Therapeutics

Cannabidiol

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Overview

Name: Cannabidiol
Synonyms: CBD, Epidiolex
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Approved for: Seizures in Dravet syndrome, Lennox-Gastaut syndrome or tuberous sclerosis complex

Background

Cannabidiol is a major active compound of the cannabis plant. It is structurally related to tetrahydrocannabinol (THC), but does not produce a high. CBD is also abundant in hemp plants, which have little to no THC, making industrial hemp the usual source of THC-free CBD oil. In many locales, hemp-derived CBD is not subject to cannabis laws, and is freely available as capsules, drops or oil suspensions, or in transdermal patches, topical lotions, or salves. CBD has been studied in clinical trials for anxiety, addiction, cognition, movement disorders, pain, and other conditions, with no strong evidence yet for its effectiveness. Nonetheless, it is widely promoted and used for these and other maladies. 

In 2018, an oral solution of CBD was approved in the U.S. to treat rare forms of severe childhood epilepsy. Common side effects include sleepiness, poor sleep, decreased appetite, diarrhea, and fatigue. This formulation can also cause an increase in liver enzymes, and interferes with metabolism of other medications.

Like the THC formulations nabilone and dronabinol, in Alzheimer's, CBD is mainly being evaluated for treatment of agitation and aggression with this disease.

In preclinical work, extensive studies with CBD in cell and animal models of Aβ-induced neurotoxicity found it had multiple actions on Aβ production, tau phosphorylation and aggregation, oxidative stress, inflammation, and neurogenesis (reviewed by Watt and Karl, 2017; also see Khodadadi et al., 2021). A combination of CBD and THC was reported to preserve memory function and reduced astrogliosis and inflammation in APP/PS1 mice, with the combination more effective than either alone (Aso et al., 2015). CBD is reportedly neuroprotective in models of tauopathy and stroke (e.g. see Kreilaus et al., 2022; Ceprian et al., 2017).

CBD’s mechanism of action is unclear. It has low affinity for the cannabinoid receptors CB1 and CB2; instead, it has been proposed to act through TRPV cation channels, the peroxisome proliferation receptor gamma (PPARγ), novel G protein coupled receptors, and serotonin receptors (reviewed by Vitale et al., 2021).

Previous small trials of CBD in Parkinson’s and Huntington’s diseases found no improvement in symptoms, but the PD patients on treatment reported higher quality of life (Chagas et al., 2014; Consroe et al., 1991).

Findings

From 2017-2019, Tikun Olam Pharmaceuticals ran a 64-person Phase 2 trial in Israel testing Avidekel oil, a high CBD/low THC cannabis extract, for the treatment of agitation and aggression in dementia patients. The oil contains 30 percent CBD and 1.5 percent THC. Participants received active or placebo drops under the tongue three times a day for 16 weeks. The primary outcome was a reduction of four points on the Cohen-Mansfield Agitation Inventory; secondary was change on the Neuropsychiatric Inventory-Nursing Home version. According to a published abstract, 72 percent of participants taking CBD oil achieved the primary outcome versus 30 percent on placebo. The average reduction on CBD was 13.3 points versus 2.3 points on placebo. NPI-NH scores were reported to be significantly better with treatment (Hermush et al., 2020; 68, see (Suppl 1):S86 abstract A202 page 86).

In January 2021, an open-label Phase 1 trial began testing an eight-week course of high CBD/low THC oil in 12 people with mild to moderate AD and anxiety and aggression. The custom-formulated hemp extract is given under the tongue twice a day. A target dose of 45 mg CBD per day also delivers approximately 1 mg THC. The primary endpoint is the clinician impression of anxiety from the Neuropsychiatric Inventory-C; other endpoints are additional measures of anxiety, as well as safety and side effects, cognition, and caregiver burden. An optional 12-month extension with similar, commercially available CBD products is offered. According to a presentation at CTAD in November 2021, one person had completed the single-center study at McLean Hospital in Massachusetts. The trial was planned to end in January 2022.

In February 2021, a Phase 2 trial started to assess the effectiveness of a THC-free CBD oil to treat agitation in people with AD dementia or mixed AD dementia. The trial will enroll 40 participants for a six-week regimen of hemp-derived CBD oil capsules or a matching placebo. The dose begins at 30 mg daily, titrating up to 90 mg, or the highest tolerated dose. Primary outcomes are change in Cohen-Mansfield Agitation Inventory, caregiver burden, and quality of life of patient and caregiver. Secondary measures include the Neuropsychiatric Inventory, MMSE, and sleep quality. The single-center study at Eastern Virginia Medical School in Norfolk is expected to finish in June 2022

In April 2021, a study began enrolling older people with mild cognitive impairment who carry the ApoE4 allele, to compare the effects of a CBD or homotaurine on cognition, daily function, and depression. The single-center, Phase 4 study is ongoing in Greece. It will randomize 90 patients to 5 percent CBD oil, homotaurine, or no intervention. Twenty primary outcomes include the MMSE, MoCA, a cognitive battery, dementia ratings, measures of anxiety and depression, and CSF biomarkers of BDNF, tau, inflammation, and oxidative stress. The trial will run through December 2022.  

CBD is also being tested for motor symptoms and pain in Parkinson’s disease. Other active studies include amyotrophic lateral sclerosis, psychosis, anxiety, autism, insomnia, pain conditions, and substance use disorders, among others.

For details on cannabidiol trials, see clinicaltrials.gov.

Last Updated: 10 Mar 2022

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References

Therapeutics Citations

  1. Alzhemed™
  2. Nabilone
  3. Dronabinol

Paper Citations

  1. Hermush et al. A Phase II, Randomized, Double-Blind, Placebo-Controlled Trial to Investigate the Efficacy and Safety of Avidekel Oil for the Treatment of Patients with Agitation Related to Dementia V. Journal of the American Geriatrics Society, May 7, 2020 Journal of the American Geriatrics Society
  2. Watt G, Karl T. In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease. Front Pharmacol. 2017;8:20. Epub 2017 Feb 3 PubMed.
  3. Khodadadi H, Salles ÉL, Jarrahi A, Costigliola V, Khan MB, Yu JC, Morgan JC, Hess DC, Vaibhav K, Dhandapani KM, Baban B. Cannabidiol Ameliorates Cognitive Function via Regulation of IL-33 and TREM2 Upregulation in a Murine Model of Alzheimer's Disease. J Alzheimers Dis. 2021;80(3):973-977. PubMed.
  4. Aso E, Sánchez-Pla A, Vegas-Lozano E, Maldonado R, Ferrer I. Cannabis-based medicine reduces multiple pathological processes in AβPP/PS1 mice. J Alzheimers Dis. 2015;43(3):977-91. PubMed.
  5. Kreilaus F, Przybyla M, Ittner L, Karl T. Cannabidiol (CBD) treatment improves spatial memory in 14-month-old female TAU58/2 transgenic mice. Behav Brain Res. 2022 May 3;425:113812. Epub 2022 Feb 21 PubMed.
  6. Ceprián M, Jiménez-Sánchez L, Vargas C, Barata L, Hind W, Martínez-Orgado J. Cannabidiol reduces brain damage and improves functional recovery in a neonatal rat model of arterial ischemic stroke. Neuropharmacology. 2017 Apr;116:151-159. Epub 2016 Dec 21 PubMed.
  7. Vitale RM, Iannotti FA, Amodeo P. The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets. Int J Mol Sci. 2021 May 5;22(9) PubMed.
  8. Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, dos Santos AC, Teixeira AL, Hallak JE, Crippa JA. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J Psychopharmacol. 2014 Nov;28(11):1088-98. Epub 2014 Sep 18 PubMed.
  9. Consroe P, Laguna J, Allender J, Snider S, Stern L, Sandyk R, Kennedy K, Schram K. Controlled clinical trial of cannabidiol in Huntington's disease. Pharmacol Biochem Behav. 1991 Nov;40(3):701-8. PubMed.

External Citations

  1. (Suppl 1):S86
  2. clinicaltrials.gov

Further Reading

Papers

  1. Liu CS, Chau SA, Ruthirakuhan M, Lanctôt KL, Herrmann N. Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer's Disease. CNS Drugs. 2015 Aug;29(8):615-23. PubMed.
  2. Legare CA, Raup-Konsavage WM, Vrana KE. Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals. Pharmacology. 2022;107(3-4):131-149. Epub 2022 Jan 28 PubMed.
  3. Bajtel Á, Kiss T, Tóth B, Kiss S, Hegyi P, Vörhendi N, Csupor-Löffler B, Gede N, Hohmann J, Csupor D. The Safety of Dronabinol and Nabilone: A Systematic Review and Meta-Analysis of Clinical Trials. Pharmaceuticals (Basel). 2022 Jan 14;15(1) PubMed.
  4. Solomon HV, Greenstein AP, DeLisi LE. Cannabis Use in Older Adults: A Perspective. Harv Rev Psychiatry. 2021 May-Jun 01;29(3):225-233. PubMed.
  5. An D, Peigneur S, Hendrickx LA, Tytgat J. Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products. Int J Mol Sci. 2020 Jul 17;21(14) PubMed.