Repeated treatment with cannabidiol but not Δ9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance
Abstract
Both Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabidiol are known to have a neuroprotective effect against cerebral ischemia. We examined whether repeated treatment with both drugs led to tolerance of their neuroprotective effects in mice subjected to 4h-middle cerebral artery (MCA) occlusion. The neuroprotective effect of Delta(9)-THC but not cannabidiol was inhibited by SR141716, cannabinoid CB(1) receptor antagonist. Fourteen-day repeated treatment with Delta(9)-THC, but not cannabidiol, led to tolerance of the neuroprotective and hypothermic effects. In addition, repeated treatment with Delta(9)-THC reversed the increase in cerebral blood flow (CBF), while cannabidiol did not reverse that effect. Repeated treatment with Delta(9)-THC caused CB(1) receptor desensitization and down-regulation in MCA occluded mice. On the contrary, cannabidiol did not influence these effects. Moreover, the neuroprotective effect and an increase in CBF induced by repeated treatment with cannabidiol were in part inhibited by WAY100135, serotonin 5-HT(1A) receptor antagonist. Cannabidiol exhibited stronger antioxidative power than Delta(9)-THC in an in vitro study using the 1,1-diphenyl-2-picryhydrazyl (DPPH) radical. Thus, cannabidiol is a potent antioxidant agent without developing tolerance to its neuroprotective effect, acting through a CB(1) receptor-independent mechanism. It is to be hoped that cannabidiol will have a palliative action and open new therapeutic possibilities for t…
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Repeated treatment with CBD (but not 9-THC) does not develop tolerance or dependence.
“Moreover, it was shown that repeated treatment with CBD (but not 9-THC) does not develop tolerance or dependence (Hayakawa et al, 2007)”
From Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients (2011) · cites this paper as Hayakawa et al, 2007
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“…4 h post-occlusion ↑CBF Resstel et al., 2006 Rats Stress (fear) 10 mg/kg i.p. Pre-test Pre-stress and during 10 min post-stress ↓MBP and HR post-stress Hayakawa et al., 2007a Mice MCAO 3 mg/kg i.p. Pre, 3 and 4 h post-occlusion, and 1 and 2 h post-reperfusion MBP and HR: pre-reperfusio No changes…”
BackgroundInfluential
- Authors
- Hayakawa, K., Mishima, K., Nozako, M., Ogata, A., Hazekawa, M., Liu, A.-X., Fujioka, M., Abe, K., Hasebe, N., Egashira, N., Iwasaki, K., & Fujiwara, M.
- Affiliations
- Fukuoka University (JP)
- Shionogi (Japan) (JP)
- Corresponding author
- Fujiwara, Michihiro
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 52
- Issue
- 4
- Pages
- 1079-1087
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W1974205523
- Cited by
- 89
- References
- 2
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 7 · 2015: 5 · 2014: 3 · 2013: 3 · 2012: 3
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Naito Foundation
- Fukuoka University
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- cannabidiol, delta-9-tetrahydrocannabinol, neuroprotection, cerebral ischemia, tolerance (pharmacology and immunology), CB1 receptor, receptor desensitization, 5-HT1A receptor, cerebral blood flow, antioxidant activity, middle cerebral artery occlusion, SR141716, DPPH radical
- MeSH terms
- Rimonabant, Analysis of Variance, Animals, Behavior, Animal, Body Temperature, Cannabidiol, Cerebral Infarction, Cerebrovascular Circulation, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Interactions, Drug Tolerance, Male, Piperazines, Piperidines, Pyrazoles, Serotonin Antagonists, Dronabinol, Time Factors, Neuroprotective Agents, Infarction, Middle Cerebral Artery, Mice
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