The therapeutic potential of purified cannabidiol

There is a small body of literature that has assessed the effects of cannabinoids (mainly THC) in the eye, with a limited number of studies showing benefit of CBD in models of diabetic retinopathy and corneal hyperalgesia [ 129 ]. There is only one clinical trial in this field that examined the effects of THC (5 mg) or CBD (20 and 40 mg, acute dose, sublingual) in patients with ocular hypertension or early primary open angle glaucoma [ 130 ]. Although THC reduced intraocular pressure 2 h after administration, CBD did not reduce intraocular pressure at any time, and in fact the higher dose produced a transient increase in intraocular pressure at 4 h.

A big question in the clinical use of CBD is how much is enough? To answer this, we have looked at the randomised controlled studies with CBD, as uncontrolled studies tend to underestimate effective doses. Single doses of CBD that have a significantly different biological impact compared to placebo are in the range 160 mg to 800 mg (see Fig.  2 A). In RCTs where a positive effect of repeated CBD treatment (on any endpoint) in patients has been recorded compared to placebo, the daily dosing was in the range of 300 to 1200 mg/day (see Fig.  2 B). In RCTs where no impact of CBD (on any endpoint) was observed, dosing was in the range of 20 to 800 mg. While there is considerable overlap here, studies that were positive did tend to use a higher mean dose of CBD. Negative trials with CBD could be the result of insufficient dosing or could also be due to poor clinical trial design or the wrong patient populations. Thus, it is sometimes difficult to tell from negative studies whether CBD is ineffective in that particular condition or whether the doses tested were too low. This is confounded by the fact that the oral bioavailability of CBD is low, and only about ~ 10% of the drug will enter circulation [ 131 ], and by the fact that many published studies have only looked at a single dose of CBD. Fig. 2 The effective (green) and ineffective (orange) doses of purified CBD (mg/day) tested through randomised controlled trials (RCTs) in the acute setting A  and with repeated dosing B  across different indications (including healthy volunteer studies). C  A summary of all doses in all contexts tested though RCTs. D  Plasma or blood levels of CBD (where tested) in acute dosing or repeated doing clinical studies with purified CBD that reported positive (green) or negative (orange) outcomes. Each dot represents an RCT The effective (green) and ineffective (orange) doses of purified CBD (mg/day) tested through randomised controlled trials (RCTs) in the acute setting A  and with repeated dosing B  across different indications (including healthy volunteer studies). C  A summary of all doses in all contexts tested though RCTs. D  Plasma or blood levels of CBD (where tested) in acute dosing or repeated doing clinical studies with purified CBD that reported positive (green) or negative (orange) outcomes. Each dot represents an RCT Unfortunately, very few studies have measured the plasma or tissue levels of CBD as a guide to the therapeutic range of CBD, but where reported, the mean plasma levels of CBD in studies that report a significant effect of CBD on endpoints measured (in either acute or repeated dosing studies) are higher than those that do not (~ 150 nM versus 30 nM respectively, see Fig.  2 D). For reference, the mean serum concentration of CBD is ~ 125 ng/ml (~ 350 nM) in patients with epilepsy [ 8 ]. CBD has dozens of molecular targets with various potency [ 50 ], mostly low, and the therapeutic target levels for CBD probably vary between conditions depending on the most important molecular targets in that particular condition.

The use, acceptance and legality of cannabinoid-based medicines and the cannabinoid cannabidiol (CBD) have grown considerably in the last 10 years. CBD is in the unusual position where it is available as both a health supplement and as a licensed medicine. As a health supplement, it is estimated that ~ 10% of populations are using CBD [ 1 ]. In the UK, the recommended daily allowance of CBD is 70 mg/day in these types of products [ 2 ]. Anecdote and survey data suggest that people take CBD for anxiety, stress, depression, sleep, gastrointestinal problems and pain [ 3 – 5 ]. Some of the reputation of CBD’s therapeutic utility across such a broad range of conditions is based on scientific evidence, albeit still at a preclinical level. Clinically, a purified oral solution of CBD (Epidiolex) is approved for the management of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome or tuberous sclerosis complex on the basis of multiple positive, phase 3 randomised controlled trials (RCTs) [ 6 ]. Patients typically take a dose of between 20 and 25 mg/kg/day, with an average seizure reduction of ~ 50% [ 7 ] and a mean serum concentration of ~ 125 ng/ml [ 8 ]. CBD products come in many forms; they can be purified synthetically or by plant extraction processes (usually at least ~ 98% pure CBD), broad spectrum distillates (including many of the other phytocannabinoids and phytochemicals) or full spectrum (including all the phytochemicals from the cannabis plant from which the CBD was extracted). Spectrum products are sometimes also called enriched or artisan products. CBD products can also come in defined ratios with Δ 9 tetrahydrocannabinol (THC), for example, 20:1 CBD to THC products. In any of the non-purified CBD products that have therapeutic utility, it is difficult to tell whether the benefit of the product arises from CBD as the active pharmaceutic ingredient (API), or as a consequence of the other chemicals present, or as a consequence of any interaction (pharmacodynamic or pharmacokinetic) between the compounds (referred to as the entourage hypothesis). The aim of this review is to establish what indications there are clinical evidence for the efficacy of purified CBD products only, without any complication of additional APIs or drug interactions. This is critical in the understanding of the CBD molecule. We have not considered epilepsy, where multiple reviews already exist, and the efficacy of purified CBD is well established [ 9 , 10 ]. We addressed the aim of the study by appraising the published literature of clinical studies that have examined the therapeutic benefit of purified CBD in various conditions. A total of 99 clinical studies testing purified CBD were identified through systematic searching of engines and hand searching; 29 were uncontrolled/observational studies, and 70 were randomised controlled trials (RCTs). These studies were categorised by disease indication and are discussed below in the order of the weight of evidence/number of studies per condition. A summary of the patient cohorts in which CBD has clinical evidence of significant efficacy through controlled studies is presented in Table  1  and Fig.  1 . Table 1 Randomised, controlled clinical studies showing a significant effect of purified CBD in patients and in healthy volunteers. Studies are divided by the patient cohort in which CBD was tested and the treatment regime. Where measured, plasma levels of CBD are reported. Abbreviations: n/a, not available; nM, nanomolar; PTSD, post traumatic stress disorder; REM, rapid eye movement; THC-COOH, 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol; Δ 9 -THC, Δ9-tetrahydrocannabinol Patient cohort/ indication Treatment regime Endpoint modified Plasma level of CBD Ref Schizophrenia 800 mg/day for 6 weeks Improvements from baseline in processing speed, visual memory, visuomotor coordination and sustained attention n/a [ 11 ] 800 mg/day for 4 weeks Improvements in Brief Psychiatric Rating Scale or Positive and Negative Syndrome Scale scores on day 14 or day 28 n/a [ 12 ] 1000 mg/day for 6 weeks Lower levels of psychotic symptoms (Positive and Negative Syndrome Scale) and more likely to be assessed by their treating clinician as clinically improved and/or not severely unwell n/a [ 13 ] Psychosis 600 mg, single dose Attenuated dysfunctions in prefrontal and mediotemporal brain regions Modulation of medial temporal and striatal function during fear processing Attenuation of activation in the left insula/parietal operculum during motivational salience processing Modulation of striatum, medial temporal cortex and midbrain regions activation during a verbal learning task ~ 250 nM after 270 min [ 14 – 17 ] 600 mg for 8 days Reduced cortisol reactivity and psychological response to social stress n/a [ 18 ] PTSD 300 mg, single dose Attenuated cognitive impact induced by the recall of traumatic events Reduced anxiety induced by the recall of traumatic events in patients with nonsexual trauma n/a [ 19 , 20 ] Health care professionals during COVID-19 300 mg/day for 28 days Reduced symptoms of burnout, emotional exhaustion, depression and anxiety in health care professionals working with patients during COVID-19 ~ 57 nM on day 21 [ 21 ] Parkinson’s disease 300 mg, single dose Decreased anxiety in response to public speaking and decreased tremor amplitude in an anxiogenic situation n/a [ 22 ] 300 mg for 14 weeks Improvement in sleep satisfaction from the 4th to 8th week n/a [ 23 ] 300 mg/day for 6 weeks Improvement in well-being and quality of life n/a [ 24 ] 300 mg/day for 14 weeks No change in REM sleep behaviour disorder but an improvement in sleep satisfaction n/a [ 23 ] Social anxiety disorder 400 mg, single dose Decreased subjective anxiety, reduced ECD uptake in the left parahippocampal gyrus, hippocampus and inferior temporal gyrus n/a [ 25 ] 600 mg, single dose Reduced anxiety, cognitive impairment, and discomfort to public speaking n/a [ 26 ] 300 mg for 4 weeks Reduction in Fear of Negative Evaluation scores and Scores of Liebowitz Social Anxiety Scale n/a [ 27 ] Autism spectrum disorder 600 mg, single dose Altered regional fractional amplitude of low-frequency fluctuations and functional connectivity in/between cerebellar vermis, the right fusiform gyrus, subcortical (striatal) and cortical targets Increased glutamate in the basal ganglia and decreased it in the dorsomedial prefrontal cortex. Decreased GABA + in prefrontal and subcortical regions n/a [ 28 , 29 ] 1200 mg/day for 8 weeks Greater improvement in the Aberrant Behaviour Checklist score n/a [ 30 ] Insomnia 160 mg, single dose Improvement in subjective sleep quality n/a [ 31 ] Thumb basal joint arthritis Topical: 6.2 mg/mL CBD for 2 weeks Improved patient-reported outcome measures (VAS pain, disabilities of the arm, shoulder, and hand; single assessment numeric evaluation) n/a [ 32 ] Peripheral neuropathy Topical: 250 mg CBD/3 fl. Oz for 4 weeks Reduction in intense pain, sharp pain, cold and itchy sensations n/a [ 33 ] Heroin use disorder 400 or 800 mg for 3 days Reduced both craving and anxiety, cortisol and heart rate induced by the presentation of salient drug cues n/a [ 34 ] Cocaine use disorder 800 mg for 92 days Reduction in inflammatory markers after detoxification ~ 245 nM at week 12 [ 35 ] Cannabis use disorder 400 mg or 800 mg for 4 weeks Reduced urinary THC-COOH to creatinine concentrations and increased abstinence from cannabis n/a [ 36 ] Cigarette smokers 800 mg, single dose Reduced the salience and pleasantness of cigarette cues and reduced explicit pleasantness of cigarette images n/a [ 37 ] 400 µg per inhalation for 7 days Reduced the number of cigarettes smoked by ~ 40% n/a [ 38 ] Healthy volunteers 1 mg/kg or 60 mg, single dose Blocked the anxiety and subjective alterations induced by Δ 9 -THC [ 39 , 40 ] 300 mg, single dose Reduced anxiety in response to public speaking n/a [ 41 – 43 ] 32 mg inhaled single dose Enhanced consolidation of explicit fear extinction n/a [ 44 ] 400 mg, single dose Decreased subjective anxiety and increased mental sedation with changes in the limbic and paralimbic brain areas n/a [ 45 ] 600 mg, single dose Disruption of prefrontal-subocritical connectivity during emotional processing Attenuated the blood oxygenation level-dependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing fearful faces Reduced resting blood pressure and blood pressure responses to stress Decreased gut permeability induced by aspirin ~ 47 nM at 2 h [ 46 – 48 ] 600 mg, 7 days Reduced blood pressure response to stress, increased internal carotid artery diameter, reduced arterial stiffness and improved flow mediation dilatation n/a [ 49 ] Randomised, controlled clinical studies showing a significant effect of purified CBD in patients and in healthy volunteers. Studies are divided by the patient cohort in which CBD was tested and the treatment regime. Where measured, plasma levels of CBD are reported. Abbreviations: n/a, not available; nM, nanomolar; PTSD, post traumatic stress disorder; REM, rapid eye movement; THC-COOH, 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol; Δ 9 -THC, Δ9-tetrahydrocannabinol Lower levels of psychotic symptoms (Positive and Negative Syndrome Scale) and more likely to be assessed by their treating clinician as clinically improved and/or not severely unwell Attenuated dysfunctions in prefrontal and mediotemporal brain regions Modulation of medial temporal and striatal function during fear processing Attenuation of activation in the left insula/parietal operculum during motivational salience processing Modulation of striatum, medial temporal cortex and midbrain regions activation during a verbal learning task Attenuated cognitive impact induced by the recall of traumatic events Reduced anxiety induced by the recall of traumatic events in patients with nonsexual trauma Altered regional fractional amplitude of low-frequency fluctuations and functional connectivity in/between cerebellar vermis, the right fusiform gyrus, subcortical (striatal) and cortical targets Increased glutamate in the basal ganglia and decreased it in the dorsomedial prefrontal cortex. Decreased GABA + in prefrontal and subcortical regions Disruption of prefrontal-subocritical connectivity during emotional processing Attenuated the blood oxygenation level-dependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing fearful faces Reduced resting blood pressure and blood pressure responses to stress Decreased gut permeability induced by aspirin Fig. 1 Summary of the therapeutic benefit of purified CBD across multiple conditions obtained through randomised controlled trials. PTSD, post traumatic stress disorder Summary of the therapeutic benefit of purified CBD across multiple conditions obtained through randomised controlled trials. PTSD, post traumatic stress disorder

Purified CBD is licensed for the treatment of some epilepsy conditions, but mounting evidence suggests that this drug could be used for the treatment of other conditions. This evidence is strongest for psychiatric conditions including anxiety, psychosis and schizophrenia, PTSD and substance abuse, which is underpinned by preclinical data implicating many of the same mechanisms of actions (for example, cannabinoid, serotonin, glycine and GABA receptors). However, this evidence is based on small, proof of concept clinical studies with low patient numbers and so considered weak in the hierarchy of evidence. The strength of evidence for CBD across multiple conditions is presented in Fig.  3 . Many of these indications continue to be investigated in registered clinical studies, so the evidence base may be strengthened in the short to medium term. By contrast, there are far fewer studies that have investigated CBD in non-neurological conditions despite a wealth of preclinical evidence of CBDs benefits in conditions such as cardiometabolic disorders and cancer that warrant testing clinically. There is also little active research in this area, so limited data will be emerging in these indications. Future clinical studies should look at the efficacy of ranges of doses of CBD in larger patient numbers and in both genders, establishing target plasma levels for CBD across various indications. Future studies could then establish whether the efficacy of purified CBD can be enhanced with the addition of other phytochemicals, and how CBD affects the efficacy of concomitant treatments. Fig. 3 The current state of affairs with regards to the therapeutic utility of purified CBD according to the hierarchy of evidence. GVHD, graft-versus-host disease; PTSD, post-traumatic stress disorder The current state of affairs with regards to the therapeutic utility of purified CBD according to the hierarchy of evidence. GVHD, graft-versus-host disease; PTSD, post-traumatic stress disorder