Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration

The medical use of cannabis dates back over 4000 years. The two major phytocannabinoids in cannabis are THC and CBD, with CBD preferred clinically due to its non-psychoactive properties. Interest in CBD for brain disorders (e.g., epilepsy, pain, depression, anxiety, psychosis) has risen, exemplified by FDA approval of oral CBD (Epidiolex) for certain refractory epilepsies. Multiple administration routes have been explored (intravenous, oral, sublingual, buccal, pulmonary, intranasal, transdermal). CBD has low aqueous solubility and low oral bioavailability (4–20%) due to extensive first-pass metabolism, leading to delayed and inefficient systemic exposure and greater risk of adverse effects with higher dosing. A better systemic delivery route with higher bioavailability is needed. This review presents an overview of CBD’s therapeutic use in brain conditions, summarizes pharmacokinetics across administration routes in animals and humans, and discusses the most suitable routes to optimize CBD delivery for brain disorders.

Mechanism of action: CBD exhibits low affinity for CB1/CB2 but acts as a negative allosteric modulator and indirectly enhances endocannabinoid signaling (e.g., increases anandamide). It engages multiple non-cannabinoid targets (GPR3/6/12/55; TRP channels TRPM8/TRPA1/TRPV1/TRPV2; 5-HT1A; μ/δ-opioid; PPAR-γ; glycine; GABAA), supporting broad CNS potential. Therapeutic effects across conditions: - Epilepsy: Robust RCT evidence in Dravet and Lennox–Gastaut syndromes and TSC. Oral CBD 10–20 mg/kg/day reduced seizures by ~37–42% vs ~17% placebo; long-term open-label extensions (20–30 mg/kg/day) sustained 45–84% reductions. In TSC, 25–50 mg/kg/day reduced seizures by ~47–49% vs 26.5% placebo; long-term ~54–68% reduction. - Pain: Preclinical and veterinary data suggest benefit in osteoarthritis models (e.g., intraarticular CBD in rats reduced joint pain/inflammation; oral transmucosal CBD improved canine pain scores), but a 6-week dog pilot and human single-dose RCTs (400 or 1600 mg oral) showed no significant analgesic effects; small open-label human series suggested chronic pain improvement with 100–300 mg/day. Systematic reviews of cannabis show limited, temporary relief; pure CBD evidence remains limited. - Parkinson’s disease: Preclinical neuroprotection/antioxidant effects; small clinical studies showed improvements in daily living and some non-motor symptoms, but mixed effects on motor/clinical measures; larger RCTs needed. - Alzheimer’s disease: Animal models show CBD reduces neuroinflammation (e.g., IL-1β, iNOS), glial activation, and improves cognition; no human trials yet. - Huntington’s disease: Small clinical trial with 10 mg/kg oral CBD showed no benefit; possibly due to low bioavailability/dose. - Depression: Animal models show antidepressant-like effects with low-dose IV and high-dose oral CBD; in humans, open-label studies (200–800 mg/day) in cannabis users and anxiety patients showed reductions in depressive symptoms. - Anxiety: Multiple animal studies show anxiolysis. Human studies show single oral doses (300–600 mg) reduce anxiety during simulated public speaking; an inverted U-shaped dose-response observed (effects at intermediate doses). Clinical trials in social anxiety disorder show reductions after 300 mg/day for 4 weeks and improvements with up to 800 mg/day add-on in treatment-resistant anxiety; some studies reported minimal or paradoxical effects. - Psychosis: In schizophrenia, 600 mg/day for 6 weeks did not improve symptoms; 800–1000 mg/day improved positive symptoms and had tolerability advantages vs amisulpride. Acute cognition effects were not significant with single doses. In Parkinson’s psychosis, open-label CBD showed rapid improvement without worsening parkinsonism. - Substance use disorders: Opioids—CBD (400–800 mg/day) reduced cue-induced craving/anxiety in heroin use disorder with effects persisting up to 7 days; preclinical heroin-seeking attenuation up to 14 days. Psychostimulants—preclinical extinction benefits; clinical trial in cocaine use disorder (800 mg/day, 12 weeks) showed no craving/relapse benefit. Tobacco—CBD MDI as-needed reduced weekly cigarettes (~40 fewer) vs placebo; single 800 mg oral reduced cue salience but not craving/withdrawal. Alcohol—preclinical reductions in intake/preference and withdrawal symptoms; observational data suggest CBD-dominant products reduce alcohol use relative to THC-dominant. - Insomnia: Animal and early human studies suggest increased slow-wave sleep and longer sleep duration at higher doses (e.g., 160 mg oral); retrospective series showed initial improvements but inconsistent durability. - Weight/appetite: Mixed findings; some animal data show reduced weight gain; human reports vary (decreased or increased appetite). Pharmacokinetics by route: - Oral: Non-invasive but lowest bioavailability (~6–19%); delayed tmax 2–7 h; food increases Cmax ~4.85× and AUC ~4.2×. High Vd (32.7 L/kg), high protein binding (86.7–92.2%), extensive first-pass via CYP2C19/3A4 to 7‑OH- and 7‑COOH-CBD. - IV: 100% bioavailability; rapid high Cmax and brain exposure but rapid clearance and short half-life necessitating frequent dosing. - Sublingual/buccal: Avoid first-pass; faster absorption than oral but variability due to saliva washout/swallowing; tmax ~4–4.5 h reported for wafers/sprays vs ~5.2 h oral; true transmucosal absorption debated. - Pulmonary (inhalation): Rapid absorption and higher bioavailability. MDI with spacer reached tmax ~6 min; estimated bioavailability ~59%. DPI increased dose-adjusted AUC 9.1× and Cmax 71× vs oral, with tmax ~3.8 min. Smoking/vaping provide rapid peaks but are not preferred clinically due to by-products and variability. - Intranasal: Non-invasive, rapid absorption (rats tmax ≤10 min; dogs tmax 0.5 h vs 3.5 h oral), animal bioavailability ~34–46%; potential nose-to-brain pathways (olfactory/trigeminal), though human PK data lacking and dose limited by small volumes and mucociliary clearance. - Transdermal: Sustained systemic levels and avoidance of first-pass; skin reservoir effects observed; slower absorption and lower Cmax vs oral in some animals due to barrier limitations for highly lipophilic CBD. - Other routes (ocular, rectal): Theoretically possible for systemic delivery based on other cannabinoids/drugs; limited or unsuccessful CBD PK data to date.

- CBD engages multiple CNS targets (endocannabinoid and non-endocannabinoid) underpinning broad therapeutic potential. - Strongest clinical efficacy is in treatment-resistant epilepsies: • Dravet and Lennox–Gastaut: Oral CBD 10–20 mg/kg/day reduced seizures by ~37–42% vs ~13–17% placebo over 14 weeks; long-term reductions 45–84% up to 156 weeks; ≥50% responders and overall condition improvements in most patients. • Tuberous sclerosis complex: 25–50 mg/kg/day reduced seizures by ~47–49% vs 26.5% placebo; long-term ~54–68% reductions. - Other indications show mixed evidence: • Pain: Preclinical/veterinary benefits; human single-dose RCTs negative; small open-label series suggest benefit with daily dosing. • Parkinson’s disease: Small studies suggest improvements in daily living and some non-motor symptoms; inconsistent effects on motor outcomes. • Alzheimer’s disease: Positive animal data; no human trials. • Huntington’s disease: Small trial negative (10 mg/kg oral). • Anxiety: Anxiolytic effects at intermediate doses (e.g., 300 mg) in public speaking paradigms; improvements in clinical anxiety with 300–800 mg/day regimens; some studies show minimal or paradoxical effects. • Psychosis: Benefit in acute schizophrenia at 800–1000 mg/day; 600 mg/day ineffective in chronic schizophrenia; CBD comparable to amisulpride with better tolerability; improved Parkinson’s psychosis in open-label study. • Substance use disorders: Reduced heroin cue-induced craving/anxiety with protracted effects; no benefit in cocaine use disorder; reduced cigarette consumption with CBD inhaler and reduced cue salience with 800 mg oral; preclinical reductions in alcohol intake/relapse proxies. • Sleep: Increased slow-wave sleep/longer sleep at higher doses in early studies; mixed durability in clinic. - Pharmacokinetics and delivery route matter substantially: • Oral CBD has low bioavailability (≈6–19%), delayed tmax (2–7 h), and extensive first-pass metabolism; high-fat meals markedly increase exposure (~4–5× Cmax; ~4× AUC). • IV achieves rapid high levels but with rapid clearance (e.g., ~90–99% decline within 1 h), making chronic use impractical. • Sublingual/buccal can speed absorption but are variable due to saliva and swallowing. • Pulmonary delivery (MDI/DPI) provides rapid absorption (tmax minutes) and higher bioavailability/exposure vs oral (e.g., DPI dose-adjusted AUC 9.1×; Cmax 71×; MDI bioavailability ~59%). • Intranasal delivery is rapid (tmax ≤10 min in animals) with moderate bioavailability (34–46%) and potential nose-to-brain access; human PK data are pending. • Transdermal delivery yields sustained plasma levels but lower Cmax vs oral in some models due to skin barriers. - Overall, intranasal and inhalation routes offer non-invasive, rapid, higher-bioavailability delivery that may better serve CNS indications requiring quick onset and efficient systemic exposure.

The review synthesizes mechanistic, therapeutic, and pharmacokinetic evidence to address how best to deliver CBD for brain disorders. Given CBD’s low oral bioavailability and delayed absorption, many acute or dose-sensitive CNS applications are suboptimally served by oral dosing. The compiled PK data across routes show that intranasal and pulmonary inhalation can deliver CBD rapidly and more efficiently, bypassing first-pass metabolism and potentially improving brain exposure—aligned with the therapeutic needs of conditions like epilepsy (rescue scenarios), acute anxiety/panic, and pain flares. While clinical efficacy beyond epilepsy remains mixed due to heterogeneity in doses, populations, and formulations, the PK advantages of intranasal and inhalation routes support further development for CNS indications. Transdermal routes may suit chronic conditions requiring steady exposure, though penetration barriers limit peak levels. Sublingual/buccal routes offer convenience but variable absorption. Overall, optimizing route and formulation to improve solubility and bioavailability is crucial to translate CBD’s broad mechanistic potential into consistent clinical benefit.

CBD shows promise across multiple brain disorders, with the strongest clinical evidence in treatment-resistant epilepsies. Its multimodal CNS actions underpin potential benefits in pain, movement disorders, psychiatric conditions, and substance use disorders, though many areas remain in early research with mixed clinical outcomes. Oral CBD suffers from slow absorption and low bioavailability; in contrast, intranasal and inhalation routes are non-invasive and provide rapid absorption with increased bioavailability, making them attractive for CNS applications. Continued formulation innovation to enhance solubility and bioavailability, and more rigorous clinical studies—particularly using intranasal and inhalable products—are warranted to realize CBD’s therapeutic potential in brain disorders.

- Most established efficacy is limited to epilepsy; for many other CNS indications evidence is preliminary, small-scale, or mixed. - Heterogeneity in formulations, doses, and co-medications (e.g., inclusion of THC in some products) complicates interpretation. - Oral bioavailability is low and variable; food effects markedly alter exposure, and oral mucosal routes may be confounded by swallowing. - Intranasal CBD human pharmacokinetic data are lacking; nasal delivery is limited by small dose volumes and rapid mucociliary clearance. - Smoking/vaping studies raise safety and dose-uniformity concerns, limiting clinical applicability. - Transdermal delivery may be constrained by skin barriers for highly lipophilic CBD, leading to lower systemic levels. - Many studies are open-label, small, or short-term; objective outcome measures are sometimes limited; some negative or inconsistent findings (e.g., cocaine use disorder, some anxiety studies).