**6. Recent clinical trials and experience**

than treatment with a purified cannabinoid [42, 44]. This is supported by preclinical studies. In the *in vitro* oxotremorine-M mouse model of epilepsy, excessive neuronal bursting activity

Ca2+ in rat hippocampal neuronal and glial cells. This effect is compounded when the two compounds are mixed together, with the greatest effect occurring with whole plant extract

'entourage' effects between the various cannabinoids provide therapeutic benefit of cannabis whole plant extract, benefit that exceeds the activity of a single purified cannabinoid. This

The use of cannabis as a treatment for a variety of ailments in eastern and Mediterranean cultures over the last several millennium has been well documented [47]. The first description of the use of cannabis to treat seizures came from Dr. W. O'Shaugnessy who while working in India reported its successful use to treat seizures in an infant [48]. Following this, cannabis extracts became widely used throughout Europe and North America as an accepted treatment for epilepsy [49]. Following prohibition and with the introduction of other anticonvulsants,

During the mid-twentieth century, several reports on the effect of recreational cannabis consumption surfaced with contrasting effects. Several case reports described patients having decreased seizure frequency following the consumption of cannabis [50]. Cannabis consumption was also shown to be protective against first unprovoked seizures. In adult males who smoked cannabis in the last 90 days, the odds of having a first unprovoked seizure was 0.38 compared to adult males who never consumed cannabis [51]. Conversely, a patient with a history of epilepsy who had been seizure free for several months on medication was reported

In 1978, Mechoulam et al. reported their double blinded placebo-controlled study of CBD used as an add-on therapy in patients with refractory focal onset seizures. Of the four patients who took CBD two were seizure free for the 3 months of the study while another had partial improvement. None of the five patients who took placebo had any improvement in their seizures [53]. Cunha et al. reported the results of their study investigating the potential of CBD in patients with refractory temporal lobe epilepsy. In the first phase of the study, healthy adult volunteers were randomized to receive either placebo or CBD at 3 mg/kg/day for 30 days. Of 8 volunteers receiving CBD, 2 reported somnolence otherwise no adverse effects were reported. In the second phase, 15 adult patients with drug-resistant temporal lobe epilepsy were randomized to receive either placebo or CBD (up to 300 mg/day) for a period of 18 weeks in a double-blinded manner. Four of 8 patients dosed with CBD had complete improvement while three had partial improvement. No adverse effects were noted in patients given CBD [54].

to have had an exacerbation of seizures following the consumption of cannabis [52].

**5. Early clinical experience with cannabis for the treatment of** 

cannabis fell out of use as a treatment for epilepsy in western cultures.





can be suppressed with ∆<sup>9</sup>

208 Recent Advances in Cannabinoid Research


remains to be demonstrated in the human clinical context.

ing both ∆<sup>9</sup>

**epilepsy**

containing both ∆<sup>9</sup>

∆9

In recent years there has been a public perception that cannabis is a potent, natural, and safe alternative therapy for epilepsy. This has driven the demand for and use of cannabis and its derived products to treat epilepsy especially in those patients whose seizures are medically intractable. Coupled with the media exposure showing examples of the apparent miraculous effects of CBD oil in select epileptic patients, treating physicians have struggled to balance the patient demand for cannabis products and the need for studies to determine their, efficacy, dosing, side-effect profile, and indication. To that end, there have been multiple studies, predominantly in children, looking into these clinical questions. Unfortunately, the overwhelming majority of these studies have been retrospective, unblinded, and uncontrolled resulting in their being hampered by various forms of bias and potential placebo effect. Despite the plethora of published research on this topic, questions still remain on the use of cannabis in epilepsy.

In this section, we will review the limitations of the studies, the studies using artisanal and CBD enriched cannabis herbal extracts (CHE), the studies using highly purified pharmaceutical grade CBD, and a meta-analysis of the CBD studies.

#### **6.1. Limitations of the studies**

The widespread use of cannabis and the effect of bias are highlighted in various published surveys. McLachlan performed a survey in London, Ontario, Canada, in which more than 60% of patients declared that cannabis was effective for their seizures and stress levels [56]. Ladina et al. reported a case series of 18 patients who all found medicinal cannabis very helpful for seizure control and improvement of mood disorder [57]. By contrast, Press had reported a significant discrepancy in reported responder rate between preexisting Colorado residents and those who moved to Colorado to obtain cannabis to treat their child's epilepsy (22 vs. 47%) suggesting there is a significant perception bias among these children's caregivers as to the therapeutic benefits of cannabis [58]. Physician bias may also play a role as a recent survey by Mathern showed contrasting opinions about CBD between neurologists and the general public. In his study, a minority of epileptologists and general neurologists said that there were sufficient data safety (34%) and efficacy data (28%) and only 48% would advise using medical cannabis and only in severe cases of epilepsy. Conversely, nearly all patients and the general public responded that there was sufficient safety (96%) and efficacy (95%) data, and 98% would recommend cannabis in cases with severe epilepsy [59].

Given the present approved indications for medical coverage, the high cost of pharmaceutical grade CBD products, and the illegal status of cannabis in some countries and US states, the overwhelming majority of patients will at this time be using CBD oil extracts or artisanal products. In many jurisdictions these products are unregulated and therefore their content and consistency are uncertain and can vary. In Australia, where medical use of cannabis is highly restricted, Suraev reported that in parents treating their children with "illicit" cannabis extracts, the majority of extract samples used by the families contained low concentrations of cannabidiol, while Δ<sup>9</sup> -THC was present in nearly every sample [60]. These findings highlighted the profound variation in the illicit cannabis extracts being used. Studies examining the use of artisanal and CBD oil extracts therefore could have had uncertain and inconsistent amounts of cannabinoids. This inconsistency in combination the inherent problems of retrospective studies, make the findings of these studies questionable; moreover, none of published studies included serum CBD levels.

in quality of life measures and spike index on electroencephalogram (EEG). Adverse events

The Cannabinoid Research Initiative of Saskatchewan is currently conducting a Canadian, multicenter, prospective, open-label, dose-escalation phase 1 trial entitled Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E). The source of the CBD oil is consistent

of the cannabinoids in the CHE were confirmed through Health Canada Quality Assurance and Good Manufacturing Practices (GMP) certification [64]. Preliminary data showed that all 6 participants had improvements in seizure frequency, Quality of Life in Childhood Epilepsy (QOLCE) and EEG rating scores—with three participants showing continued improvements in these measures after the oil extract was discontinued. In addition, serum CBD levels suggested linear dose independent pharmacokinetics in all but one participant. In most participants, serum


intoxication clinically throughout the study. Preliminary data suggests that an effective and welltolerated CBD initial target dose of 5–6 mg/kg/day is effective and well tolerated when a 1:20 Δ<sup>9</sup>

THC:CBD CHE is used. In addition, the serum concentration of CBD follows dose-independent linear pharmacokinetics for most participants, although non-linear pharmacokinetics might occur but requires confirmation. Continued improvement in seizure frequency and QOLCE following the discontinuation of CHE suggest a possible enduring anticonvulsant effect [65].

With the production of a highly purified, pharmaceutical grade CBD (Epidiolex), studies could now be performed with a CBD source of greater reliability. Although potential bias

Devinksy published an open label trial in patients aged 1–30 with severe, intractable, childhood-onset, drugs resistant epilepsy. All patients were receiving their regular anti-epileptic drugs. Patients were given CBD at 2–5 mg/kg/day, titrated over a period of 2 weeks till intolerance or to a maximum dose of 25 mg/kg to 50 mg/kg/day. The main objective of the study was to establish safety and tolerability of CBD and the primary end point was the median percentage in the mean monthly frequency of motor seizures at 12 weeks. This study included mainly patients with Dravet and Lennox-Gastaut syndromes. One hundred and sixty-two patients were enrolled. A significant high rate of adverse events was reported in 128 patients (79%). The most common were somnolence (n = 41 [25%]), decreased appetite (n = 31 [19%]), diarrhea (n = 31 [19%]) and fatigue (n = 21 [13%]). This high rate of side effects (many of which were seen during the titration period) suggests that too rapid a titration rate may predispose toward side effects. The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) at 12 weeks of treatment. The median reduction in

From this same cohort, Rosenberg et al. reported that caregivers of 48 patients indicated an 8.2–9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness,

at the maximum dose of oil extract. None of the participants displayed any evidence of Δ<sup>9</sup>

**6.3. The highly purified, pharmaceutical grade CBD products**

remained, better clinical studies had been performed.

monthly motor seizures was 36·5% (IQR 0–64·7) [66].


Cannabis for Pediatric and Adult Epilepsy http://dx.doi.org/10.5772/intechopen.85719



211

during the titration period included somnolence, anorexia and diarrhea [63].

with a single batch of 1:20 Δ<sup>9</sup>

Δ9

To date, there are few prospective, double blind, placebo-controlled studies which all only examined the use of the highly purified, pharmaceutical grade CBD (Epidiolex). None involved artisanal CBD or the CBD oil extracts.

#### **6.2. The artisanal and CBD oil extracts**

While keeping the limitations of the studies examining artisanal and CBD oil extracts in epilepsy in mind, most of these studies did find that CBD oil extracts are effective in reducing seizures and improving quality of life.

Tzadok reported out of 74 children being treated with a 20% CBD and 1% Δ<sup>9</sup> -THC CHE, 89% reported reduction in seizure frequency with only 43% of patients having a >50% reduction in seizures. Five patients reported aggravation of seizures leading to withdrawal from the study. Improvement in behavior and alertness, language, communication, motor skills and sleep were noted. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in five patients. The CBD dosing ranged from 1 to 20 mg/kg/day with 83% taking <10 mg/kg/day [61].

Similarly, Porcari retrospectively studied the efficacy of artisanal CBD preparations in children with epilepsy. The study also included a subgroup comparison to determine if the addition of clobazam was related to any beneficial effects of CBD. Overall, the addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The difference in effect between CBD alone and CBD with clobazam was not statistically significant. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. The average dose of CBD was 2.9 mg/kg/day in the CBD group and 5.8 mg/kg/day in the CBD and clobazam group [62].

McCoy et al. performed a prospective open label study using a 2:100 Δ<sup>9</sup> -THC:CBD CHE in 20 children with Dravet syndrome. The dose of CBD ranged from 7 to 16 mg/kg/day (mean 13.3 mg CBD/kg/day). They reported that during the 20-week intervention period the median monthly reduction in motor seizures was 70.6%. The CHE also resulted in improvements in quality of life measures and spike index on electroencephalogram (EEG). Adverse events during the titration period included somnolence, anorexia and diarrhea [63].

The Cannabinoid Research Initiative of Saskatchewan is currently conducting a Canadian, multicenter, prospective, open-label, dose-escalation phase 1 trial entitled Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E). The source of the CBD oil is consistent with a single batch of 1:20 Δ<sup>9</sup> -THC:CBD CHE used for all study participants. Concentrations of the cannabinoids in the CHE were confirmed through Health Canada Quality Assurance and Good Manufacturing Practices (GMP) certification [64]. Preliminary data showed that all 6 participants had improvements in seizure frequency, Quality of Life in Childhood Epilepsy (QOLCE) and EEG rating scores—with three participants showing continued improvements in these measures after the oil extract was discontinued. In addition, serum CBD levels suggested linear dose independent pharmacokinetics in all but one participant. In most participants, serum Δ9 -THC concentrations remained lower than what would be expected to cause intoxication even at the maximum dose of oil extract. None of the participants displayed any evidence of Δ<sup>9</sup> -THC intoxication clinically throughout the study. Preliminary data suggests that an effective and welltolerated CBD initial target dose of 5–6 mg/kg/day is effective and well tolerated when a 1:20 Δ<sup>9</sup> - THC:CBD CHE is used. In addition, the serum concentration of CBD follows dose-independent linear pharmacokinetics for most participants, although non-linear pharmacokinetics might occur but requires confirmation. Continued improvement in seizure frequency and QOLCE following the discontinuation of CHE suggest a possible enduring anticonvulsant effect [65].

#### **6.3. The highly purified, pharmaceutical grade CBD products**

Given the present approved indications for medical coverage, the high cost of pharmaceutical grade CBD products, and the illegal status of cannabis in some countries and US states, the overwhelming majority of patients will at this time be using CBD oil extracts or artisanal products. In many jurisdictions these products are unregulated and therefore their content and consistency are uncertain and can vary. In Australia, where medical use of cannabis is highly restricted, Suraev reported that in parents treating their children with "illicit" cannabis extracts, the majority of extract samples used by the families contained low concentrations

lighted the profound variation in the illicit cannabis extracts being used. Studies examining the use of artisanal and CBD oil extracts therefore could have had uncertain and inconsistent amounts of cannabinoids. This inconsistency in combination the inherent problems of retrospective studies, make the findings of these studies questionable; moreover, none of pub-

To date, there are few prospective, double blind, placebo-controlled studies which all only examined the use of the highly purified, pharmaceutical grade CBD (Epidiolex). None

While keeping the limitations of the studies examining artisanal and CBD oil extracts in epilepsy in mind, most of these studies did find that CBD oil extracts are effective in reducing

reported reduction in seizure frequency with only 43% of patients having a >50% reduction in seizures. Five patients reported aggravation of seizures leading to withdrawal from the study. Improvement in behavior and alertness, language, communication, motor skills and sleep were noted. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in five patients. The CBD dosing ranged

Similarly, Porcari retrospectively studied the efficacy of artisanal CBD preparations in children with epilepsy. The study also included a subgroup comparison to determine if the addition of clobazam was related to any beneficial effects of CBD. Overall, the addition of CBD resulted in 39% of patients having a >50% reduction in seizures, with 10% becoming seizure-free. The difference in effect between CBD alone and CBD with clobazam was not statistically significant. Increased alertness and improved verbal interactions were reported in 14% of patients in the CBD group and 8% of patients in the CBD and clobazam group. The average dose of CBD was 2.9 mg/kg/day in the CBD group and 5.8 mg/kg/day in the CBD and

20 children with Dravet syndrome. The dose of CBD ranged from 7 to 16 mg/kg/day (mean 13.3 mg CBD/kg/day). They reported that during the 20-week intervention period the median monthly reduction in motor seizures was 70.6%. The CHE also resulted in improvements

Tzadok reported out of 74 children being treated with a 20% CBD and 1% Δ<sup>9</sup>

McCoy et al. performed a prospective open label study using a 2:100 Δ<sup>9</sup>

from 1 to 20 mg/kg/day with 83% taking <10 mg/kg/day [61].




of cannabidiol, while Δ<sup>9</sup>

210 Recent Advances in Cannabinoid Research

lished studies included serum CBD levels.

**6.2. The artisanal and CBD oil extracts**

seizures and improving quality of life.

clobazam group [62].

involved artisanal CBD or the CBD oil extracts.

With the production of a highly purified, pharmaceutical grade CBD (Epidiolex), studies could now be performed with a CBD source of greater reliability. Although potential bias remained, better clinical studies had been performed.

Devinksy published an open label trial in patients aged 1–30 with severe, intractable, childhood-onset, drugs resistant epilepsy. All patients were receiving their regular anti-epileptic drugs. Patients were given CBD at 2–5 mg/kg/day, titrated over a period of 2 weeks till intolerance or to a maximum dose of 25 mg/kg to 50 mg/kg/day. The main objective of the study was to establish safety and tolerability of CBD and the primary end point was the median percentage in the mean monthly frequency of motor seizures at 12 weeks. This study included mainly patients with Dravet and Lennox-Gastaut syndromes. One hundred and sixty-two patients were enrolled. A significant high rate of adverse events was reported in 128 patients (79%). The most common were somnolence (n = 41 [25%]), decreased appetite (n = 31 [19%]), diarrhea (n = 31 [19%]) and fatigue (n = 21 [13%]). This high rate of side effects (many of which were seen during the titration period) suggests that too rapid a titration rate may predispose toward side effects. The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) at 12 weeks of treatment. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7) [66].

From this same cohort, Rosenberg et al. reported that caregivers of 48 patients indicated an 8.2–9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global quality of life (QOL). Interestingly, these differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure reducing effects [67].

12 months, −57% at 15 months and −55% at 18 months. The transdermal patch was well tolerated. Serious adverse events were as follows: seizures (n = 2) and increased anxiety (n = 1); one death was reported after the 15 month visit. In addition, no significant elevations in alanine aminotransferase and aspartate aminotransferase levels >3 times upper limit of normal were

In comparing cannabis derived treatments to standard therapies, it is worthwhile to note that the STICLO group examining the effects of stiripentol in Dravet patients in a double blind randomized placebo controlled study showed that 15 (71%) patients had >50% seizure reduction (including nine free of clonic or tonic-clonic seizures) compared to only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52.1–90.7 vs. placebo 0–14.6). Stiripentol's responder rate is therefore suggested to be superior to Epidiolex with a far lower placebo responder rate [72]. Similarly, in a double-blind, randomized, placebo-controlled trial of the anti-epileptic drug rufinamide in patients with Lennox-Gastaut syndrome, the median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7 vs. 11.7%, p = 0.0015). There was also a difference (p < 0.0001) in tonic-atonic ("drop attack") seizure frequency with rufinamide (42.5% median percentage reduction) vs. placebo (1.4% increase). These findings are comparable with the results with Epidiolex. One also has to keep in mind that the median reduction of atonic seizures in the placebo group was markedly higher with the Epidiolex study suggesting potential bias [73]. Of note, the results from the study by McCoy et al. and the preliminary data from CARE-E study showed a much higher responder rate than those with pharmaceutical grade CBD. This appar-

effect in which the various cannabinoids can act synergistically with one another [42, 44].

The cannabinoids found in cannabis appear to offer a unique pharmacological mode of action in the treatment of epilepsy. This, combined with the apparent low risk of serious side effects, makes cannabis and an attractive potential option for patients with treatment resistant epilepsy. Currently, there is a large public perception that cannabis products are superior to and safer than conventional anti-epileptic medications especially in treating patients with Dravet syndrome and other pediatric onset epileptic encephalopathies. Based on interpretation of the available data, the authors feel that cannabis based therapies show promise in the treatment of children with treatment resistant epilepsies. While the studies to date assessing cannabis based therapies for the treatment of epilepsy have been encouraging, they should be interpreted with caution. At this time, the long-term adverse effects, the indicated epilepsy and seizure types suitable for treatment with cannabis, the dosing of CBD and other cannabinoids, remain unknown. Also, there is minimal data regarding the pharmacokinetics of the cannabinoids especially in children and when used in patients with multiple concomitant medications. Moreover, the existing studies are limited with the majority of them being retrospective

and subject to bias, possible placebo effect, and other limitations.


Cannabis for Pediatric and Adult Epilepsy http://dx.doi.org/10.5772/intechopen.85719 213

seen [71].

ent superiority of a CHE containing Δ<sup>9</sup>

**7. Conclusion**

Devinsky et al. later performed a double blind, placebo-controlled trial in patients with Dravet syndrome including 120 children and young adults using Epidiolex with a CBD dosage of 20 mg/kg/day. The median frequency of convulsive seizures per month decreased from 12.4 (baseline) to 5.9 with CBD, as compared with a decrease from 14.9 (baseline) to 14.1 with placebo (adjusted median difference between cannabidiol vs. placebo was −22.8% points [CI], −41.1 to −5.4; p = 0.01). The percentage of patients who had at least a 50% reduction in convulsive seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93–4.30; p = 0.08). This study shows an overall benefit of CBD over placebo but also a large placebo effect in the control group [68].

Another trial that assessed the efficacy of Epidiolex in reducing atonic seizures in patients with Lennox-Gastaut syndrome. In this double blind, placebo-controlled trial, a total of 225 patients were enrolled, 76 patients were assigned to a treatment group (20 mg/kg/day CBD) and 76 to the placebo group. The median percent reduction from baseline in monthly atonic seizure frequency during the treatment period was 41.9% in the treatment group vs. 21.8% in the placebo group. As with the other studies assessing Epidiolex, the most common adverse events among the patients in the treatment groups were somnolence, decreased appetite, and diarrhea [69].

A recent systematic review assessed the safety and efficacy of pharmaceutical grade CBD in pediatric onset drug resistant epilepsy with outcome measures including 50% seizure reduction, complete seizure freedom, improved QOL. A total of 36 studies were identified including 6 randomized controlled trials and 30 observational studies. Overall CBD at a dose of 20 mg/kg/day was more effective than placebo in reducing seizure frequency by 50% (Relative Risk 1.74: 1.24–2.43). For one patient to achieve a 50% reduction in seizures the number of patient needed to treat was 8. In pooled data of 17 of the observational studies CBD at 20 mg/ kg/day resulted in 48.5% of patients achieving a 50% reduction in seizures (95% CI: 39.0–58.1%) while pooled data from 14 observational studies showed 8.5% of patients became seizure free (95% CI: 3.8–14.5%). Quality of life improved in 55.8% of patients (95% CI: 40.5–70.6%) while serious adverse events related to treatment with CBD was very low at 2.2% of patients (95% CI: 0.0–7.9%). From this data, the authors concluded that pharmaceutical grade CBD may reduce seizure frequency but other randomized controlled trials examining a more diverse group of epilepsy syndromes and other cannabinoids was needed [70].

To date, the evidence to support the use of cannabis in adults is minimal. STAR 1 is a phase 2A, randomized, double blind, placebo-controlled study that evaluated the safety and efficacy of synthetic transdermal CBD in adult patients with focal epilepsy. In this study 174 patients were randomized to receive either 195 mg CBD, 390 mg CBD or placebo via a transdermal patch. Patients who completed the 12-week study were able to continue into the 24-month open-label extension STAR 2 study (n = 171). In as of yet published data from these trials there was an increase in efficacy of transdermal CBD over 18 months. Median percentage change in seizure rates was −25% at 3 months, −40% at 6 months, −48% at 9 months, −52% at 12 months, −57% at 15 months and −55% at 18 months. The transdermal patch was well tolerated. Serious adverse events were as follows: seizures (n = 2) and increased anxiety (n = 1); one death was reported after the 15 month visit. In addition, no significant elevations in alanine aminotransferase and aspartate aminotransferase levels >3 times upper limit of normal were seen [71].

In comparing cannabis derived treatments to standard therapies, it is worthwhile to note that the STICLO group examining the effects of stiripentol in Dravet patients in a double blind randomized placebo controlled study showed that 15 (71%) patients had >50% seizure reduction (including nine free of clonic or tonic-clonic seizures) compared to only one (5%) on placebo (none were seizure free; stiripentol 95% CI 52.1–90.7 vs. placebo 0–14.6). Stiripentol's responder rate is therefore suggested to be superior to Epidiolex with a far lower placebo responder rate [72]. Similarly, in a double-blind, randomized, placebo-controlled trial of the anti-epileptic drug rufinamide in patients with Lennox-Gastaut syndrome, the median percentage reduction in total seizure frequency was greater in the rufinamide therapy group than in the placebo group (32.7 vs. 11.7%, p = 0.0015). There was also a difference (p < 0.0001) in tonic-atonic ("drop attack") seizure frequency with rufinamide (42.5% median percentage reduction) vs. placebo (1.4% increase). These findings are comparable with the results with Epidiolex. One also has to keep in mind that the median reduction of atonic seizures in the placebo group was markedly higher with the Epidiolex study suggesting potential bias [73].

Of note, the results from the study by McCoy et al. and the preliminary data from CARE-E study showed a much higher responder rate than those with pharmaceutical grade CBD. This apparent superiority of a CHE containing Δ<sup>9</sup> -THC would be in keeping with the proposed entourage effect in which the various cannabinoids can act synergistically with one another [42, 44].
