Highway to hell or magic smoke? The dose-dependence of Δ9-THC in place conditioning paradigms.
Rimas A Kubilius, Paul M Kaplick, Carsten T. Wotjak
Learning & Memory September 2018 preprint DOI: 10.1101/lm.046870.117 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Meta-analysis |
|---|---|
| Population | Rodents (rats and/or mice) in place-conditioning studies |
| Intervention | Δ9-tetrahydrocannabinol (Δ9-THC) |
| Dose | 1 mg/kg (rewarding) and 5 mg/kg (aversive) |
| Topics | Addiction Cannabis |
| Key findings | The authors report that Δ9-THC produces dose-dependent rewarding effects at 1 mg/kg and aversive effects at 5 mg/kg in place-conditioning paradigms, and argue that inconsistent priming injections across studies may explain the many nonsignificant findings. They contend that other cannabinoid pharmacological studies support this biphasic pattern. |
Abstract
The prerequisites for responsible cannabis use are at the heart of current inquiries into cannabis decriminalization by policy makers as well as academic and nonacademic stakeholders at a global scale. Δ9-tetrahydrocannabinol (Δ9-THC), the prime psychoactive compound of the cannabis sativa, as well as cannabimimetics that resemble the pharmacological properties and psychological effects of Δ9-THC, lend themselves handsomely to the preclinical scrutiny of reward-related behavior because they carry marked translational value. Although a functional dichotomy of the psychological effects of Δ9-THC (rewarding versus aversive) has been abundantly reported in place conditioning (PC) paradigms, and might be best attributed to a dose-dependence of Δ9-THC, most PC studies with Δ9-THC feature no significant effects at all. Therefore, after decades of rigorous research, it still remains undetermined whether Δ9-THC generally exerts rewarding or aversive effects in rodents. Here, we set out to extrapolate the commonly alleged dose-dependence of the rewarding and aversive effects of Δ9-THC from the existing literature, at the behavioral pharmacological level of analysis. Specifically, our meta-analysis investigated: (i) the alleged bidirectional effects and dose-dependence of Δ9-THC in the PC test; (ii) methodological inconsistencies between PC studies; and (iii) other pharmacological studies on cannabinoids (i.e., dopamine release, anxiety, stress, conditioned taste aversion, catalepsy) to substantiate the validity of PC findings. Our findings suggest that: (i) Δ9-THC dose-dependently generates rewarding (1 mg/kg) and aversive (5 mg/kg) effects in PC; (ii) an inconsistent use of priming injections hampers a clear establishment of the rewarding effects of Δ9-THC in PC tests and might explain the seemingly contradictory plethora of nonsignificant THC studies in the PC test; and (iii) other pharmacological studies on Δ9-THC substantiate the dose-dependent biphasic effects of Δ9-THC in PC. A standardized experimental design would advance evidence-based practice in future PC studies with Δ9-THC and facilitate the pointed establishment of rewarding and aversive effects of the substance.
Comparable studies
Other systematic reviews and meta-analyses on cannabis for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Effects of Ayahuasca and its Alkaloids on Drug Dependence: A Systematic Literature Review of Quantitative Studies in Animals and Humans | 2016 | Systematic review | |
| Cannabis and cannabinoids for the treatment of mental and substance use disorders and symptoms: A systematic review and meta-analysis of experimental and observational studies. Adults (≥18 years) with ADHD, anxiety, depression, PTSD, psychosis or Tourette... | 2026 | Systematic review and meta-analysis | |
| Association of cannabis potency with mental ill health and addiction: a systematic review. Human participants in observational studies comparing high-potency and low-potency... | 2022 | Systematic review |
Citations in the library
Cited by 7
- Optogenetic brain‐stimulation reward: A new procedure to re‐evaluate the rewarding versus aversive effects of cannabinoids in dopamine transporter‐Cre mice Addiction Biology February 3, 2021
- Effects of acute THC challenge on behavior and neuroinflammation in HIV-1 Tg26 mice vary based on HIV status, chronic THC history, and sex. Brain, Behavior, and Immunity May 1, 2026
- Evaluation of the Modulatory Effects of Minor Cannabinoids and Terpenes on Delta-9-Tetrahydrocannabinol Discrimination in Rats. Cannabis and Cannabinoid Research September 2023
- Effects of Δ9-THC and Type-1 Cannabinoid Receptor Agonists in the Elevated Plus Maze Test of Anxiety: A Systematic Review and Meta-Analysis. Cannabis and Cannabinoid Research February 2023
- Cannabis: Drug of Abuse and Therapeutic Agent, Two Sides of the Same Coin. Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion 2023
and 2 more in the library
Cites 13
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- Modulation of Mediotemporal and Ventrostriatal Function in Humans by Δ9-Tetrahydrocannabinol Archives of General Psychiatry April 1, 2009
- Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors PLoS Biology July 9, 2015
- Neuropharmacology of New Psychoactive Substances (NPS): Focus on the Rewarding and Reinforcing Properties of Cannabimimetics and Amphetamine-Like Stimulants Frontiers in Neuroscience April 19, 2016
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