ThePineapple - Journal Club #43: Neuroplasticity, Memory, Palliative Care, Entourage Effect

Journal Club #43: Neuroplasticity, Memory, Palliative Care, Entourage Effect

Week of 05-22-22

This week was noteworthy, because there was a tornado that injured dozens of people in Paderborn, Germany. This is noteworthy, because there are no tornadoes in Paderborn, Germany. However, while it is noteworthy, it has absolutely nothing to do with cannabis. But you are in luck, those 4 new papers down below do. There is some new work on epilepsy, state-dependent memory retrieval, management of cancer symptoms and the interaction between THC and CBD in the brain. 

Note: This is a post for cannabis scientists. A weekly curation of fresh papers that help advance our understanding of cannabis and the endocannabinoid system.

Neuroplastic alterations in cannabinoid receptors type 1 (CB1) in animal models of epileptic seizures.

Lazarini-Lopes, Willian, and Gleice Kelli Silva-Cardoso

Neuroscience and biobehavioral reviews vol. 137 (2022): 104675. 

Currently, there is an urgent need to better comprehend neuroplastic alterations in cannabinoid receptors type 1 (CB1) and to understand the biological meaning of these alterations in epileptic disorders. The present study reviewed neuroplastic changes in CB1 distribution, expression, and functionality in animal models of epileptic seizures. Neuroplastic alterations in CB1 were consistently observed in chemical, genetic, electrical, and febrile seizure models. Most studies assessed changes in hippocampal and cortical CB1, while thalamic, hypothalamic, and brainstem nuclei were rarely investigated. Additionally, the relationship between CB1 alteration and the control of brain excitability through modulation of specific neuronal networks, such as striatonigral, nigrotectal and thalamocortical pathways, and inhibitory projections to hippocampal pyramidal neurons, were all presented and discussed in the present review. Neuroplastic alterations in CB1 detected in animal models of epilepsy may reflect two different scenarios: (1) endogenous adaptations aimed to control neuronal hyperexcitability in epilepsy or (2) pathological alterations that facilitate neuronal hyperexcitability. Additionally, a better comprehension of neuroplastic and functional alterations in CB1 can improve pharmacological therapies for epilepsies and their comorbidities.


Cross state-dependent memory retrieval between cannabinoid CB1 and serotonergic 5-HT1A receptor agonists in the mouse dorsal hippocampus.

Jafari-Sabet M, Amiri S, Aghamiri H, Fatahi N. 

Neurobiol Learn Mem. 2022 May 17:107638. 

Understanding the neurobiological mechanisms of drug-related learning and memory formation may help the treatment of cognitive disorders. Dysfunction of the cannabinoid and serotonergic systems has been demonstrated in learning and memory disorders. The present paper investigates the phenomenon called state-dependent memory (SDM) induced by ACPA (a selective cannabinoid CB1 receptor agonist) and 8-OH-DPAT (a nonselective 5-HT1A receptor agonist) with special focus on the role of the 5-HT1A receptor in the effects of both ACPA and 8-OH-DPAT SDM and cross state-dependent memory retrieval between ACPA and 8-OH-DPAT in a step-down inhibitory avoidance task. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended injection sites. A single-trial step-down inhibitory avoidance task was used to assess memory retrieval and state-dependence. Post-training and/or pre-test microinjections of ACPA (1 and 2 ng/mouse) and 8-OH-DPAT (0.5 and 1 μg/mouse) dose-dependently induced amnesia. Pre-test administration of the same doses of ACPA and 8-OH-DPAT reversed the post-training ACPA- and 8-OH-DPAT-induced amnesia, respectively. This phenomenon has been named SDM. 8-OH-DPAT (1 μg/mouse) reversed the amnesia induced by ACPA (0.5, 1, and 2 ng/mouse) and induced ACPA SDM. ACPA (2 ng/mouse) reversed the amnesia induced by 8-OH-DPAT (0.25, 0.5, and 1 μg/mouse) and induced 8-OH-DPAT SDM. Pre-test administration of a 5-HT1A receptor antagonist, (S)-WAY 100135 (0.25 and 0.5 μg/mouse), 5 min before ACPA and 8-OH-DPAT dose-dependently inhibited ACPA- and 8-OH-DPAT-induced SDM, respectively. The present study results demonstrated ACPA- and 8-OH-DPAT- induced SDM. Overall, the data revealed that dorsal hippocampal 5-HT1A receptor mechanisms play a pivotal role in modulating cross state-dependent memory retrieval between ACPA and 8-OH-DPAT.

doi: 10.1016/j.nlm.2022.107638. Epub ahead of print. PMID: 35595026.

Rate of cannabis use in older adults with cancer.

Rajasekhara S, Portman DG, Chang YD, Haas MF, Randich AL, Bromberg HS, Rashid S, Donovan KA. 

BMJ Support Palliat Care. 2022 Jun;12(2):178-181. 

Older adults with cancer are increasingly inquiring about and using cannabis. Despite this, few studies have examined cannabis use in patients with cancer aged 65 years and older as a separate group and identified characteristics associated with use. The current study sought to determine the rate of cannabis use in older adult patients with cancer and to identify demographic and clinical correlates of use. We conducted a retrospective review of patients with cancer referred for specialised symptom management between January 2014 and May 2017 who underwent routine urine drug testing for tetrahydrocannabinol as part of their initial clinic visit. Approximately 8% (n=24) of patients with cancer aged 65 years and older tested positive for tetrahydrocannabinol compared with 30% (n=51) of young adults and 21% (n=154) of adults. At the univariate level, more cannabis users had lower performance status than non-users (p=0.02, Fisher's exact test). There were no other demographic and clinical characteristics significantly associated with cannabis use in older adults. Older adult patients made up nearly 25% (n=301) of the total sample and had a rate of cannabis use of 8%. As one of the first studies to assess cannabis use via objective testing rather than self-report, this study adds significantly to the emerging literature on cannabis use in people aged 65 years and older. Findings suggest the rate of use in older adults living with cancer is higher than that among older adults in the general population.

doi: 10.1136/bmjspcare-2020-002384. Epub 2020 Nov 11. PMID: 33177114.

Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain.

Wall MB, Freeman TP, Hindocha C, Demetriou L, Ertl N, Freeman AM, Jones AP, Lawn W, Pope R, Mokrysz C, Solomons D, Statton B, Walker HR, Yamamori Y, Yang Z, Yim JL, Nutt DJ, Howes OD, Curran HV, Bloomfield MA.

J Psychopharmacol. 2022 May 20:2698811221092506. 

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity. To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor). Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach. Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks. THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

doi: 10.1177/02698811221092506. Epub ahead of print. PMID: 35596578.