides Med. J. 2020, 11, e0007. [Google Scholar] [CrossRef][Green Version]
  196. Fukuda, S.; Kohsaka, H.; Takayasu, A.; Yokoyama, W.; Miyabe, C.; Miyabe, Y.; Harigai, M.; Miyasaka, N.; Nanki, T. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis. BMC Musculoskelet. Disord. 2014, 15, 275. [Google Scholar] [CrossRef][Green Version]
  197. Zhu, M.; Yu, B.; Bai, J.; Wang, X.; Guo, X.; Liu, Y.; Lin, J.; Hu, S.; Zhang, W.; Tao, Y.; et al. Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis. J. Bone Miner. Res. 2019, 34, 739–751. [Google Scholar] [CrossRef]
  198. Fechtner, S.; Singh, A.K.; Srivastava, I.; Szlenk, C.T.; Muench, T.R.; Natesan, S.; Ahmed, S. Cannabinoid Receptor 2 Agonist JWH-015 Inhibits Interleukin-1β-Induced Inflammation in Rheumatoid Arthritis Synovial Fibroblasts and in Adjuvant Induced Arthritis Rat via Glucocorticoid Receptor. Front. Immunol. 2019, 10, 1027. [Google Scholar] [CrossRef]
  199. HealthlineEditorialTeam. Everything You Need to Know About Inflammatory Bowel Disease (IBD). Healthlin. 1 March 2021. Available online: (accessed on 11 August 2021).
  200. Higuera, V. What to Know If You Have Ulcerative Colitis. Healthline. 30 October 2020. Available online: (accessed on 11 August 2021).
  201. Holland, K. Everything to Know About Crohn’s Disease. Healthline. 16 April 2021. Available online: (accessed on 14 August 2021).
  202. Marquéz, L.; Suárez, J.; Iglesias, M.; Bermudez-Silva, F.J.; Rodríguez de Fonseca, F.; Andreu, M. Ulcerative colitis induces changes on the expression of the endocannabinoid system in the human colonic tissue. PLoS ONE 2009, 4, e6893. [Google Scholar] [CrossRef] [PubMed][Green Version]
  203. Galligan, J.J. Cannabinoid signalling in the enteric nervous system. Neurogastroenterol. Motil. 2009, 21, 899–902. [Google Scholar] [CrossRef] [PubMed]
  204. Vianna, C.R.; Donato, J., Jr.; Rossi, J.; Scott, M.; Economides, K.; Gautron, L.; Pierpont, S.; Elias, C.F.; Elmquist, J.K. Cannabinoid receptor 1 in the vagus nerve is dispensable for body weight homeostasis but required for normal gastrointestinal motility. J. Neurosci. 2012, 32, 10331–10337. [Google Scholar] [CrossRef][Green Version]
  205. Carabotti, M.; Scirocco, A.; Maselli, M.A.; Severi, C. The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann. Gastroenterol. 2015, 28, 203–209. [Google Scholar]
  206. Fichna, J.; Bawa, M.; Thakur, G.A.; Tichkule, R.; Makriyannis, A.; McCafferty, D.M.; Sharkey, K.A.; Storr, M. Cannabinoids alleviate experimentally induced intestinal inflammation by acting at central and peripheral receptors. PLoS ONE 2014, 9, e109115. [Google Scholar] [CrossRef][Green Version]
  207. Ahmed, W.; Katz, S. Therapeutic Use of Cannabis in Inflammatory Bowel Disease. Gastroenterol. Hepatol. 2016, 12, 668–679. [Google Scholar]
  208. Massa, F.; Marsicano, G.; Hermann, H.; Cannich, A.; Monory, K.; Cravatt, B.F.; Ferri, G.L.; Sibaev, A.; Storr, M.; Lutz, B. The endogenous cannabinoid system protects against colonic inflammation. J. Clin. Investig. 2004, 113, 1202–1209. [Google Scholar] [CrossRef] [PubMed][Green Version]
  209. Massa, F.; Storr, M.; Lutz, B. The endocannabinoid system in the physiology and pathophysiology of the gastrointestinal tract. J. Mol. Med. 2005, 83, 944–954. [Google Scholar] [CrossRef]
  210. Wright, K.; Rooney, N.; Feeney, M.; Tate, J.; Robertson, D.; Welham, M.; Ward, S. Differential expression of cannabinoid receptors in the human colon: Cannabinoids promote epithelial wound healing. Gastroenterology 2005, 129, 437–453. [Google Scholar] [CrossRef]
  211. Wright, K.L.; Duncan, M.; Sharkey, K.A. Cannabinoid CB2 receptors in the gastrointestinal tract: A regulatory system in states of inflammation. Br. J. Pharmacol. 2008, 153, 263–270. [Google Scholar] [CrossRef][Green Version]
  212. Kienzl, M.; Storr, M.; Schicho, R. Cannabinoids and Opioids in the Treatment of Inflammatory Bowel Diseases. Clin. Transl. Gastroenterol. 2020, 11, e00120. [Google Scholar] [CrossRef]
  213. Picardo, S.; Kaplan, G.G.; Sharkey, K.A.; Seow, C.H. Insights into the role of cannabis in the management of inflammatory bowel disease. Ther. Adv. Gastroenterol. 2019, 12, 1756284819870977. [Google Scholar] [CrossRef] [PubMed]
  214. Benson, M.J.; Abelev, S.V.; Connor, S.J.; Corte, C.J.; Martin, L.J.; Gold, L.K.; Suraev, A.S.; McGregor, I.S. Medicinal Cannabis for Inflammatory Bowel Disease: A Survey of Perspectives, Experiences, and Current Use in Australian Patients. Crohn’s Colitis 2020, 360, 2. [Google Scholar] [CrossRef][Green Version]
  215. Scott, F.I. Marijuana Use in Inflammatory Bowel Disease: Understanding the Prevalence and the Potential Pitfalls. Crohn’s Colitis 2020, 360, 2, otaa016. [Google Scholar] [CrossRef] [PubMed]
  216. Naftali, T. Is Cannabis of Potential Value as a Therapeutic for Inflammatory Bowel Disease? Dig. Dis. Sci. 2019, 64, 2696–2698. [Google Scholar] [CrossRef][Green Version]
  217. Naftali, T.; Bar-Lev Schleider, L.; Sklerovsky Benjaminov, F.; Lish, I.; Konikoff, F.M.; Ringel, Y. Medical cannabis for inflammatory bowel disease: Real-life experience of mode of consumption and assessment of side-effects. Eur. J. Gastroenterol. Hepatol. 2019, 31, 1376–1381. [Google Scholar] [CrossRef]
  218. Swaminath, A.; Berlin, E.P.; Cheifetz, A.; Hoffenberg, E.; Kinnucan, J.; Wingate, L.; Buchanan, S.; Zmeter, N.; Rubin, D.T. The Role of Cannabis in the Management of Inflammatory Bowel Disease: A Review of Clinical, Scientific, and Regulatory Information. Inflamm. Bowel Dis. 2019, 25, 427–435. [Google Scholar] [CrossRef][Green Version]
  219. Lal, S.; Prasad, N.; Ryan, M.; Tangri, S.; Silverberg, M.S.; Gordon, A.; Steinhart, H. Cannabis use amongst patients with inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 2011, 23, 891–896. [Google Scholar] [CrossRef] [PubMed]
  220. Naftali, T.; Bar-Lev Schleider, L.; Dotan, I.; Lansky, E.P.; Sklerovsky Benjaminov, F.; Konikoff, F.M. Cannabis induces a clinical response in patients with Crohn’s disease: A prospective placebo-controlled study. Clin. Gastroenterol. Hepatol. 2013, 11, 1276–1280.e1. [Google Scholar] [CrossRef]
  221. Perisetti, A.; Rimu, A.H.; Khan, S.A.; Bansal, P.; Goyal, H. Role of cannabis in inflammatory bowel diseases. Ann. Gastroenterol. 2020, 33, 134–144. [Google Scholar] [CrossRef] [PubMed]
  222. Lintzeris, N.; Mills, L.; Suraev, A.; Bravo, M.; Arkell, T.; Arnold, J.C.; Benson, M.J.; McGregor, I.S. Medical cannabis use in the Australian community following introduction of legal access: The 2018-2019 Online Cross-Sectional Cannabis as Medicine Survey (CAMS-18). Harm Reduct. J. 2020, 17, 37. [Google Scholar] [CrossRef]
  223. Goyal, H.; Singla, U.; Gupta, U.; May, E. Role of cannabis in digestive disorders. Eur. J. Gastroenterol. Hepatol. 2017, 29, 135–143. [Google Scholar] [CrossRef]
  224. Gotfried, J.; Naftali, T.; Schey, R. Role of Cannabis and Its Derivatives in Gastrointestinal and Hepatic Disease. Gastroenterology 2020, 159, 62–80. [Google Scholar] [CrossRef] [PubMed]
  225. Zuardi, A.W. History of cannabis as a medicine: A review. Rev. Bras. Psiquiatr. 2006, 28, 153–157. [Google Scholar] [CrossRef][Green Version]
  226. Storr, M.; Devlin, S.; Kaplan, G.G.; Panaccione, R.; Andrews, C.N. Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn’s disease. Inflamm. Bowel Dis. 2014, 20, 472–480. [Google Scholar] [CrossRef]
  227. Touw, M. The Religious and Medicinal Uses of Cannabis in China, India and Tibet. J. Psychoact. Drugs 1981, 13, 23–34. [Google Scholar] [CrossRef]
  228. DiPatrizio, N.V. Endocannabinoids in the Gut. Cannabis Cannabinoid Res. 2016, 1, 67–77. [Google Scholar] [CrossRef]
  229. Kerlin, A.M.; Long, M.; Kappelman, M.; Martin, C.; Sandler, R.S. Profiles of Patients Who Use Marijuana for Inflammatory Bowel Disease. Dig. Dis. Sci. 2018, 63, 1600–1604. [Google Scholar] [CrossRef] [PubMed]
  230. Schicho, R.; Storr, M. Cannabis finds its way into treatment of Crohn’s disease. Pharmacology 2014, 93, 1–3. [Google Scholar] [CrossRef] [PubMed][Green Version]
  231. Carvalho, A.; Souza, G.A.; Marqui, S.V.; Guiguer, É.L.; Araújo, A.C.; Rubira, C.J.; Goulart, R.A.; Flato, U.; Bueno, P.; Buchaim, R.L.; et al. Cannabis and Canabidinoids on the Inflammatory Bowel Diseases: Going Beyond Misuse. Int. J. Mol. Sci. 2020, 21, 2940. [Google Scholar] [CrossRef] [PubMed]
  232. Hasenoehrl, C.; Storr, M.; Schicho, R. Cannabinoids for treating inflammatory bowel diseases: Where are we and where do we go? Expert Rev. Gastroenterol. Hepatol. 2017, 11, 329–337. [Google Scholar] [CrossRef] [PubMed]
  233. Naftali, T.; Mechulam, R.; Lev, L.B.; Konikoff, F.M. Cannabis for inflammatory bowel disease. Dig. Dis. 2014, 32, 468–474. [Google Scholar] [CrossRef]
  234. Storr, M.A.; Keenan, C.M.; Zhang, H.; Patel, K.D.; Makriyannis, A.; Sharkey, K.A. Activation of the cannabinoid 2 receptor (CB2) protects against experimental colitis. Inflamm. Bowel Dis. 2009, 15, 1678–1685. [Google Scholar] [CrossRef] [PubMed][Green Version]
  235. Izzo, A.A.; Camilleri, M. Cannabinoids in intestinal inflammation and cancer. Pharmacol. Res. 2009, 60, 117–125. [Google Scholar] [CrossRef]
  236. Di Sabatino, A.; Battista, N.; Biancheri, P.; Rapino, C.; Rovedatti, L.; Astarita, G.; Vanoli, A.; Dainese, E.; Guerci, M.; Piomelli, D.; et al. The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease. Mucosal Immunol. 2011, 4, 574–583. [Google Scholar] [CrossRef][Green Version]
  237. Shook, J.E.; Burks, T.F. Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents. J. Pharmacol. Exp. Ther. 1989, 249, 444–449. [Google Scholar] [PubMed]
  238. Naftali, T.; Lev, L.B.; Yablecovitch, D.; Half, E.; Konikoff, F.M. Treatment of Crohn’s disease with cannabis: An observational study. Isr. Med Assoc. J. IMAJ 2011, 13, 455–458. [Google Scholar] [PubMed]
  239. Esposito, G.; Filippis, D.D.; Cirillo, C.; Iuvone, T.; Capoccia, E.; Scuderi, C.; Steardo, A.; Cuomo, R.; Steardo, L. Cannabidiol in Inflammatory Bowel Diseases: A Brief Overview. Phytother. Res. 2013, 27, 633–636. [Google Scholar] [CrossRef] [PubMed]
  240. Medical Cannabis Oil for Inflammatory Skin Disease. (n.d.). Retrieved 25 March 2021. Available online: (accessed on 26 July 2021).
  241. Trusler, A.R.; Clark, A.K.; Sivamani, R.K.; Shi, V.Y. The Endocannabinoid System and Its Role in Eczematous Dermatoses. Dermat. Contact Atopic Occup. Drug 2017, 28, 22–32. [Google Scholar] [CrossRef]
  242. Del Río, C.; Navarrete, C.; Collado, J.A.; Bellido, M.L.; Gómez-Cañas, M.; Pazos, M.R.; Fernández-Ruiz, J.; Pollastro, F.; Appendino, G.; Calzado, M.A.; et al. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways. Sci. Rep. 2016, 6, 21703. [Google Scholar] [CrossRef] [PubMed]
  243. Muñoz, E. Cannabinoids and Inflammatory Skin Diseases. Fundación CANNA: Scientific Studies and Cannabis Testin. 1 January 2021. Available online: (accessed on 26 July 2021).
  244. Hübotter, F. Cbinesisch-Tibetische Pharmakologie und Rezeptur; Karl Haug Verlag: Ulm, Germany, 1957. [Google Scholar]
  245. Benet, S. Early diffusion and folk uses of hemp. In Cannabis and Culture; Rubin, V., Ed.; Mouton: The Hague, The Netherlands, 1975. [Google Scholar]
  246. Manasse, A.G.C. Composition for the Treatment of Skin Lesions. U.S. Patent US20140302185A1, 9 October 2014. [Google Scholar]
  247. Clarke, R.C.; Merlin, M.D. Cannabis: Evolution and Ethnobotany; University of California Press: Berkeley, CA, USA, 2013. [Google Scholar]
  248. Avila, C.; Massick, S.; Kaffenberger, B.H.; Kwatra, S.G.; Bechtel, M. Cannabinoids for the treatment of chronic pruritus: A review. J. Am. Acad. Dermatol. 2020, 82, 1205–1212. [Google Scholar] [CrossRef] [PubMed]
  249. Olson, D. “Hemp culture in Japan” in Journal of Industrial Hemp Association, 1997. Dave Olson’s Creative Life Archive. 16 July 2018. Available online: (accessed on 26 July 2021).
  250. Pisanti, S.; Bifulco, M. Medical Cannabis: A plurimillennial history of an evergreen. J. Cell. Physiol. 2019, 234, 8342–8351. [Google Scholar] [CrossRef]
  251. Lozano, I. The Therapeutic Use of Cannabis sativa (L.) in Arabic Medicine. J. Cannabis Ther. 2001, 1, 63–70. [Google Scholar] [CrossRef]
  252. Tabassum, N.; Hamdani, M. Plants used to treat skin diseases. Pharmacogn. Rev. 2014, 8, 52–60. [Google Scholar] [CrossRef] [PubMed][Green Version]
  253. Scheau, C.; Badarau, I.A.; Mihai, L.G.; Scheau, A.E.; Costache, D.O.; Constantin, C.; Calina, D.; Caruntu, C.; Costache, R.S.; Caruntu, A. Cannabinoids in the Pathophysiology of Skin Inflammation. Molecules 2020, 25, 652. [Google Scholar] [CrossRef][Green Version]
  254. Klein, T.W. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat. Rev. Immunol. 2005, 5, 400–411. [Google Scholar] [CrossRef] [PubMed]
  255. Richardson, J.D.; Kilo, S.; Hargreaves, K.M. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 1998, 75, 111–119. [Google Scholar] [CrossRef]
  256. Bíró, T.; Tóth, B.I.; Haskó, G.; Paus, R.; Pacher, P. The endocannabinoid system of the skin in health and disease: Novel perspectives and therapeutic opportunities. Trends Pharmacol. Sci. 2009, 30, 411–420. [Google Scholar] [CrossRef][Green Version]
  257. Pucci, M.; Rapino, C.; Di Francesco, A.; Dainese, E.; D’Addario, C.; Maccarrone, M. Epigenetic control of skin differentiation genes by phytocannabinoids. Br. J. Pharmacol. 2013, 170, 581–591. [Google Scholar] [CrossRef] [PubMed][Green Version]
  258. Tóth, K.F.; Ádám, D.; Bíró, T.; Oláh, A. Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System. Molecules 2019, 24, 918. [Google Scholar] [CrossRef][Green Version]
  259. Sheriff, T.; Lin, M.J.; Dubin, D.; Khorasani, H. The potential role of cannabinoids in dermatology. J. Dermatol. Treat. 2020, 31, 839–845. [Google Scholar] [CrossRef]
  260. Nickles, M.A.; Lio, P.A. Cannabinoids in Dermatology: Hope or Hype? Cannabis Cannabinoid Res. 2020, 5, 279–282. [Google Scholar] [CrossRef]
  261. Zheng, D.; Bode, A.M.; Zhao, Q.; Cho, Y.Y.; Zhu, F.; Ma, W.Y.; Dong, Z. The cannabinoid receptors are required for ultraviolet-induced inflammation and skin cancer development. Cancer Res. 2008, 68, 3992–3998. [Google Scholar] [CrossRef][Green Version]
  262. Preedy, V.R.; Tüting, T.; Gaffal, E. Regulatory Role of Cannabinoids for Skin Barrier Functions and Cutaneous Inflammation. In Handbook of Cannabis and Related Pathologies: Biology, Pharmacology, Diagnosis, and Treatment, 1st ed.; Elsevier/Academic Press: Cambridge, MA, USA, 2017; pp. 543–549. [Google Scholar]
  263. Adelson, K.I. What Does CBD in Skin Care Actually Do? The Strategist. 15 May 2020. Available online: (accessed on 28 July 2021).
  264. Dobrosi, N.; Tóth, B.I.; Nagy, G.; Dózsa, A.; Géczy, T.; Nagy, L.; Zouboulis, C.C.; Paus, R.; Kovács, L.; Bíró, T. Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2008, 22, 3685–3695. [Google Scholar] [CrossRef][Green Version]
  265. Zákány, N.; Oláh, A.; Markovics, A.; Takács, E.; Aranyász, A.; Nicolussi, S.; Piscitelli, F.; Allarà, M.; Pór, Á.; Kovács, I.; et al. Endocannabinoid Tone Regulates Human Sebocyte Biology. J. Investig. Dermatol. 2018, 138, 1699–1706. [Google Scholar] [CrossRef][Green Version]
  266. Oláh, A.; Tóth, B.I.; Borbíró, I.; Sugawara, K.; Szöllõsi, A.G.; Czifra, G.; Pál, B.; Ambrus, L.; Kloepper, J.; Camera, E.; et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J. Clin. Investig. 2014, 124, 3713–3724. [Google Scholar] [CrossRef][Green Version]
  267. Maccarrone, M.; Di Rienzo, M.; Battista, N.; Gasperi, V.; Guerrieri, P.; Rossi, A.; Finazzi-Agrò, A. The endocannabinoid system in human keratinocytes. Evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activation protein-1, and transglutaminase. J. Biol. Chem. 2003, 278, 33896–33903. [Google Scholar] [CrossRef] [PubMed][Green Version]
  268. Friedman, A. Researchers Explore Potential of Cannabinoids in Inflammatory, Neoplastic Skin Diseases. Healio. 3 May 2019. Available online: (accessed on 28 July 2021).
  269. Eagleston, L.; Kalani, N.K.; Patel, R.R.; Flaten, H.K.; Dunnick, C.A.; Dellavalle, R.P. Cannabinoids in dermatology: A scoping review. Dermatol. Online J. 2018, 24, 13030/qt7pn8c0sb. [Google Scholar] [CrossRef] [PubMed]
  270. Derakhshan, N.; Kazemi, M. Cannabis for Refractory Psoriasis-High Hopes for a Novel Treatment and a Literature Review. Curr. Clin. Pharmacol. 2016, 11, 146–147. [Google Scholar] [CrossRef] [PubMed]
  271. Ramot, Y.; Sugawara, K.; Zákány, N.; Tóth, B.I.; Bíró, T.; Paus, R. A novel control of human keratin expression: Cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytes in vitro and in situ. PeerJ 2013, 1, e40. [Google Scholar] [CrossRef][Green Version]
  272. Mangkorntongsakul, V.; Lee, Y.J. Cannabinoids in dermatology. Cannabinoids in dermatology|DermNet NZ. 1 January 2020. Available online: (accessed on 28 July 2021).
  273. Morris, S.Y. Psoriasis: Is Cannabis an Effective Treatment? Healthline. 11 July 2019. Available online: (accessed on 28 July 2021).
  274. McIntosh, J. Eczema: Symptoms, treatment, causes, and types. Medical News Today. 21 July 2020. Available online: (accessed on 28 July 2021).
  275. Palmieri, B.; Laurino, C.; Vadalà, M. A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars. Clin. Ter. 2019, 170, e93–e99. [Google Scholar] [CrossRef] [PubMed]
  276. Mounessa, J.S.; Siegel, J.A.; Dunnick, C.A.; Dellavalle, R.P. The role of cannabinoids in dermatology. J. Am. Acad. Dermatol. 2017, 77, 188–190. [Google Scholar] [CrossRef]
  277. Marks, D.H.; Friedman, A. The Therapeutic Potential of Cannabinoids in Dermatology. Ski. Ther. Lett. 2018, 23, 1–5. [Google Scholar]
  278. Maghfour, J.; Rietcheck, H.R.; Rundle, C.W.; Runion, T.M.; Jafri, Z.A.; Dercon, S.; Lio, P.; Fernandez, J.; Fujita, M.; Dellavalle, R.P.; et al. An Observational Study of the Application of a Topical Cannabinoid Gel on Sensitive Dry Skin. J. Drugs Dermatol. JDD 2020, 19, 1204–1208. [Google Scholar] [CrossRef]
  279. Mayo Foundation for Medical Education and Research. Scleroderma. Mayo Clinic. 18 May 2019. Available online: (accessed on 28 July 2021).
  280. Akhmetshina, A.; Dees, C.; Busch, N.; Beer, J.; Sarter, K.; Zwerina, J.; Zimmer, A.; Distler, O.; Schett, G.; Distler, J.H. The cannabinoid receptor CB2 exerts antifibrotic effects in experimental dermal fibrosis. Arthritis Rheum. 2009, 60, 1129–1136. [Google Scholar] [CrossRef] [PubMed][Green Version]
  281. Marquart, S.; Zerr, P.; Akhmetshina, A.; Palumbo, K.; Reich, N.; Tomcik, M.; Horn, A.; Dees, C.; Engel, M.; Zwerina, J.; et al. Inactivation of the cannabinoid receptor CB1 prevents leukocyte infiltration and experimental fibrosis. Arthritis Rheum. 2010, 62, 3467–3476. [Google Scholar] [CrossRef] [PubMed]
  282. Balistreri, E.; Garcia-Gonzalez, E.; Selvi, E.; Akhmetshina, A.; Palumbo, K.; Lorenzini, S.; Maggio, R.; Lucattelli, M.; Galeazzi, M.; Distler, J.W. The cannabinoid WIN55, 212-2 abrogates dermal fibrosis in scleroderma bleomycin model. Ann. Rheum. Dis. 2011, 70, 695–699. [Google Scholar] [CrossRef] [PubMed]
  283. Kirkham, T.C.; Williams, C.M.; Fezza, F.; Di Marzo, V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: Stimulation of eating by 2-arachidonoyl glycerol. Br. J. Pharmacol. 2002, 136, 550–557. [Google Scholar] [CrossRef]
  284. Pagotto, U.; Marsicano, G.; Cota, D.; Lutz, B.; Pasquali, R. The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance. Endocr. Rev. 2006, 27, 73–100. [Google Scholar] [CrossRef]
  285. Kirkham, T.C.; Williams, C.M. Endogenous cannabinoids and appetite. Nutr. Res. Rev. 2001, 14, 65–86. [Google Scholar] [CrossRef][Green Version]
  286. Hao, S.; Avraham, Y.; Mechoulam, R.; Berry, E.M. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice. Eur. J. Pharmacol. 2000, 392, 147–156. [Google Scholar] [CrossRef]
  287. Jamshidi, N.; Taylor, D.A. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br. J. Pharmacol. 2001, 134, 1151–1154. [Google Scholar] [CrossRef][Green Version]
  288. Williams, C.M.; Kirkham, T.C. Anandamide induces overeating: Mediation by central cannabinoid (CB1) receptors. Psychopharmacology 1999, 143, 315–317. [Google Scholar] [CrossRef] [PubMed]
  289. Rinaldi-Carmona, M.; Barth, F.; Héaulme, M.; Shire, D.; Calandra, B.; Congy, C.; Martinez, S.; Maruani, J.; Néliat, G.; Caput, D.; et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994, 350, 240–244. [Google Scholar] [CrossRef][Green Version]
  290. Freedland, C.S.; Sharpe, A.L.; Samson, H.H.; Porrino, L.J. Effects of SR141716A on ethanol and sucrose self-administration. Alcohol. Clin. Exp. Res. 2001, 25, 277–282. [Google Scholar] [CrossRef] [PubMed]
  291. Simiand, J.; Keane, M.; Keane, P.E.; Soubrié, P. SR 141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset. Behav. Pharmacol. 1998, 9, 179–181. [Google Scholar] [PubMed]
  292. Gallate, J.E.; McGregor, I.S. The motivation for beer in rats: Effects of ritanserin, naloxone and SR 141716. Psychopharmacology 1999, 142, 302–308. [Google Scholar] [CrossRef]
  293. Gallate, J.E.; Saharov, T.; Mallet, P.E.; McGregor, I.S. Increased motivation for beer in rats following administration of a cannabinoid CB1 receptor agonist. Eur. J. Pharmacol. 1999, 370, 233–240. [Google Scholar] [CrossRef]
  294. Scopinho, A.A.; Guimarães, F.S.; Corrêa, F.M.; Resstel, L.B. Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists. Pharmacol. Biochem. Behav. 2011, 98, 268–272. [Google Scholar] [CrossRef] [PubMed]
  295. Frieling, H.; Albrecht, H.; Jedtberg, S.; Gozner, A.; Lenz, B.; Wilhelm, J.; Hillemacher, T.; de Zwaan, M.; Kornhuber, J.; Bleich, S. Elevated cannabinoid 1 receptor mRNA is linked to eating disorder related behavior and attitudes in females with eating disorders. Psychoneuroendocrinology 2009, 34, 620–624. [Google Scholar] [CrossRef] [PubMed]
  296. Scherma, M.; Satta, V.; Collu, R.; Boi, M.F.; Usai, P.; Fratta, W.; Fadda, P. Cannabinoid CB1/CB2 receptor agonists attenuate hyperactivity and body weight loss in a rat model of activity-based anorexia. Br. J. Pharmacol. 2017, 174, 2682–2695. [Google Scholar] [CrossRef] [PubMed][Green Version]
  297. Verty, A.N.; Evetts, M.J.; Crouch, G.J.; McGregor, I.S.; Stefanidis, A.; Oldfield, B.J. The cannabinoid receptor agonist THC attenuates weight loss in a rodent model of activity-based anorexia. Neuropsychopharmacology 2011, 36, 1349–1358. [Google Scholar] [CrossRef][Green Version]
  298. Costiniuk, C.T.; Mills, E.; Cooper, C.L. Evaluation of oral cannabinoid-containing medications for the management of interferon and ribavirin-induced anorexia, nausea and weight loss in patients treated for chronic hepatitis C virus. Can. J. Gastroenterol. 2008, 22, 376–380. [Google Scholar] [CrossRef]
  299. Lutge, E.E.; Gray, A.; Siegfried, N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst. Rev. 2013, CD005175. [Google Scholar] [CrossRef] [PubMed]
  300. Samji, H.; Yu, A.; Kuo, M.; Alavi, M.; Woods, R.; Alvarez, M.; Dore, G.J.; Tyndall, M.; Krajden, M.; Janjua, N.Z.; et al. Hepatitis Testers Cohort Team Late hepatitis B and C diagnosis in relation to disease decompensation and hepatocellular carcinoma development. J. Hepatol. 2017, 67, 909–917. [Google Scholar] [CrossRef]
  301. Lowe, H.I.; Toyang, N.J.; McLaughlin, W. Potential of Cannabidiol for the Treatment of Viral Hepatitis. Pharmacogn. Res. 2017, 9, 116–118. [Google Scholar] [CrossRef][Green Version]
  302. Hegde, V.L.; Nagarkatti, P.S.; Nagarkatti, M. Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS ONE 2011, 6, e18281. [Google Scholar] [CrossRef][Green Version]
  303. Pertwee, R.G.; Howlett, A.C.; Abood, M.E.; Alexander, S.P.; Di Marzo, V.; Elphick, M.R.; Greasley, P.J.; Hansen, H.S.; Kunos, G.; Mackie, K.; et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB1 and CB2. Pharmacol. Rev. 2010, 62, 588–631. [Google Scholar] [CrossRef][Green Version]
  304. Meye, F.J.; Trezza, V.; Vanderschuren, L.J.; Ramakers, G.M.; Adan, R.A. Neutral antagonism at the cannabinoid 1 receptor: A safer treatment for obesity. Mol. Psychiatry 2013, 18, 1294–1301. [Google Scholar] [CrossRef][Green Version]
  305. Carchman, R.A.; Harris, L.S.; Munson, A.E. The inhibition of DNA synthesis by cannabinoids. Cancer Res. 1976, 36, 95–100. [Google Scholar]
  306. Munson, A.E.; Harris, L.S.; Friedman, M.A.; Dewey, W.L.; Carchman, R.A. Antineoplastic activity of cannabinoids. J. Natl. Cancer Inst. 1975, 55, 597–602. [Google Scholar] [CrossRef] [PubMed]
  307. Dumitru, C.A.; Sandalcioglu, I.E.; Karsak, M. Cannabinoids in Glioblastoma Therapy: New Applications for Old Drugs. Front. Mol. Neurosci. 2018, 11, 159. [Google Scholar] [CrossRef]
  308. Marcu, J.P.; Christian, R.T.; Lau, D.; Zielinski, A.J.; Horowitz, M.P.; Lee, J.; Pakdel, A.; Allison, J.; Limbad, C.; Moore, D.H.; et al. Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblastoma cell proliferation and survival. Mol. Cancer Ther. 2010, 9, 180–189. [Google Scholar] [CrossRef] [PubMed][Green Version]
  309. Ruiz, L.; Miguel, A.; Díaz-Laviada, I. Delta9-tetrahydrocannabinol induces apoptosis in human prostate PC-3 cells via a receptor-independent mechanism. FEBS Lett. 1999, 458, 400–404. [Google Scholar] [CrossRef][Green Version]
  310. Sánchez, M.G.; Ruiz-Llorente, L.; Sánchez, A.M.; Díaz-Laviada, I. Activation of phosphoinositide 3-kinase/PKB pathway by CB(1) and CB(2) cannabinoid receptors expressed in prostate PC-3 cells. Involvement in Raf-1 stimulation and NGF induction. Cell. Signal. 2003, 15, 851–859. [Google Scholar] [CrossRef]
  311. Velasco, L.; Ruiz, L.; Sánchez, M.G.; Díaz-Laviada, I. delta(9)-Tetrahydrocannabinol increases nerve growth factor production by prostate PC-3 cells. Involvement of CB1 cannabinoid receptor and Raf-1. Eur. J. Biochem. 2001, 268, 531–535. [Google Scholar] [CrossRef] [PubMed]
  312. Caffarel, M.M.; Sarrió, D.; Palacios, J.; Guzmán, M.; Sánchez, C. Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. Cancer Res. 2006, 66, 6615–6621. [Google Scholar] [CrossRef] [PubMed][Green Version]
  313. Sánchez, C.; Galve-Roperh, I.; Canova, C.; Brachet, P.; Guzmán, M. Delta9-tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS Lett. 1998, 436, 6–10. [Google Scholar] [CrossRef][Green Version]
  314. Appendino, G.; Gibbons, S.; Giana, A.; Pagani, A.; Grassi, G.; Stavri, M.; Smith, E.; Rahman, M.M. Antibacterial cannabinoids from Cannabis sativa: A structure-activity study. J. Nat. Prod. 2008, 71, 1427–1430. [Google Scholar] [CrossRef]
  315. Pellati, F.; Borgonetti, V.; Brighenti, V.; Biagi, M.; Benvenuti, S.; Corsi, L. Cannabis sativa L. and Nonpsychoactive Cannabinoids: Their Chemistry and Role against Oxidative Stress, Inflammation, and Cancer. BioMed Res. Int. 2018, 2018, 1691428. [Google Scholar] [CrossRef][Green Version]
  316. Velasco, G.; Hernández-Tiedra, S.; Dávila, D.; Lorente, M. The use of cannabinoids as anticancer agents. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2016, 64, 259–266. [Google Scholar] [CrossRef][Green Version]
  317. Greenhough, A.; Patsos, H.A.; Williams, A.C.; Paraskeva, C. The cannabinoid delta(9)-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells. Int. J. Cancer 2007, 121, 2172–2180. [Google Scholar] [CrossRef] [PubMed]
  318. Guzmán, M. Cannabinoids: Potential anticancer agents. Nat. Rev. Cancer 2003, 3, 745–755. [Google Scholar] [CrossRef] [PubMed]
  319. Preet, A.; Ganju, R.K.; Groopman, J.E. Delta9-Tetrahydrocannabinol inhibits epithelial growth factor-induced lung cancer cell migration in vitro as well as its growth and metastasis in vivo. Oncogene 2008, 27, 339–346. [Google Scholar] [CrossRef] [PubMed][Green Version]
  320. Weber, J.; Schley, M.; Casutt, M.; Gerber, H.; Schuepfer, G.; Rukwied, R.; Schleinzer, W.; Ueberall, M.; Konrad, C. Tetrahydrocannabinol (Delta 9-THC) Treatment in Chronic Central Neuropathic Pain and Fibromyalgia Patients: Results of a Multicenter Survey. Anesthesiol. Res. Pract. 2009, 827290. [Google Scholar] [CrossRef][Green Version]
  321. Zurier, R.B. Prospects for cannabinoids as anti-inflammatory agents. J. Cell. Biochem. 2003, 88, 462–466. [Google Scholar] [CrossRef]
  322. Roberto, D.; Klotz, L.H.; Venkateswaran, V. Cannabinoid WIN 55,212-2 induces cell cycle arrest and apoptosis, and inhibits proliferation, migration, invasion, and tumor growth in prostate cancer in a cannabinoid-receptor 2 dependent manner. Prostate 2019, 79, 151–159. [Google Scholar] [CrossRef] [PubMed]
  323. Singh, K.; Jamshidi, N.; Zomer, R.; Piva, T.J.; Mantri, N. Cannabinoids and Prostate Cancer: A Systematic Review of Animal Studies. Int. J. Mol. Sci. 2020, 21, 6265. [Google Scholar] [CrossRef]
  324. Morell, C.; Bort, A.; Vara, D.; Ramos-Torres, A.; Rodríguez-Henche, N.; Díaz-Laviada, I. The cannabinoid WIN 55,212-2 prevents neuroendocrine differentiation of LNCaP prostate cancer cells. Prostate Cancer Prostatic Dis. 2016, 19, 248–257. [Google Scholar] [CrossRef] [PubMed][Green Version]
  325. Sarfaraz, S.; Afaq, F.; Adhami, V.M.; Mukhtar, H. Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res. 2005, 65, 1635–1641. [Google Scholar] [CrossRef][Green Version]
  326. Sarfaraz, S.; Afaq, F.; Adhami, V.M.; Malik, A.; Mukhtar, H. Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest. J. Biol. Chem. 2006, 281, 39480–39491. [Google Scholar] [CrossRef] [PubMed][Green Version]
  327. Blair, R.E.; Deshpande, L.S.; Sombati, S.; Elphick, M.R.; Martin, B.R.; DeLorenzo, R.J. Prolonged exposure to WIN55,212-2 causes downregulation of the CB1 receptor and the development of tolerance to its anticonvulsant effects in the hippocampal neuronal culture model of acquired epilepsy. Neuropharmacology 2009, 57, 208–218. [Google Scholar] [CrossRef][Green Version]
  328. Suleymanova, E.M.; Shangaraeva, V.A.; van Rijn, C.M.; Vinogradova, L.V. The cannabinoid receptor agonist WIN55.212 reduces consequences of status epilepticus in rats. Neuroscience 2016, 334, 191–200. [Google Scholar] [CrossRef] [PubMed]
  329. Jafari, M.R.; Ghiasvand, F.; Golmohammadi, S.; Zarrindast, M.R.; Djahanguiri, B. Influence of central nicotinic receptors on arachidonylcyclopropylamide (ACPA)-induced antinociception in mice. Int. J. Neurosci. 2008, 118, 531–543. [Google Scholar] [CrossRef]
  330. Kumar, R.; Prasoon, P.; Gautam, M.; Ray, S.B. Comparative antinociceptive effect of arachidonylcyclopropylamide, a cannabinoid 1 receptor agonist & lignocaine, a local anaesthetic agent, following direct intrawound administration in rats. Indian J. Med. Res. 2016, 144, 730–740. [Google Scholar] [CrossRef] [PubMed][Green Version]
  331. Ebrahimi-Ghiri, M.; Nasehi, M.; Zarrindast, M.R. Anxiolytic and antidepressant effects of ACPA and harmaline co-treatment. Behav. Brain Res. 2019, 364, 296–302. [Google Scholar] [CrossRef]
  332. McElroy, D.L.; Roebuck, A.J.; Scott, G.A.; Greba, Q.; Garai, S.; Denovan-Wright, E.M.; Thakur, G.A.; Laprairie, R.B.; Howland, J.G. Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: Preclinical in vitro and in vivo studies. Psychopharmacology 2021, 238, 1087–1098. [Google Scholar] [CrossRef] [PubMed]
  333. Onofrychuk, T.J.; Cai, S.; McElroy, D.L.; Roebuck, A.J.; Greba, Q.; Garai, S.; Thakur, G.A.; Laprairie, R.B.; Howland, J.G. Effects of the cannabinoid receptor 1 positive allosteric modulator GAT211 and acute MK-801 on visual attention and impulsivity in rats assessed using the five-choice serial reaction time task. Advance online publication. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2020, 109, 110235. [Google Scholar] [CrossRef]
  334. Slivicki, R.A.; Xu, Z.; Kulkarni, P.M.; Pertwee, R.G.; Mackie, K.; Thakur, G.A.; Hohmann, A.G. Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. Biol. Psychiatry 2018, 84, 722–733. [Google Scholar] [CrossRef][Green Version]
  335. Datta, U.; Kelley, L.K.; Middleton, J.W.; Gilpin, N.W. Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats. Psychopharmacology 2020, 237, 3729–3739. [Google Scholar] [CrossRef] [PubMed]
  336. Laprairie, R.B.; Kulkarni, P.M.; Deschamps, J.R.; Kelly, M.; Janero, D.R.; Cascio, M.G.; Stevenson, L.A.; Pertwee, R.G.; Kenakin, T.P.; Denovan-Wright, E.M.; et al. Enantiospecific Allosteric Modulation of Cannabinoid 1 Receptor. ACS Chem. Neurosci. 2017, 8, 1188–1203. [Google Scholar] [CrossRef]
  337. Laprairie, R.B.; Mohamed, K.A.; Zagzoog, A.; Kelly, M.; Stevenson, L.A.; Pertwee, R.; Denovan-Wright, E.M.; Thakur, G.A. Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling. Front. Mol. Neurosci. 2019, 12, 257. [Google Scholar] [CrossRef] [PubMed]
  338. Thapa, D.; Cairns, E.A.; Szczesniak, A.M.; Kulkarni, P.M.; Straiker, A.J.; Thakur, G.A.; Kelly, M. Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation. Molecules 2020, 25, 417. [Google Scholar] [CrossRef][Green Version]
  339. Jing, L.; Qiu, Y.; Zhang, Y.; Li, J.X. Effects of the cannabinoid CB1 receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine-seeking behavior in rats. Drug Alcohol Depend. 2014, 143, 251–256. [Google Scholar] [CrossRef][Green Version]
  340. Gamage, T.F.; Ignatowska-Jankowska, B.M.; Wiley, J.L.; Abdelrahman, M.; Trembleau, L.; Greig, I.R.; Thakur, G.A.; Tichkule, R.; Poklis, J.; Ross, R.A.; et al. In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav. Pharmacol. 2014, 25, 182–185. [Google Scholar] [CrossRef] [PubMed][Green Version]
  341. Gamage, T.F.; Anderson, J.C.; Abood, M.E. CB1 allosteric modulator Org27569 is an antagonist/inverse agonist of ERK1/2 signaling. Cannabis Cannabinoid Res. 2016, 1, 272–280. [Google Scholar] [CrossRef][Green Version]
  342. Ahn, K.H.; Mahmoud, M.M.; Kendall, D.A. Allosteric modulator ORG27569 induces CB1 cannabinoid receptor high affinity agonist binding state, receptor internalization, and Gi protein-independent ERK1/2 kinase activation. J. Biol. Chem. 2012, 287, 12070–12082. [Google Scholar] [CrossRef] [PubMed][Green Version]
  343. Ding, Y.; Qiu, Y.; Jing, L.; Thorn, D.A.; Zhang, Y.; Li, J.X. Behavioral effects of the cannabinoid CB1 receptor allosteric modulator ORG27569 in rats. Pharmacol. Res. Perspect. 2014, 2, e00069. [Google Scholar] [CrossRef][Green Version]
  344. Aderibigbe, A.O.; Pandey, P.; Doerksen, R.J. Negative allosteric modulators of cannabinoid receptor 1: Ternary complexes including CB1, orthosteric CP55940 and allosteric ORG27569. Advance online publication. J. Biomol. Struct. Dyn. 2021, 1–19. [Google Scholar] [CrossRef]
  345. Mulpuri, Y.; Marty, V.N.; Munier, J.J.; Mackie, K.; Schmidt, B.L.; Seltzman, H.H.; Spigelman, I. Synthetic peripherally-restricted cannabinoid suppresses chemotherapy-induced peripheral neuropathy pain symptoms by CB1 receptor activation. Neuropharmacology 2018, 139, 85–97. [Google Scholar] [CrossRef] [PubMed]
  346. Seltzman, H.H.; Shiner, C.; Hirt, E.E.; Gilliam, A.F.; Thomas, B.F.; Maitra, R.; Snyder, R.; Black, S.L.; Patel, P.R.; Mulpuri, Y.; et al. Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain. J. Med. Chem. 2016, 59, 7525–7543. [Google Scholar] [CrossRef] [PubMed][Green Version]
  347. Lozano-Ondoua, A.N.; Wright, C.; Vardanyan, A.; King, T.; Largent-Milnes, T.M.; Nelson, M.; Jimenez-Andrade, J.M.; Mantyh, P.W.; Vanderah, T.W. A cannabinoid 2 receptor agonist attenuates bone cancer-induced pain and bone loss. Life Sci. 2010, 86, 646–653. [Google Scholar] [CrossRef] [PubMed][Green Version]
  348. Curto-Reyes, V.; Llames, S.; Hidalgo, A.; Menéndez, L.; Baamonde, A. Spinal and peripheral analgesic effects of the CB2 cannabinoid receptor agonist AM1241 in two models of bone cancer-induced pain. Br. J. Pharmacol. 2010, 160, 561–573. [Google Scholar] [CrossRef][Green Version]
  349. Spigelman, I. Therapeutic Targeting of Peripheral Cannabinoid Receptors in Inflammatory and Neuropathic Pain States. In Translational Pain Research: From Mouse to Man; Kruger, L., Light AR, Eds.; CRC Press/Taylor & Francis: Boca Raton, FL, USA, 2010; Chapter 5. Available online: (accessed on 15 August 2021).
  350. Malan, P.T., Jr.; Ibrahim, M.M.; Deng, H.; Liu, Q.; Mata, H.P.; Vanderah, T.; Porreca, F.; Makriyannis, A. CB2 cannabinoid receptor-mediated peripheral antinociception. Pain 2001, 93, 239–245. [Google Scholar] [CrossRef]
  351. Ibrahim, M.M.; Deng, H.; Zvonok, A.; Cockayne, D.A.; Kwan, J.; Mata, H.P.; Vanderah, T.W.; Lai, J.; Porreca, F.; Makriyannis, A.; et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS. Proc. Natl. Acad. Sci. USA 2003, 100, 10529–10533. [Google Scholar] [CrossRef] [PubMed][Green Version]
  352. Yao, B.B.; Hsieh, G.C.; Frost, J.M.; Fan, Y.; Garrison, T.R.; Daza, A.V.; Grayson, G.K.; Zhu, C.Z.; Pai, M.; Chandran, P.; et al. In vitro and in vivo characterization of A-796260: A selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models. Br. J. Pharmacol. 2008, 153, 390–401. [Google Scholar] [CrossRef][Green Version]
  353. Hanuš, L.; Breuer, A.; Tchilibon, S.; Shiloah, S.; Goldenberg, D.; Horowitz, M.; Pertwee, R.G.; Ross, R.A.; Mechoulam, R.; Fride, E. HU-308: A specific agonist for CB(2), a peripheral cannabinoid receptor. Proc. Natl. Acad. Sci. USA 1999, 96, 14228–14233. [Google Scholar] [CrossRef][Green Version]
  354. Thapa, D.; Cairns, E.A.; Szczesniak, A.M.; Toguri, J.T.; Caldwell, M.D.; Kelly, M. The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation. Cannabis Cannabinoid Res. 2018, 3, 11–20. [Google Scholar] [CrossRef] [PubMed][Green Version]
  355. Toguri, J.T.; Lehmann, C.; Laprairie, R.B.; Szczesniak, A.M.; Zhou, J.; Denovan-Wright, E.M.; Kelly, M.E. Anti-inflammatory effects of cannabinoid CB(2) receptor activation in endotoxin-induced uveitis. Br. J. Pharmacol. 2014, 171, 1448–1461. [Google Scholar] [CrossRef][Green Version]
  356. Giblin, G.M.; Billinton, A.; Briggs, M.; Brown, A.J.; Chessell, I.P.; Clayton, N.M.; Eatherton, A.J.; Goldsmith, P.; Haslam, C.; Johnson, M.R.; et al. Discovery of 1-[4-(3-chlorophenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridin-7-yl]-1-morpholin-4-ylmethanone (GSK554418A), a brain penetrant 5-azaindole CB2 agonist for the treatment of chronic pain. J. Med. Chem. 2009, 52, 5785–5788. [Google Scholar] [CrossRef] [PubMed]
  357. Giblin, G.M.; O’Shaughnessy, C.T.; Naylor, A.; Mitchell, W.L.; Eatherton, A.J.; Slingsby, B.P.; Rawlings, D.A.; Goldsmith, P.; Brown, A.J.; Haslam, C.P.; et al. Discovery of 2-[(2,4-dichlorophenyl)amino]-N-[(tetrahydro- 2H-pyran-4-yl)methyl]-4-(trifluoromethyl)- 5-pyrimidinecarboxamide, a selective CB2 receptor agonist for the treatment of inflammatory pain. J. Med. Chem. 2007, 50, 2597–2600. [Google Scholar] [CrossRef]
  358. Li, A.L.; Carey, L.M.; Mackie, K.; Hohmann, A.G. Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice. J. Pharmacol. Exp. Ther. 2017, 362, 296–305. [Google Scholar] [CrossRef] [PubMed][Green Version]
  359. Wang, Z.Y.; Wang, P.; Bjorling, D.E. Treatment with a cannabinoid receptor 2 agonist decreases severity of established cystitis. J. Urol. 2014, 191, 1153–1158. [Google Scholar] [CrossRef] [PubMed]
  360. Sheng, W.S.; Chauhan, P.; Hu, S.; Prasad, S.; Lokensgard, J.R. Antiallodynic Effects of Cannabinoid Receptor 2 (CB2R) Agonists on Retrovirus Infection-Induced Neuropathic Pain. Pain Res. Manag. 2019, 2019, 1260353. [Google Scholar] [CrossRef][Green Version]
  361. Gorantla, S.; Makarov, E.; Roy, D.; Finke-Dwyer, J.; Murrin, L.C.; Gendelman, H.E.; Poluektova, L. Immunoregulation of a CB2 receptor agonist in a murine model of neuroAIDS. J. Neuroimmune Pharmacol. 2010, 5, 456–468. [Google Scholar] [CrossRef][Green Version]
  362. Mao, Y.; Huang, Y.; Zhang, Y.; Wang, C.; Wu, H.; Tian, X.; Liu, Y.; Hou, B.; Liang, Y.; Rong, H.; et al. Cannabinoid receptor 2-selective agonist JWH015 attenuates bone cancer pain through the amelioration of impaired autophagy flux induced by inflammatory mediators in the spinal cord. Mol. Med. Rep. 2019, 20, 5100–5110. [Google Scholar] [CrossRef] [PubMed][Green Version]
  363. Lombard, C.; Nagarkatti, M.; Nagarkatti, P. CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: Potential role for CB2-selective ligands as immunosuppressive agents. Clin. Immunol. 2007, 122, 259–270. [Google Scholar] [CrossRef] [PubMed][Green Version]
  364. Gu, X.; Mei, F.; Liu, Y.; Zhang, R.; Zhang, J.; Ma, Z. Intrathecal administration of the cannabinoid 2 receptor agonist JWH015 can attenuate cancer pain and decrease mRNA expression of the 2B subunit of N-methyl-D-aspartic acid. Anesth. Analg. 2011, 113, 405–411. [Google Scholar] [CrossRef]
  365. Verty, A.N.; Stefanidis, A.; McAinch, A.J.; Hryciw, D.H.; Oldfield, B. Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice. PLoS ONE 2015, 10, e0140592. [Google Scholar] [CrossRef][Green Version]
  366. Zhang, M.; Jiang, S.K.; Tian, Z.L.; Wang, M.; Zhao, R.; Wang, L.L.; Li, S.S.; Liu, M.; Li, J.Y.; Zhang, M.Z.; et al. CB2R orchestrates fibrogenesis through regulation of inflammatory response during the repair of skeletal muscle contusion. Int. J. Clin. Exp. Pathol. 2015, 8, 3491–3502. [Google Scholar]
  367. Jonsson, K.O.; Persson, E.; Fowler, C.J. The cannabinoid CB2 receptor selective agonist JWH133 reduces mast cell oedema in response to compound 48/80 in vivo but not the release of beta-hexosaminidase from skin slices in vitro. Life Sci. 2006, 78, 598–606. [Google Scholar] [CrossRef]
  368. Vidinský, B.; Gál, P.; Pilátová, M.; Vidová, Z.; Solár, P.; Varinská, L.; Ivanová, L.; Mojžíš, J. Anti-proliferative and anti-angiogenic effects of CB2R agonist (JWH-133) in non-small lung cancer cells (A549) and human umbilical vein endothelial cells: An in vitro investigation. Folia Biol. 2012, 58, 75–80. [Google Scholar]
  369. Li, Q.; Wang, F.; Zhang, Y.M.; Zhou, J.J.; Zhang, Y. Activation of cannabinoid type 2 receptor by JWH133 protects heart against ischemia/reperfusion-induced apoptosis. Cell. Physiol. Biochem. 2013, 31, 693–702. [Google Scholar] [CrossRef]
  370. Jafari, M.R.; Golmohammadi, S.; Ghiasvand, F.; Zarrindast, M.R.; Djahanguiri, B. Influence of nicotinic receptor modulators on CB2 cannabinoid receptor agonist (JWH133)-induced antinociception in mice. Behav. Pharmacol. 2007, 18, 691–697. [Google Scholar] [CrossRef]
  371. Perescis, M.F.; de Bruin, N.; Heijink, L.; Kruse, C.; Vinogradova, L.; Lüttjohann, A.; van Luijtelaar, G.; van Rijn, C.M. Cannabinoid antagonist SLV326 induces convulsive seizures and changes in the interictal EEG in rats. PLoS ONE 2017, 12, e0165363. [Google Scholar] [CrossRef] [PubMed][Green Version]
  372. Christopoulou, F.D.; Kiortsis, D.N. An overview of the metabolic effects of rimonabant in randomized controlled trials: Potential for other cannabinoid 1 receptor blockers in obesity. J. Clin. Pharm. Ther. 2011, 36, 10–18. [Google Scholar] [CrossRef] [PubMed]
  373. Beardsley, P.M.; Thomas, B.F.; McMahon, L.R. Cannabinoid CB1 receptor antagonists as potential pharmacotherapies for drug abuse disorders. Int. Rev. Psychiatry 2009, 21, 134–142. [Google Scholar] [CrossRef] [PubMed]
  374. Ueda, M.; Iwasaki, H.; Wang, S.; Murata, E.; Poon, K.Y.; Mao, J.; Martyn, J.A. Cannabinoid receptor type 1 antagonist, AM251, attenuates mechanical allodynia and thermal hyperalgesia after burn injury. Anesthesiology 2014, 121, 1311–1319. [Google Scholar] [CrossRef][Green Version]
  375. Bialuk, I.; Winnicka, M.M. AM251, cannabinoids receptors ligand, improves recognition memory in rats. Pharmacol. Rep. PR 2011, 63, 670–679. [Google Scholar] [CrossRef]
  376. Fiori, J.L.; Sanghvi, M.; O’Connell, M.P.; Krzysik-Walker, S.M.; Moaddel, R.; Bernier, M. The cannabinoid receptor inverse agonist AM251 regulates the expression of the EGF receptor and its ligands via destabilization of oestrogen-related receptor α protein. Br. J. Pharmacol. 2011, 164, 1026–1040. [Google Scholar] [CrossRef][Green Version]
  377. Felder, C.C.; Joyce, K.E.; Briley, E.M.; Glass, M.; Mackie, K.P.; Fahey, K.J.; Cullinan, G.J.; Hunden, D.C.; Johnson, D.W.; Chaney, M.O.; et al. LY320135, a novel cannabinoid CB1 receptor antagonist, unmasks coupling of the CB1 receptor to stimulation of cAMP accumulation. J. Pharmacol. Exp. Ther. 1998, 284, 291–297. [Google Scholar]
  378. He, X.H.; Jordan, C.J.; Vemuri, K.; Bi, G.H.; Zhan, J.; Gardner, E.L.; Makriyannis, A.; Wang, Y.L.; Xi, Z.X. Cannabinoid CB1 receptor neutral antagonist AM4113 inhibits heroin self-administration without depressive side effects in rats. Acta Pharmacol. Sin. 2019, 40, 365–373. [Google Scholar] [CrossRef]
  379. Gueye, A.B.; Pryslawsky, Y.; Trigo, J.M.; Poulia, N.; Delis, F.; Antoniou, K.; Loureiro, M.; Laviolette, S.R.; Vemuri, K.; Makriyannis, A.; et al. The CB1 Neutral Antagonist AM4113 Retains the Therapeutic Efficacy of the Inverse Agonist Rimonabant for Nicotine Dependence and Weight Loss with Better Psychiatric Tolerability. Int. J. Neuropsychopharmacol. 2016, 19, pyw068. [Google Scholar] [CrossRef][Green Version]
  380. Sink, K.S.; McLaughlin, P.J.; Wood, J.A.; Brown, C.; Fan, P.; Vemuri, V.K.; Peng, Y.; Olszewska, T.; Thakur, G.A.; Makriyannis, A.; et al. The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 2008, 33, 946–955. [Google Scholar] [CrossRef] [PubMed][Green Version]
  381. Järbe, T.U.; LeMay, B.J.; Olszewska, T.; Vemuri, V.K.; Wood, J.T.; Makriyannis, A. Intrinsic effects of AM4113, a putative neutral CB1 receptor selective antagonist, on open-field behaviors in rats. Pharmacol. Biochem. Behav. 2008, 91, 84–90. [Google Scholar] [CrossRef][Green Version]
  382. Cluny, N.L.; Chambers, A.P.; Vemuri, V.K.; Wood, J.T.; Eller, L.K.; Freni, C.; Reimer, R.A.; Makriyannis, A.; Sharkey, K.A. The neutral cannabinoid CB1 receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat. Pharmacol. Biochem. Behav. 2011, 97, 537–543. [Google Scholar] [CrossRef] [PubMed][Green Version]
  383. Di Marzo, V.; Piscitelli, F. The Endocannabinoid System and its Modulation by Phytocannabinoids. Neurotherapeutics 2015, 12, 692–698. [Google Scholar] [CrossRef]
  384. Bisogno, T.; Maurelli, S.; Melck, D.; De Petrocellis, L.; Di Marzo, V. Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J. Biol. Chem. 1997, 272, 3315–3323. [Google Scholar] [CrossRef] [PubMed][Green Version]
  385. Burstein, S.H.; Huang, S.M.; Petros, T.J.; Rossetti, R.G.; Walker, J.M.; Zurier, R.B. Regulation of anandamide tissue levels by N-arachidonylglycine. Biochem. Pharmacol. 2002, 64, 1147–1150. [Google Scholar] [CrossRef]
  386. Bradshaw, H.B.; Rimmerman, N.; Hu, S.S.J.; Benton, V.M.; Stuart, J.M.; Masuda, K.; Cravatt, B.F.; O’Dell, D.K.; Walker, J.M. The endocannabinoid anandamide is a precursor for the signaling lipid N-arachidonoyl glycine by two distinct pathways. BMC Biochem. 2009, 10, 14. [Google Scholar] [CrossRef][Green Version]
  387. Saghatelian, A.; McKinney, M.K.; Bandell, M.; Patapoutian, A.; Cravatt, B.F. A FAAH-regulated class of N-acyl taurines that activates TRP ion channels. Biochemistry 2006, 45, 9007–9015. [Google Scholar] [CrossRef]
  388. Di Marzo, V.; Goparaju, S.K.; Wang, L.; Liu, J.; Bátkai, S.; Járai, Z.; Fezza, F.; Miura, G.I.; Palmiter, R.D.; Sugiura, T.; et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001, 410, 822–825. [Google Scholar] [CrossRef]
  389. Nagayama, T.; Sinor, A.D.; Simon, R.P.; Chen, J.; Graham, S.H.; Jin, K.; Greenberg, D.A. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J. Neurosci. 1999, 19, 2987–2995. [Google Scholar] [CrossRef] [PubMed][Green Version]
  390. Alonso-Alconada, D.; Alvarez, A.; Hilario, E. Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury. Neurosci. Bull. 2011, 27, 275–285. [Google Scholar] [CrossRef] [PubMed][Green Version]
  391. Bortolato, M.; Mangieri, R.A.; Fu, J.; Kim, J.H.; Arguello, O.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; Piomelli, D. Antidepressant-like activity of the fatty acid amide hydrolase inhibitor URB597 in a rat model of chronic mild stress. Biol. Psychiatry 2007, 62, 1103–1110. [Google Scholar] [CrossRef] [PubMed][Green Version]
  392. Petrosino, S.; Di Marzo, V. FAAH and MAGL inhibitors: Therapeutic opportunities from regulating endocannabinoid levels. Curr. Opin. Investig. Drugs 2010, 11, 51–62. [Google Scholar]
  393. Ahn, K.; Johnson, D.S.; Mileni, M.; Beidler, D.; Long, J.Z.; McKinney, M.K.; Weerapana, E.; Sadagopan, N.; Liimatta, M.; Smith, S.E.; et al. Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain. Chem. Biol. 2009, 16, 411–420. [Google Scholar] [CrossRef][Green Version]
  394. Campos, A.C.; Moreira, F.A.; Gomes, F.V.; Del Bel, E.A.; Guimarães, F.S. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 2012, 367, 3364–3378. [Google Scholar] [CrossRef]
  395. Moore, S.A.; Nomikos, G.G.; Dickason-Chesterfield, A.K.; Schober, D.A.; Schaus, J.M.; Ying, B.P.; Xu, Y.C.; Phebus, L.; Simmons, R.M.; Li, D.; et al. Identification of a high-affinity binding site involved in the transport of endocannabinoids. Proc. Natl. Acad. Sci. USA 2005, 102, 17852–17857. [Google Scholar] [CrossRef][Green Version]
  396. Pawsey, S.; Wood, M.; Browne, H.; Donaldson, K.; Christie, M.; Warrington, S. Safety, Tolerability and Pharmacokinetics of FAAH Inhibitor V158866: A Double-Blind, Randomised, Placebo-Controlled Phase I Study in Healthy Volunteers. Drugs RD 2016, 16, 181–191. [Google Scholar] [CrossRef] [PubMed][Green Version]
  397. Hart, T.; Macias, A.T.; Benwell, K.; Brooks, T.; D’Alessandro, J.; Dokurno, P.; Francis, G.; Gibbons, B.; Haymes, T.; Kennett, G.; et al. Fatty acid amide hydrolase inhibitors. Surprising selectivity of chiral azetidine ureas. Bioorg. Med. Chem. Lett. 2009, 19, 4241–4244. [Google Scholar] [CrossRef] [PubMed]
  398. Roughley, S.D.; Browne, H.; Macias, A.T.; Benwell, K.; Brooks, T.; D’Alessandro, J.; Daniels, Z.; Dugdale, S.; Francis, G.; Gibbons, B.; et al. Fatty acid amide hydrolase inhibitors. 3: Tetra-substituted azetidine ureas with in vivo activity. Bioorga. Med. Chem. Lett. 2012, 22, 901–906. [Google Scholar] [CrossRef] [PubMed]
  399. Russo, R.; Loverme, J.; La Rana, G.; Compton, T.R.; Parrott, J.; Duranti, A.; Tontini, A.; Mor, M.; Tarzia, G.; Calignano, A.; et al. The fatty acid amide hydrolase inhibitor URB597 (cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J. Pharmacol. Exp. Ther. 2007, 322, 236–242. [Google Scholar] [CrossRef]
  400. Mor, M.; Rivara, S.; Lodola, A.; Plazzi, P.V.; Tarzia, G.; Duranti, A.; Tontini, A.; Piersanti, G.; Kathuria, S.; Piomelli, D. Cyclohexylcarbamic acid 3′- or 4′-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: Synthesis, quantitative structure-activity relationships, and molecular modeling studies. J. Med. Chem. 2004, 47, 4998–5008. [Google Scholar] [CrossRef] [PubMed][Green Version]
Table 1. Components of the ECS and possible targets for the treatment of various diseases.
Table 1. Components of the ECS and possible targets for the treatment of various diseases.
(“Endogenous Cannabinoids”/
2-AG [17]
AEA [17]
PEA [17]
OEA [17]
DAGL (2-AG) [18]
FAAH (AEA) [19]
NAAA (AEA) [19]
ABHD6 and ABHD12 (2-AG) [18]
MAGL (2-AG) [18]
(2-AG and AEA)
GPR18 [20]
GPR55 [21,22],
GPR119 [23],
TRPV1 (AEA) [24]
PPARγ [15]
FABPs [25,26]
HSP70s [27]
Serum albumin [27]
FAAH-like AEA transporter (FLAT) [28]
AMT aka EMT [19,29,30].
Table 2. Synthetic cannabinoids and their therapeutic window for pain.
Table 2. Synthetic cannabinoids and their therapeutic window for pain.
Synthetic CannabinoidsTherapeutic WindowReferences
1.HU-308 and AM-124 (CB2R agonists)Pain and inflammation[6]
2.Pyrimidinecarboxamide (and its derivatives) (CB2R modulators)Acute, chronic, and inflammatory pain[6]
3.JWH-133 (intrathecal administration)Reduction in post-operative hypersensitivity[57]
4.Peripherally restricted CB1R agonistsChronic pain [58]
Table 3. Uses and properties of cannabinoids for bowel disorders.
Table 3. Uses and properties of cannabinoids for bowel disorders.
1.Inflammatory bowel diseases such as Chron’s disease, ulcerative colitis and irritable bowel syndrome[212,213,214,215,216,217,218,219,220,221,222]
2.Secretion and motility-related disorders[223]
3.Ant-secretory [224]
4.Digestive [225]
5.Appetite-stimulant [225]
7.Anti-spasmodic (for diarrhoea and colic) [225]
8.Antiparasitic (for internal and external worms)[225]
9.Gastric ulcers [225]
10.Gastric neuroses [225]
11.Gastralgia (indigestion) [225]
12.Dispepsia [225]
13.Diarrhoea [212,226]
14.Abdominal cramping [226]
15.Abdominal pain [226]
16.Loss of appetite [227]
17.Anorexia [219]
18.Anti-inflammatory [212]
19.Anti-emetic [212]
20.Analgesic [212]
Table 4. Commonly used cannabinoid receptor ligands in cannabinoid research [303].
Table 4. Commonly used cannabinoid receptor ligands in cannabinoid research [303].
CB1R-Selective LigandsCB1 R/CB2R LigandsCB2R-Selective Ligands
Inverse Agonists
Inverse Agonists
Arachidonyl-2-chloroethylamide (ACEA)
propylamide (ACPA)
Of note is that CB1R inverse agonists may have adverse effects [304].
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Lowe, H.; Toyang, N.; Steele, B.; Bryant, J.; Ngwa, W. The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases. Int. J. Mol. Sci. 2021, 22, 9472.

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Lowe H, Toyang N, Steele B, Bryant J, Ngwa W. The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases. International Journal of Molecular Sciences. 2021; 22(17):9472.

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Lowe, Henry, Ngeh Toyang, Blair Steele, Joseph Bryant, and Wilfred Ngwa. 2021. "The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases" International Journal of Molecular Sciences 22, no. 17: 9472.

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