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].

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.

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-HT_1A, 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-HT_1A receptor (5-HT_1AR) 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-HT_1A 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.

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.

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].

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.

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].

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.

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].

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).