PET Imaging Reveals CB1 Receptor Drugs Need Only 20-30% Brain Occupancy for Anti-Obesity Effects
PET brain imaging in primates showed that the clinical doses of CB1 receptor blockers rimonabant and taranabant that produce weight loss only occupy about 20-30% of CB1 receptors, much less than expected for this class of drugs.
Quick Facts
What This Study Found
As part of efforts to develop safer anti-obesity drugs targeting the CB1 receptor, researchers used PET brain imaging in six non-human primates to measure how much of the CB1 receptor population different drugs actually occupied at therapeutic-equivalent doses.
The surprise finding was that rimonabant and taranabant, both proven effective for weight loss in humans, only needed to occupy about 20-30% of CB1 receptors to produce their therapeutic effects. This is much lower than the typical 60-80% occupancy needed for most drugs targeting G-protein coupled receptors.
Three novel CB1 antagonists developed by AstraZeneca showed similar binding characteristics. The researchers also noted that "neutral" CB1 antagonists (which block the receptor without reducing its baseline activity) might achieve therapeutic benefit with fewer psychiatric side effects than inverse agonists like rimonabant.
Key Numbers
42 PET measurements in 6 primates. 5 CB1 antagonists tested. Clinical efficacy doses produced only 20-30% CB1 receptor occupancy. Typical GPCR antagonists require 60-80% occupancy. Three novel AstraZeneca compounds showed binding affinity similar to rimonabant and taranabant.
How They Did This
Forty-two PET measurements in six non-human primates using the CB1-specific radioligand [11C]SD5024. Five CB1 receptor antagonists were compared for receptor occupancy relative to dose and plasma exposure. Occupancy at clinically effective doses was estimated.
Why This Research Matters
Understanding that only 20-30% receptor occupancy is needed for therapeutic effects opens the possibility of using much lower doses of CB1 antagonists, potentially staying below the threshold for psychiatric side effects while maintaining efficacy. This finding could guide clinical dose optimization for future CB1-targeting drugs.
The Bigger Picture
The failure of rimonabant and taranabant due to psychiatric side effects stalled the field of CB1-based obesity treatment. This PET data suggests that the problem may have been dose-related rather than target-related, reinvigorating interest in developing CB1 antagonists at more carefully optimized doses.
What This Study Doesn't Tell Us
Non-human primate pharmacokinetics may differ from humans. The 20-30% occupancy estimate is an approximation based on cross-species dose translation. No direct measurement of psychiatric side effects at different occupancy levels was performed.
Questions This Raises
- ?Is there a receptor occupancy threshold below which psychiatric side effects do not occur?
- ?Would neutral CB1 antagonists at 20-30% occupancy produce weight loss without depression or anxiety?
Trust & Context
- Key Stat:
- Only 20-30% CB1 receptor occupancy needed for clinical weight loss effects
- Evidence Grade:
- Carefully controlled PET imaging study in primates with multiple compounds, but occupancy-efficacy and occupancy-side effect relationships require human confirmation.
- Study Age:
- Published in 2016. Development of peripherally restricted and neutral CB1 antagonists has continued.
- Original Title:
- A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.
- Published In:
- Neuropharmacology, 101, 519-30 (2016)
- Authors:
- Hjorth, Stephan, Karlsson, Cecilia, Jucaite, Aurelija, Varnäs, Katarina, Wählby Hamrén, Ulrika, Johnström, Peter, Gulyás, Balázs, Donohue, Sean R, Pike, Victor W, Halldin, Christer, Farde, Lars
- Database ID:
- RTHC-01178
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
Why were CB1 receptor blockers pulled from the market?
Rimonabant and taranabant caused depression and anxiety at the doses used for weight loss. This PET study suggests those doses may have been higher than necessary for the therapeutic effect.
Could lower doses work without side effects?
The finding that only 20-30% receptor occupancy is needed for efficacy suggests that lower doses might maintain weight loss benefits while staying below the threshold for psychiatric side effects, though this needs human testing.
Read More on RethinkTHC
- THC-amygdala-anxiety-brain
- anandamide-weed-withdrawal
- cannabinoid-receptors-recovery-time
- cannabis-developing-brain-teenagers
- cant-enjoy-anything-without-weed
- dopamine-recovery-after-quitting-weed
- endocannabinoid-system-explained-simply
- endocannabinoid-system-withdrawal
- nervous-system-weed-withdrawal-fight-flight
- teen-weed-use-under-18-effects-brain
- thc-brain-withdrawal
- thc-prefrontal-cortex-brain-effects
- weed-cortisol-stress-hormones
- weed-memory-loss-recovery
- weed-motivation-amotivational-syndrome
- weed-nervous-system-effects
- weed-reward-system-brain
Cite This Study
https://rethinkthc.com/research/RTHC-01178APA
Hjorth, Stephan; Karlsson, Cecilia; Jucaite, Aurelija; Varnäs, Katarina; Wählby Hamrén, Ulrika; Johnström, Peter; Gulyás, Balázs; Donohue, Sean R; Pike, Victor W; Halldin, Christer; Farde, Lars. (2016). A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.. Neuropharmacology, 101, 519-30. https://doi.org/10.1016/j.neuropharm.2015.03.002
MLA
Hjorth, Stephan, et al. "A PET study comparing receptor occupancy by five selective cannabinoid 1 receptor antagonists in non-human primates.." Neuropharmacology, 2016. https://doi.org/10.1016/j.neuropharm.2015.03.002
RethinkTHC
RethinkTHC Research Database. "A PET study comparing receptor occupancy by five selective c..." RTHC-01178. Retrieved from https://rethinkthc.com/research/hjorth-2016-a-pet-study-comparing
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.