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Biphasic Effects of THC in Memory and Cognition
European Journal of Clinical Investigation
... CB1 receptors are located on presynaptic neurons and are richly expressed in the limbic system, particularly in the hippocampus, as well as in regions of the cerebral cortex. CB1 activation, i.e. by THC, inhibits cholinergic neurotransmission in the hippocampus and this is one of the mechanisms proposed to explain the effect of these cannabinoids on memory (Calabrese & Rubio-Casillas, 2018;Ramaekers et al., 2021). However, evidence suggests that cannabis variants with higher concentrations of CBD may exert a protective effect that mitigates the potential harm caused by THC (Broyd et al., 2016;Ramaekers et al., 2021). ...
... However, F. Z. Boos et al. besides not causing neuronal death, low doses of THC activating CB1 receptors can induce neurogenesis in the hippocampus and promote neuroplasticity, processes fundamental to memory. THC exhibits a biphasic effect: at high doses, it may inhibit neurogenesis (Calabrese & Rubio-Casillas, 2018). ...
... On the other hand, the loss of function of the endocannabinoid system throughout life may make CB1 receptor activation in older age help recover some functions. In addition to promoting hippocampal neurogenesis and neuroplasticity, preclinical studies indicate that chronic administration of low doses of THC may reverse natural cognitive impairments in elderly mice (Bilkei-Gorzo et al., 2017) and delay the formation of amyloid plaques associated with Alzheimer's disease (Calabrese & Rubio-Casillas, 2018;Eubanks et al., 2006). Clinical observations also suggest that cannabis oil with THC may partially recover memory processes in patients with dementia. ...
The register of experiences and information through memory is crucial for the expression and adaptation of future behaviors. The use of psychotropic substances, a practice that has accompanied human history, can alter various cognitive functions. This chapter discusses the impact of drug use on memory in humans, with an emphasis on working memory and explicit episodic long-term memory. Initially, we address the neuropsychological models that categorize types of memory and present the processes of acquisition, consolidation, and retrieval of long-term memories. We explore how the acute use can induce transient changes, while the chronic use induces neuroadaptations in the brain which can enduringly alter different types and processes of memory. We highlight factors such as heavy use pattern and early age of onset, which increase the likelihood and magnitude of neuropsychological alterations. We also discuss the bidirectional, and not necessarily causal, relationship between drug use and changes in mnemonic functions. Finally, we select the most socially relevant drugs (alcohol, cannabis, cocaine/crack, and opioids) and review scientific studies on the effects of their acute and chronic use, emphasizing the importance of understanding these effects to optimize the treatment of subjects with problematic substance use.
... THC shows behavioral effects that are often biphasic, i.e., high and low doses of THC show opposite effects on a broad set of behaviors, such as memory and cognition, response to stress, and locomotion (Calabrese and Rubio-Casillas, 2018;Rey et al., 2012;Sañudo-Peña et al., 2000;Sulcova et al., 1998). It is known that the endocannabinoid system plays a role in motor control, motor coordination, and spontaneous activity. ...
... The long-term consequences of THC abuse include cannabis use disorder (CUD), which leads to some of the worst symptoms of cognitive deficits, heavy dependence and paranoia [2][3][4], and cannabinoid-induced psychosis [3,5,6]. In animal models, THC implies biphasic behavioral effects: to name some, low doses of THC result in reward [7], enhance memory and cognition [8], and increase locomotion behavior [7,9], while high doses of THC generate aversion [7], impair memory and cognition (Calabrese and Rubio-Casillas, 2018), and decrease locomotion behavior [7,10] in rodents. In line with the opposite effect of THC on reward and aversion in animals, it was reported that usual THC consumers adjust the puffs intensity of cannabis cigarettes to intake small amounts of THC [11]. ...
... The long-term consequences of THC abuse include cannabis use disorder (CUD), which leads to some of the worst symptoms of cognitive deficits, heavy dependence and paranoia [2][3][4], and cannabinoid-induced psychosis [3,5,6]. In animal models, THC implies biphasic behavioral effects: to name some, low doses of THC result in reward [7], enhance memory and cognition [8], and increase locomotion behavior [7,9], while high doses of THC generate aversion [7], impair memory and cognition (Calabrese and Rubio-Casillas, 2018), and decrease locomotion behavior [7,10] in rodents. In line with the opposite effect of THC on reward and aversion in animals, it was reported that usual THC consumers adjust the puffs intensity of cannabis cigarettes to intake small amounts of THC [11]. ...
Cannabis sativa is among the most abused drugs worldwide. THC, its main psychoactive component, represents a risk factor of several mental pathologies, such as cannabis use disorder, addiction, and psychosis. Being a biphasic drug, high doses of THC cause hypoactivity and aversion, whereas low doses of THC cause hyperactivity and reward. THC acts on the type-1 cannabinoid receptor (CB1), one of the most abundant G-protein coupled-receptors (GPCRs) in the brain, whose signaling is biased, meaning that different transducers can carry specific pathway following different conditions. Biased signaling was proven to be extremely relevant in drug discovery and understanding CB1 signaling in pathologic conditions is essential for cannabinoid-based drug development. It is known that different doses of THC bring along different behavioral, cellular, and molecular outcomes. However, the link between those phenomena has never been investigated.Thus, for a therapeutic purpose PREG-like CB1-SSi compounds have been synthetized that share the same PREG therapeutic potential, but cannot be metabolized in downstream steroids. The CB1-SSi studied in the current work is the CB1-SSi lead compound, AEF0117.The first aim of the current work was to understand the intracellular signaling pathways following low, medium, and high doses of THC, leading to three distinct known behavioral outputs in mice, hyperlocomotion, asociability, and hypolocomotion, respectively.The second aim of the thesis was to understand the mechanism of action of AEF0117, and its capability to block the behavioral and molecular effects of THC at low, medium, and high doses.The doctoral dissertation is divided into five main parts. The introduction serves to preface the concepts of the endocannabinoid system, as well as cannabis abuse in humans and the counterpart behavioral outcomes of THC in mice, including hyperlocomotion, asociability, and hypolocomotion. The state of the art of CB1 signaling involving the biased CB1 system is described with particular emphasis on CB1 Signaling Specific Inhibitors (CB1-SSi), in particular the endogenous pregnenolone (PREG), and its synthetic analogue, the lead CB1-SSi compound, AEF0117.The article Zanese*, Tomaselli* et al., 2020 (published in J. Neurosci. Methods) oversees the validation of the high throughput analytical technique (AlphaLISA) of choice in this study for detection of protein phosphorylation in brain tissue lysates.The article Tomaselli et al. (to be submitted), is devoted to the studies of the low dose of THC that causes hyperlocomotion, with the discovering of its related intracellular CB1 signaling pathway, along with the signaling transducer involved in the CB1-rich brain areas relevant for locomotor activity (NAc, Str, CB). The main data revealed that THC via CB1 recruits the β-Arrestin1-PI3K-Akt-GSK3β signaling pathway that lead to hyperlocomotion. Furthermore, both PREG and AEF0117 were able to block the THC-induced hyperlocomotion and altered signaling in mice.The third part of the data represent studies on the effects of THC at medium and high doses that induce asocial behavior and hypolocomotion, respectively. Each dose of THC induced specific alterations in the CB1intracellular signaling pathways in the most CB1-rich brain areas, and the treatment with AEF0117 rescued both behaviors.The general discussion then addresses conclusions and perspectives, highlighting the role of specific CB1 pathways in THC-induced addiction and psychosis, and proposes a mechanism of action for CB1-SSi compounds, including AEF0117.
... The treatment based on cannabis extracts provide different responses depending on many variables including individuals and schedule of administration (such as dose and duration). In fact, it has been highlighted that the biphasic effects of THC on cognitive processes are dose-dependent (Calabrese and Rubio-Casillas, 2018). In this context, high THC doses have been linked to cognitive impairment, while chronic administration of low THC doses improve cognitive performance of aging subjects (Calabrese and Rubio-Casillas, 2018;Bilkei-Gorzo et al., 2017). ...
... In fact, it has been highlighted that the biphasic effects of THC on cognitive processes are dose-dependent (Calabrese and Rubio-Casillas, 2018). In this context, high THC doses have been linked to cognitive impairment, while chronic administration of low THC doses improve cognitive performance of aging subjects (Calabrese and Rubio-Casillas, 2018;Bilkei-Gorzo et al., 2017). Additionally, we recently described original findings showing that microdoses of cannabis extract improved the cognitive performance of Alzheimer's disease patients (Ruver-Martins et al., 2022). ...
Introduction
Parkinson’s disease (PD) is mainly characterized by motor symptoms including muscle rigidity, resting tremor and bradykinesia. However, the management of the non-motor symptoms represent a relevant clinical challenger in PD. These non-motor symptoms include cognitive and sleep disturbance and there is evidence that cannabinoids may represent alternative and effective treatments for non-motor symptoms of PD.
Methods
Therefore, this study addressed the effects of oral treatment with cannabis extract on cognition, insomnia, and daytime sleepiness in six patients with moderate PD. The patients were randomized to receive two different doses of a cannabis extract: THC:CBD 250:28 μg/day (n = 3) or 1000:112 μg/day (n = 3). The assessment of cannabis administration related to the cognitive field was measured by the Montreal Cognitive Assessment test (MoCA test), the insomnia was assessed by the Insomnia Severity Index (ISI), and daytime sleepiness was assessed using the Epworth sleepiness scale (ESS). All clinical evaluations were performed before treatment and at 15, 30, 60, and 90 days of treatment.
Results
The statistical analysis indicated a significant benefit of the cannabis extract treatment, at dose of 1000:112 μg/day after 60 days of treatment, on insomnia assessed by ISI. Moreover, the statistical analysis of data from ISI and MoCA tests showed a trend toward improvement over time, while no significant effect was observed in the ESS. There were no reports of significant adverse effects during the cannabis extract treatment.
Discussion
These results demonstrate benefits of short-time treatment (60 days) with low doses of cannabis extract on insomnia in PD patients. This study provide novel findings of the potential of combining CBD and THC as safe and effective treatments for non-motor symptoms of PD.
... The endocannabinoid (eCB) system is a neuromodulator system that plays important roles in learning and memory processing, distributed in areas of the brain related to cognition (Harkany et al., 2003) and implicated in cholinergic neurotransmission (Goonawardena et al., 2010;Puighermanal et al., 2012). Cannabinoid agonists induce memory impairment (Broyd et al., 2016;Urits et al., 2021), but in the last decade, evidence has been accumulating showing a beneficial effect of low cannabinoid doses upon cognitive impairment (Bilkei-Gorzo et al., 2017;Calabrese & Rubio-Casillas, 2018;Ozaita & Aso, 2017). The role of the eCB system in neurodegenerative diseases is still unknown. ...
... Meanwhile, earlier studies, using the NORT assay, revealed that doses of WIN55,212-2 between 0.3 and 1.2 mgÁkg À1 are enough to completely impair short-term memory storage and different stages of long-term recognition memory (Galanopoulos et al., 2014;Schneider et al., 2008). However, there are other reports of either a biphasic effect of cannabinoid agonism on cognition (Calabrese & Rubio-Casillas, 2018), or a beneficial effects of low, as opposed to high, doses (Nitzan et al., 2022;Sarne, 2019). These results suggest that the dual effects of cannabinoids on cognition depend on several factors, for example, the state of the baso-cortical cholinergic pathway, or, more generally, the previous cognitive status of the subjects (Bilkei-Gorzo et al., 2017). ...
Background and Purpose
Recent research linking choline‐containing lipids to degeneration of basal forebrain cholinergic neurons in neuropathological states illustrates the challenge of balancing lipid integrity with optimal acetylcholine levels, essential for memory preservation. The endocannabinoid system influences learning and memory processes regulated by cholinergic neurotransmission. Therefore, we hypothesised that activation of the endocannabinoid system may confer neuroprotection against cholinergic degeneration.
Experimental Approach
We examined the neuroprotective potential of sub‐chronic treatments with the cannabinoid agonist WIN55,212‐2, using ex vivo organotypic tissue cultures including nucleus basalis magnocellularis and cortex and in vivo rat models of specific cholinergic damage induced by 192IgG‐saporin. Levels of lipids, choline and acetylcholine were measured with histochemical and immunofluorescence assays, along with [³⁵S]GTPγS autoradiography of cannabinoid and muscarinic GPCRs and MALDI‐mass spectrometry imaging analysis. Learning and memory were assessed by the Barnes maze and the novel object recognition test in rats and in the 3xTg‐AD mouse model.
Key Results
Degeneration, induced by 192IgG‐saporin, of baso‐cortical cholinergic pathways resulted in memory deficits and decreased cortical levels of lysophosphatidylcholines (LPC). WIN55,212‐2 restored cortical cholinergic transmission and LPC levels via activation of cannabinoid receptors. This activation altered cortical lipid homeostasis mainly by reducing sphingomyelins in lesioned animals. These modifications were crucial for memory recovery.
Conclusion and Implications
We hypothesise that WIN55,212‐2 facilitates an alternative choline source by breaking down sphingomyelins, leading to elevated cortical acetylcholine levels and LPCs. These results imply that altering choline‐containing lipids via activation of cannabinoid receptors presents a promising therapeutic approach for dementia linked to cholinergic dysfunction.
... Biphasic dose response is a typical pharmacological phenomenon observed in several medications, hormones, and neurotransmitters [102,103]. Numerous reports demonstrate the biphasic effects of ∆9-THC and other cannabinoid agonists, in which low and high dosages commonly induce opposing effects [104][105][106]. THC showed opposite dose-related effects on cortical evoked responses in animal model studies. ...
... Regarding the medicinal aspects, cannabinoids have long been used to treat nausea and vomiting; however, due to their biphasic effect, large dosages produce cannabinoid hyperemesis syndrome (CHS), characterized by repeated nausea and vomiting. The major contributor to the symptoms is THC compounds, which cause alterations in the endocannabinoid system by activating the cannabinoid 1 (CB1) receptor [104]. ...
Since legalization, cannabis/marijuana has been gaining considerable attention as a functional ingredient in food. ∆-9 tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids are key bioactive compounds with health benefits. The oral consumption of cannabis transports much less hazardous chemicals than smoking. Nevertheless, the response to cannabis is biphasically dose-dependent (hormesis; a low-dose stimulation and a high-dose inhibition) with wide individuality in responses. Thus, the exact same dose and preparation of cannabis may be beneficial for some but toxic to others. The purpose of this review is to highlight the concept of individual variations in response to cannabinoids, which leads to the challenge of establishing standard safe doses of cannabis products for the general population. The mechanisms of actions, acute and chronic toxicities, and factors affecting responses to cannabis products are updated. Based on the literature review, we found that the response to cannabis products depends on exposure factors (delivery route, duration, frequency, and interactions with food and drugs), individual factors (age, sex), and susceptibility factors (genetic polymorphisms of cannabinoid receptor gene, N-acylethanolamine-hydrolyzing enzymes, THC-metabolizing enzymes, and epigenetic regulations). Owing to the individuality of responses, the safest way to use cannabis-containing food products is to start low, go slow, and stay low.
... The psychoactive cannabinoid THC, first discovered in 1964, is derived from one of the major components of Cannabis sativa, THCA (Calabrese & Rubio-Casillas, 2018;Gaoni & Mechoulam, 1964). THC is a pharmacological paradox due to its biphasic effect: at high concentrations it is responsible for reversible short-term memory disruption (Calabrese & Rubio-Casillas, 2018;Iversen, 2003), however, at low doses, it offers a range of therapeutic properties potentially relevant to AD. ...
... The psychoactive cannabinoid THC, first discovered in 1964, is derived from one of the major components of Cannabis sativa, THCA (Calabrese & Rubio-Casillas, 2018;Gaoni & Mechoulam, 1964). THC is a pharmacological paradox due to its biphasic effect: at high concentrations it is responsible for reversible short-term memory disruption (Calabrese & Rubio-Casillas, 2018;Iversen, 2003), however, at low doses, it offers a range of therapeutic properties potentially relevant to AD. It should be noted that chronic abuse of high dose THC, particularly during adolescence, is viewed as a component cause of schizophrenia, and whether cannabis-abuse related memory deficits are reversible is a complex and hotly debated topic (Hall & Degenhardt, 2008;Patel et al., 2020). ...
Alzheimer's disease (AD) is the most common form of dementia, and currently there is no cure. New therapeutic strategies that have the potential to address the complex pathophysiology of AD are urgently required; medicinal cannabis offers this possibility. Several potential leads can be extracted from Cannabis sativa (cannabis) that can target AD pathophysiology and alleviate symptoms, making it a prime candidate for AD drug discovery research. To date, most cannabis and AD research has focused on the major cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), paying little attention to other plant constituents with therapeutic properties for AD. This chapter will highlight emerging evidence on the therapeutic potential of medicinal cannabis going beyond CBD and THC to discuss cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabinoid acids, and other cannabinoid homologs, terpenes, and flavonoids that may have relevance to AD therapy. Further, the entourage effect, clinical implications, and directions for future research will be discussed.
... In contrast, translational research using healthyaging, 18-24-month-old mice shows improved cognitive function to very low dose Δ9-THC (Bilkei-Gorzo et al., 2017;Sarne et al., 2018). There are also preliminary findings in humans that exposure to cannabis in old age may enhance learning and memory and quality of life (Calabrese and Rubio-Casillas, 2018). To study this topic, old mice (~20 months average) were exposed to daily treatments of vaporized placebo or cannabis high in CBD or Δ9-THC for 28 days. ...
... Heavy cannabis use, especially in adolescence, had been associated with adverse effects on several systems including executive, emotional, reward, and memory processing which increase the risk of mental illnesses including addiction and psychosis (Bloomfield et al., 2019). Calabrese and Rubio reported cannabis use in old mice enhanced cognitive function, but the effects were dosedependent, with only chronic low doses improving neurological function (Calabrese and Rubio-Casillas, 2018). Likewise, a study conducted on mice aged 12 to 18 months found that extremely low doses of Δ9-THC administered continuously through an osmotic minipump for several weeks reversed age-related decline in cognitive performance including memory, learning, and flexibility; and after treatment, closely resembled Δ9-THC-free animals aged 2 months (Bilkei-Gorzo et al., 2017). ...
With the recent legalization of inhaled cannabis for medicinal and recreational use, the elderly represents one of the newest, rapidly growing cohorts of cannabis users. To understand the neurobiological effects of cannabis on the aging brain, 19–20 months old mice were divided into three groups exposed to vaporized cannabis containing ~10% Δ9-THC, ~10% CBD, or placebo for 30 min each day. Voxel based morphometry, diffusion weighted imaging, and resting state functional connectivity data were gathered after 28 days of exposure and following a two-week washout period. Tail-flick, open field, and novel object preference tests were conducted to explore analgesic, anxiolytic, and cognitive effects of cannabis, respectively. Vaporized cannabis high in Δ9-THC and CBD achieved blood levels reported in human users. Mice showed antinociceptive effects to chronic Δ9-THC without tolerance while the anxiolytic and cognitive effects of Δ9-THC waned with treatment. CBD had no effect on any of the behavioral measures. Voxel based morphometry showed a decrease in midbrain dopaminergic volume to chronic Δ9-THC followed but an increase after a two-week washout. Fractional anisotropy values were reduced in the same area by chronic Δ9-THC, suggesting a reduction in gray matter volume. Cannabis high in CBD but not THC increased network strength and efficiency, an effect that persisted after washout. These data would indicate chronic use of inhaled cannabis high in Δ9-THC can be an effective analgesic but not for treatment of anxiety or cognitive decline. The dopaminergic midbrain system was sensitive to chronic Δ9-THC but not CBD showing robust plasticity in volume and water diffusivity prior to and following drug cessation an effect possibly related to the abuse liability of Δ9-THC. Chronic inhaled CBD resulted in enhanced global network connectivity that persisted after drug cessation. The behavioral consequences of this sustained change in brain connectivity remain to be determined.
... A third possibility is dose-response effects of cannabis on cognition and memory. Rodent models suggest that hippocampal neurogenesis and the rescue of age-related deficits in memory is a result of biphasic dose-response to THC 109 . Consistent with the importance of dose in cannabis effects, recent work has shown regular and heavy cannabis use in healthy individuals is associated with impaired fear extinction 110 , but acute low dose THC appears to improve fear extinction and may help modulate amygdala reactivity in response to fear in those with PTSD 111,112 . ...
Posttraumatic stress disorder (PTSD) is associated with poor hippocampal function and disrupted pattern recognition. Cannabis use is highly prevalent in individuals with PTSD, yet the impact on these cognitive functions is poorly understood. Participants (n = 111) with a range of PTSD symptoms with and without regular cannabis use completed the mnemonic similarity task. We hypothesized that regular use would be associated with alterations in pattern separation ability in individuals with PTSD
symptoms. High PTSD symptoms were associated with reduced pattern separation performance in minimal users. Regular users with high PTSD symptoms showed greater pattern separation, but reduced pattern separation with low PTSD symptoms. These results suggest that regular cannabis use may disrupt pattern separation and similar hippocampal-dependent processes, while it may improve pattern separation in individuals with high PTSD symptoms. These cross-sectional results require longitudinal follow-up studies to evaluate the causal effects of regular cannabis use on
cognitive function in PTSD.
... These discrepancies may be attributed to various factors, including differences in animal models, experimental design, and treatment selection. Moreover, a potential dose-dependent effect has been proposed, suggesting that cannabinoids may stimulate neurogenesis at low concentrations (up to 1 µmol/L) and have inhibitory effects at higher concentrations [22]. Notwithstanding, given the intrinsic complexity of the ECS and the numerous signaling pathways with which it interacts, it is reasonable to speculate that possible communications with other signaling systems may constitute additional points of modulation. ...
Neurogenesis is considered the most robust form of plasticity in the adult brain. To better decipher this process, we evaluated the potential crosstalk of Kisspeptin and Endocannabinoid Systems (KPS and ECS, respectively) on hippocampal neurogenesis. Male adolescent rats were exposed to kisspeptin-10 (KP10) and the endocannabinoid anandamide (AEA) administered alone or in combination with the type 1 cannabinoid receptor (CB1R) antagonist SR141716A. The expression of Kiss1 and Kisspeptin receptor (Kiss1R) has been characterized for the first time in rat hippocampus together with the expression of the CB1R and the Transient Receptor Potential Vanilloid 1 ion channel receptor (TRPV1). Results show that both systems inhibit neurogenesis by reducing the extracellular signal-regulated kinase (ERK) signaling. Despite little differences in the expression of Kiss1R and CB1R, TRPV1 is enhanced by both KP10 and AEA treatments, suggesting TRPV1 as a common thread. KP10 administration reduces CB1R expression in the dentate gyrus, while AEA does not. KPS, unlike ECS, promotes the expression of estrogen receptor α (ER-α) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), also upregulating sirtuin 1 (SIRT1), brain-derived-neurotrophic factor (BDNF), and c-Jun. These findings suggest that the interaction between ECS and KPS could be involved in the fine-tuning of neurogenesis, highlighting a novel role for KPS.
... Accordingly, acute THC administration dosedependently induces a spectrum of behavioral phenotypes that may recapitulate some addictive and toxic effects of cannabis use in experimental animals 13 , including THC-induced acute psychotic-like states (CIAPS) 14 . THC exerts dose-dependent biphasic behavioral effects on locomotor activity, food intake, cognitive function, and reward processes [14][15][16][17] . In particular, whereas high doses decrease locomotion, low doses of THC (< 0.5mg/kg) can produce a stimulation of locomotor activity in rodent models 14,17,18 . ...
Administration of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of the plant Cannabis sativa, can induce psychotic symptomatology in humans and a large spectrum of acute psychotic-like behaviors in mice, including hyperlocomotion observed at low dose of THC (0.3 mg/kg). The cellular and molecular substrates of this effect have not been fully identified yet. Here we demonstrate that THC-induced hyperlocomotion depends on plasma membrane CB1R, which regulate the β-arrestin 1/Akt/GSK3β signaling pathway in D2R-positive neurons of the dorsal striatum forming the striatopallidal pathway of the basal ganglia. Pregnenolone (PREG) and its clinically developed analog, AEF0117, which are signaling specific inhibitors of CB1R (CB1-SSi), prevented GSK3β-dependent psychomotor stimulation induced by THC. Overall, this work highlights a novel intracellular mechanism of CB1R, thereby revealing a neuronal pathway underlying an important but still underexplored effect of THC and cannabis consumption, which could help the development of innovative therapeutic concepts against psychotic conditions.
... Its active compounds have a variety of effects on the CNS, making them promising alternatives for psychopharmacological use in the treatment of many neuropsychiatric disorders. 150,151,[157][158][159][160] To improve and better understand the Cannabis sativa plant, there are more than 550 chemical compounds in it, with more than 140 phytocannabinoids (cannabinoids found in the cannabis plant) identified. Cannabis sativa also contains aromatic terpenes, of which more than 100 have been identified. ...
Introduction: Cannabinoids are increasingly being explored as a potential treatment for neurodegenerative diseases. This article aims to provide a narrative review of available data on the treatment of neurological disorders with cannabis constituents, focusing on ischemic stroke. Methods: Selected articles are summarized to describe design, results, limitations, conclusions, and implications about this theme. Results: The growing understanding of the endocannabinoid system and the cannabinoid receptors distribution in all human body systems and organs and particularly in brain structures importantly involved in myelination processes, suggests potential benefits for stroke symptoms and overall patient improvement. However, the variety of studied compounds, the different administration routes, dosages, and timing complicates data comparison, especially due to limited studies about these compounds, peculiarly in stroke patients. Thereat, this review to showcase disparities in findings and to summarize current advancements in cannabinoid use for potential future treatments. Conclusion: This article offers a review of the current literature in the field and discuss a pragmatic approach to the clinical use of cannabinoids in patients with ischemic stroke.
... The heavy use of uniform dosages may reflect an indirect influence of regulatory frameworks on scientific exploration. Given the biphasic dose-response nature of cannabinoids (Calabrese and Rubio-Casillas, 2018, Hodges et al., 2020, Kitdumrongthum and Trachootham, 2023, it is imperative to broaden the spectrum of investigation to fully understand their pharmacological impact. ...
... Delta-9-tetrahidrokanabinolis (THC) yra stipriausiai veikianti psichoaktyvi medžiaga, randama kanapėse [12]. Tiek THC, tiek kanabidiolis (CBD), veikdami kaip dalinis agonistas [13], aktyvuoja abiejų subtipų (CB1 ir CB2) endokanabinoidų sistemos receptorius [14]. ...
Insomnia is a sleep disorder characterized by difficulty falling asleep or maintaining sleep after waking up. With the increasing pace of life and high levels of stress, there is a rising number of individuals reporting sleep disturbances. Recently, there has been a growing interest in various cannabis preparations, particularly in cannabinoids derived from Cannabis sativa plants, for the treatment of insomnia. Delta-tetrahydrocannabinol (THC) and cannabidiol (CBD) are commonly used to treat insomnia. Both of these substances have shown potential in improving sleep quality and have historically been used to induce sleep. Despite their widespread use, there is still a lack of reliable research to prove their effectiveness. Nevertheless, cannabinoids remain frequently used substances in the management of sleep disorders. While THC and CBD may enhance the sleep quality by reducing nighttime awakenings, shortening sleep onset latency, and increasing the total sleep time, their efficacy in treating insomnia lacks scientific validation. Additionally, there are safety concerns associated with cannabinoids, including potential negative impacts on the sleep quality, risk of abuse or dependence, and the development of tolerance with long-term use.This article provides a comprehensive review of literature concerning the effects and safety of cannabinoids on sleep and sleep-wake rhythms, as well as their potential benefits in treating insomnia and other sleep disorders.
... In observational studies, the correlation between CUD and AD is inconsistent. According to previous studies, attention deficit disorder can be prevented by promoting hippocampal neurogenesis through smoking marijuana 34 . But another study says that overdose will lead to hippocampal atrophy and poor cognitive function, and that mild cognitive deficits and hippocampal atrophy at midlife are risk factors for advanced dementia 35 . ...
Observational studies have shown some association between cannabis use disorder (CUD) and neurological disorders, but their causal relationship is unclear. In this study, we tested the potential causal relationship between CUD and three common neurological disorders using two-sample Mendelian randomization (TSMR) and multivariate MR (MVMR) methods. Thirty-two genetic loci were extracted as exposure factors from the largest genome-wide association study (GWAS) summary statistics for CUD to date. TSMR results showed that genetic prediction of CUD with all stroke, ischemic stroke, large-artery atherosclerotic stroke, migraine with aura, and Alzheimer’s disease (AD) had a positive causal relationship (P < 0.05), which was not found in several other diseases. The association between CUD and stroke, ischemic stroke, and AD in the MVMR study may have been influenced by confounding factors (P > 0.05). Subgroup analyses highlighted a causal relationship between genetically predicted CUD and large-artery atherosclerotic stroke (OR = 1.169; 95%CI 1.030–1.328; P = 0.016) and migraine with aura (OR = 1.142; 95% 1.021–1.278; P = 0.020). Our further functional mapping and annotation enrichment analyses using FUMA suggest that the brain-gut axis may serve as another layer of explanation for the existence of an association between CUD and neurological disorders.
... However, clinical evidence has shown that excessive use of cannabinoids can lead to psychiatric symptoms and a decline in memory compared with low-dose use. [94][95][96] Such reports further emphasize the importance of safety testing and dose control prior to the initiation of synthetic cannabinoid agonist therapy in patients with PTSD. In this study, we interfered with the function of CB1Rs locally at the LPB Glu /CeL SOM pathway to avoid the side effects of systemic cannabinoid administration. ...
Somatostatin (SOM)-expressing neurons in the central lateral amygdala (CeL) are responsible for fear memory learning, but the circuit and molecular mechanisms underlying this biology remain elusive. Here, we found that glutamatergic neurons in the lateral parabrachial nucleus (LPB) directly dominated the activity of CeLSOM neurons, and that selectively inhibiting the LPBGlu→CeLSOM pathway suppressed fear memory acquisition. By contrast, inhibiting CeL-projecting glutamatergic neurons in the paraventricular thalamic nucleus (PVT) interfered with consolidation-related processes. Notably, CeLSOM-innervating neurons in the LPB were modulated by presynaptic cannabinoid receptor 1 (CB1R), and knock down of CB1Rs in LPB glutamatergic neurons enhanced excitatory transmission to the CeL and partially rescued the impairment in fear memory induced by CB1R activation in the CeL. Overall, our study reveals the mechanisms by which CeLSOM neurons mediate the formation of fear memories during fear conditioning in mice, which may provide a new direction for the clinical research of fear-related disorders.
... First, the placenta lacks cannabinoid-clearing mechanisms and acts as a reservoir for CBD, resulting in a slow but prolonged distribution to the fetus (Berman et al. 2023). Second, cannabinoids exhibit a dose-dependent biphasic effect (Calabrese and Rubio-Casillas, 2018;Eggers et al. 2019). Consequently, it is important to study their effects across a range of concentrations extending beyond those currently accepted for therapeutic use to fully understand their potential effects on TRP metabolism. ...
... The notion that gait variability may be a putative marker of cognitive-cortical deterioration in neurodegenerative disorders has diagnostic and prognostic implications. In light of data suggesting chronic ultra-low-dose THC is associated with significant augmentation of memory and other aspects of cognition in animal models and in older adults with dementing illness (Bilkei-Gorzo, 2017 [38]; Sarne et al., 2011 [39] and 2018 [40]; Calabrese & Rubio-Casillas, 2018 [41]), the finding that mobility and gait stability are not likely to acutely deteriorate with THC on board represents reassurance about safety. ...
In this overview, we seek to appraise recent experimental and observational studies investigating THC and its potential role as adjunctive therapy in various medical illnesses. Recent clinical trials are suggestive of the diverse pharmacologic potentials for THC but suffer from small sample sizes, short study duration, failure to address tolerance, little dose variation, ill-defined outcome measures, and failure to identify and/or evaluate confounds, all of which may constitute significant threats to the validity of most trials. However, the existing work underscores the potential therapeutic value of THC and, at the same time, calls attention to the critical need for better-designed protocols to fully explore and demonstrate safety and efficacy. In the most general sense, the present brief review illuminates some intriguing findings about THC, along with the basic threats to the validity of the research that supports those findings. The intent is to highlight existing generic weaknesses in the existing randomized controlled trial literature and, most importantly, provide guidance for improved clinical research.
... Cannabidiol (CBD) and delta-tetrahydrocannabidiol (THC) are the two most important and widely studied components [3,4]. Cannabis is associated with recreational drugs due to THC, which is known as the primary psychoactive component of the plant [5]. However, CBD has no psychotropic effects and has a confirmed safety profile [6,7]. ...
Due to cannabidiol’s health benefits and absence of serious side effects, its use is constantly growing. This is a survey-based cross-sectional study that was conducted to determine Croatian pharmacists’, physicians’, and students’ knowledge and attitudes about cannabidiol (CBD). Two questionnaires were created, one for students and the other for physicians and pharmacists. Our participants (in total 874: 473 students and 401 physicians and pharmacists) generally had positive attitudes towards CBD therapy as approximately 60% of them believe that CBD treatment is generally efficacious. Participants had positive attitudes toward the therapeutic value of CBD, especially pharmacists and pharmacy students (63.8% and 72.2%, respectively). Pharmacists were significantly more convinced that CBD could reduce the use of opioids prescribed for chronic pain (p < 0.05). Only 17.5% of students had read scientific papers about CBD, compared to a significantly higher percentage of physicians and pharmacists (43.0% and 47.8%, respectively) (p < 0.05). This study revealed a gap in knowledge regarding CBD, since 89.3% of pharmacists and physicians, as well as 84.8% of students, believe they need more education about CBD. We conclude that it is important to improve the educational curricula so that medical professionals can recommend CBD use to their patients when needed.
... Impairments in cognition have also been observed with both acute and chronic exposure to THC. Most consistently these dose-dependent impairments are seen in attention, verbal learning, working memory, and memory functions in both preclinical and clinical studies (Calabrese and Rubio-Casillas, 2018). Behavioral tests, such as novel object recognition and delayed alternating T-maze, have provided evidence of long-lasting disruption of working memory associated with THC exposure in adolescent mice (Chen and Mackie, 2020;Kasten et al., 2017). ...
Fatty acid binding protein 5 (FABP5) interacts with the endocannabinoid system in the brain via intracellular transport of anandamide, as well as Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. Previous work has established the behavioral effects of genetic deletion of FABP5, but not in the presence of THC. The present study sought to further elucidate the role of FABP5 on the pharmacokinetic and behavioral response to THC through global deletion. Adult FABP5+/+ and FABP5−/− mice were tested for behavioral response to THC using Open Field (OF), Novel Object Recognition (NOR), T-Maze, Morris Water Maze (MWM), and Elevated Plus Maze (EPM). An additional cohort of mice was used to harvest blood, brains, and liver samples to measure THC and metabolites after acute administration of THC. Behavioral tests showed that some cognitive deficits from FABP5 deletion, particularly in MWM, were blocked by THC administration, while this was not observed in other measures of memory and anxiety (such as T-Maze and EPM). Measurement of THC and metabolites in blood serum and brain tissue through UPLC-MS/MS analysis showed that the pharmacokinetics of THC was altered by FABP5. The present study shows further evidence of the importance of FABP5 in cognitive function. Additionally, results showed that FABP5 is an important regulator of the physiological effects and pharmacokinetics of THC.
... In this case, this inverted U-shaped graph can be interpreted as typically moderate cannabis users exhibited longer sleep durations than either lighter or heavier users; non-users were not included in these analyses. Across numerous scientific domains, non-linear cannabis dose-response curves have been observed (Calabrese & Rubio-Casillas, 2018;Childs et al., 2017;Hodges, Marshall, & Ashpole, 2020;Latif & Garg, 2020;Zuardi et al., 2017). For example, recent epidemiological studies (Corroon et al., 2017;Cuttler et al., 2018) and some administration research (Childs et al., 2017;Fusar-Poli et al., 2010) suggest that low-to-moderate cannabis consumption has some anxiolytic properties, but higher doses can be anxiogenic (Bossong et al., 2013;Karniol et al., 1974;Petrie et al., 2021;Sharpe et al., 2020). ...
This study characterized how quantities of cannabis and alcohol use affect sleep. Single-day and typical cannabis and alcohol use patterns were considered to assess acute-chronic use interactions. Linear and non-linear associations assessed dose-dependence. College students (n=337; 52% female) provided 11,417 days of data, with up to five time points per day. Daily self-reported sleep duration, cannabis use quantity, and alcohol use quantity were subjected to linear mixed modeling to capture linear and curvilinear associations between single-day and typical use on same-night and typical sleep. Sleep duration (difference between bedtime and waketime) was the outcome. Quantity of cannabis used each day andtypical quantity used across all days were predictors in the cannabis models. Parallel single-day and typical alcohol variables were predictors in the alcohol models. Follow-up analyses excluded days with alcohol-cannabis co-use. Main effects of single-day and typical cannabis quantity on sleep duration were observed when all cannabis-use days were modeled. Higher than typical doses of single-day and typical cannabis were associated with longer sleep durations, but only to a point; at the highest doses, cannabis shortened sleep. A main effect of single-day alcohol quantity and two interactions (single-day use with both linear and curvilinear typical use) on sleep duration were observed when all alcohol-use days were modeled. Greater alcohol consumption on a given day led to shorter same-night sleep, but typically heavier drinkers required higher doses than typically lighter drinkers to experience these adverse effects. Follow-up models suggested alcohol co-use may contribute to the purported sleep-promoting effects of cannabis.
... Performancebased and direct observation everyday functioning measures may be advantageous to employ in future studies of cannabis use to improve the ecological validity of everyday functioning assessment. Future research is also needed to determine whether the biphasic, age-and dose-dependent effects of THC on memory observed in animal studies (i.e., low dose THC administration improves memory function selectively in older mice, while high dose THC induces memory impairment) translate to older human populations [52,53]. Such work will be critical for establishing cannabinoid-specific recommendations for older adult medical and recreational use to limit any possible negative cognitive outcomes due to use of THC. ...
Cannabis use is rapidly increasing among older adults in the United States, in part to treat symptoms of common health conditions (e.g., chronic pain, sleep problems). Longitudinal studies of cannabis use and cognitive decline in aging populations living with chronic disease are lacking. We examined different levels of cannabis use and cognitive and everyday function over time among 297 older adults with HIV (ages 50–84 at baseline). Participants were classified based on average cannabis use: frequent (> weekly) (n = 23), occasional (≤ weekly) (n = 83), and non-cannabis users (n=191) and were followed longitudinally for up to 10 years (average years of follow-up = 3.9). Multi-level models examined the effects of average and recent cannabis use on global cognition, global cognitive decline, and functional independence. Occasional cannabis users showed better global cognitive performance overall compared to non-cannabis users. Rates of cognitive decline and functional problems did not vary by average cannabis use. Recent cannabis use was linked to worse cognition at study visits when participants had THC+ urine toxicology—this short-term decrement in cognition was driven by worse memory and did not extend to reports of functional declines. Occasional (≤ weekly) cannabis use was associated with better global cognition over time in older adults with HIV, a group vulnerable to chronic inflammation and cognitive impairment. Recent THC exposure may have a temporary adverse impact on memory. To inform safe and efficacious medical cannabis use, the effects of specific cannabinoid doses on cognition and biological mechanisms must be investigated in older adults.
... Ultra-low (0.002 mg/kg; i.p) and low (3 mg/kg; i.p) doses of THC resulted in improved cognitive function in old mice (24 and 18-month-old, respectively), whereas the same dose induced cognitive impairments in adult mice (2-months-old; Bilkei-Gorzo et al., 2017;Sarne et al., 2018). However, higher doses of THC have the reverse effect (Calabrese and Rubio-Casillas, 2018). This dose-dependent alteration was also observed in microglia in the 2-month-old mouse brain, where higher doses (20 mg/kg; i.p) of THC resulted in the increased release of pro-inflammatory cytokines compared to lower doses (Cutando et al., 2013). ...
Consumption of cannabis is on the rise as public opinion trends toward acceptance and its consequent legalization. Specifically, the senior population is one of the demographics increasing their use of cannabis the fastest, but research aimed at understanding cannabis' impact on the aged brain is still scarce. Aging is characterized by many brain changes that slowly alter cognitive ability. One process that is greatly impacted during aging is axonal myelination. The slow degradation and loss of myelin (i.e., demyelination) in the brain with age has been shown to associate with cognitive decline and, furthermore, is a common characteristic of numerous neurological diseases experienced in aging. It is currently not known what causes this age-dependent degradation, but it is likely due to numerous confounding factors (i.e., heightened inflammation, reduced blood flow, cellular senescence) that impact the many cells responsible for maintaining overall homeostasis and myelin integrity. Importantly, animal studies using non-human primates and rodents have also revealed demyelination with age, providing a reliable model for researchers to try and understand the cellular mechanisms at play. In rodents, cannabis was recently shown to modulate the myelination process. Furthermore, studies looking at the direct modulatory impact cannabis has on microglia, astrocytes and oligodendrocyte lineage cells hint at potential mechanisms to prevent some of the more damaging activities performed by these cells that contribute to demyelination in aging. However, research focusing on how cannabis impacts myelination in the aged brain is lacking. Therefore, this review will explore the evidence thus far accumulated to show how cannabis impacts myelination and will extrapolate what this knowledge may mean for the aged brain.
... Side effects are comprised of behavioral and physical manifestations. As an example, cannabinoids are known to cause a disruption in working memory, attention impairments, increased anxiety, insomnia, etc. [10,15]. One theory as to why cannabinoid users tend to also use nicotine, and vice versa, is that they may both decrease these adverse effects and increase the reinforcing effects of one another [25,85]. ...
Cannabis is among the most widely consumed psychoactive drugs around the world and cannabis use disorder (CUD) has no current approved pharmacological treatment. Nicotine and cannabis are commonly co-used which suggests there to be overlapping neurobiological actions supported primarily by the co-distribution of both receptor systems in the brain. There appears to be strong rationale to explore the role that nicotinic receptors play in cannabinoid dependence. Preclinical studies suggest that the ɑ7 nAChR subtype may play a role in modulating the reinforcing and discriminative stimulus effects of cannabinoids, while the ɑ4β2* nAChR subtype may be involved in modulating the motor and sedative effects of cannabinoids. Preclinical and human genetic studies point towards a potential role of the ɑ5, ɑ3, and β4 nAChR subunits in CUD, while human GWAS studies strongly implicate the ɑ2 subunit as playing a role in CUD susceptibility. Clinical studies suggest that current smoking cessation agents, such as varenicline and bupropion, may also be beneficial in treating CUD, although more controlled studies are necessary. Additional behavioral, molecular, and mechanistic studies investigating the role of nAChR in the modulation of the pharmacological effects of cannabinoids are needed.
... Ponadto układ endokannabinoidowy partycypuje w synchronizacji i komunikacji międzysystemowej -również metabolicznej, glukozowo-lipidowej czy np. immunologicznej, a także ściśle wiąże się z dystrybucją fal mózgowych bądź wykazuje powiązania z progresją chorób neurodegeneracyjnych/degeneracyjnych (Calabrese et al., 2018;Cassani et al., 2018;Cecchetti et al., 2021;Cristino et al., 2020;Fowler, 2020;Kesner et al., 2020;Minichino et al., 2021;Santoro et al., 2021;Tirozzi et al., 2020). ...
... Hence, it might be possible that the effects of high doses of THC on spine dynamics might be different or even opposite to what we observed. For instance, a dose-dependent, biphasic effect of THC was shown for its anxiolytic/anxiogenic properties, but also in relation to cognition 29,30 . On the other hand, not only 3 mg/kg that we used in our study, but also lower doses seem to cause a similar effect in old mice. ...
Cognitive functions decline during aging. This decline could be caused by changes in dendritic spine stability and altered spine dynamics. Previously, we have shown that a low dose chronic THC treatment improves learning abilities in old whereas impairs learning abilities in young mice. The mechanism underlying this age-dependent effect is not known. Dendritic spine stability is a key for memory formation, therefore we hypothesized that THC affects spine dynamics in an age-dependent manner. We applied longitudinal 2-photon in vivo imaging to 3- and 18-month-old mice treated with 3 mg/kg/day of THC for 28 days via an osmotic pump. We imaged the same dendritic segments before, during and after the treatment and assessed changes in spine density and stability. We now show that in old mice THC improved spine stability resulting in a long-lasting increase in spine density. In contrast, in young mice THC transiently increased spine turnover and destabilized the spines.
... [33][34][35][36] Additional preclinical work has also provided some evidence that THC may be associated with neurogenesis, anti-inflammatory effects, and prevention of neurodegenerative processes in animal models of disease, as well as in older animals via CB1 receptor-mediated processes and inhibition of enzymatic hydrolysis of acetylcholine. 37 However, only one study to date has examined the specific impact of MC use on WM coherence in humans. Houston et al recently reported increased FA and reduced MD in patients with treatment-resistant epilepsy after taking Epidiolex, a highly purified oral solution of CBD. ...
Background
Previous studies have demonstrated abnormal white matter (WM) microstructure in recreational cannabis consumers; however, the long-term impact of medical cannabis (MC) use on WM coherence is unknown. Accordingly, this study assessed the longitudinal impact of MC treatment on WM coherence. Given results from preclinical studies, we hypothesized that MC treatment would be associated with increased fractional anisotropy (FA) and reduced mean diffusivity (MD).
Methods
As part of a larger, longitudinal investigation, patients interested in treating at least one medical condition with commercially available MC products of their choosing were assessed before initiating MC use (baseline n=37; female=25, male=12) and following three (n=31) and six (n=22) months of treatment. WM coherence was assessed via diffusion tensor imaging for bilateral regions of interest including the genu of the corpus callosum, anterior limb of the internal capsule, external capsule, and anterior corona radiata, as well as an occipital control region not expected to change over time.
Results
In MC patients, FA values significantly increased bilaterally in several callosal regions relative to baseline following both 3 and 6 months of treatment; MD values significantly decreased in all callosal regions but only following 6 months of treatment. No significant changes in WM coherence were observed in the control region or in a pilot sample of treatment-as-usual patients (baseline n=14), suggesting that increased WM coherence observed in MC patients may be attributed to MC treatment as opposed to confounding factors. Interestingly, significant reductions in MD values correlated with higher cannabidiol (CBD) exposure but not Δ-9-tetrahydrocannabinol exposure.
Conclusions
Overall, MC treatment was associated with increased WM coherence, which contrasts with prior research examining recreational cannabis consumers, likely related to inherent differences between recreational consumers and MC patients (e.g., product choice, age of onset). In addition, increased CBD exposure was associated with reduced MD following 6 months of treatment, extending evidence from preclinical research indicating that CBD may be neuroprotective against demyelination. However, additional research is needed to elucidate the clinical efficacy of MC treatment and the risks and benefits of long-term MC use.
... Concentrates contain much higher levels of delta-9-tetrahydrocannabinol (THC) than flower (52%-95% in concentrates vs. 16%-21% in flower; Bidwell et al., 2021;Raber et al., 2015;Stogner & Miller, 2015). The use of extremely high levels of THC is associated with an increased risk of cannabis use disorder (Arterberry et al., 2019;Freeman et al., 2018), increased severity of dependence (Freeman & Winstock, 2015;Meier, 2017), cognitive impairment (Calabrese & Rubio-Casillas, 2018;Pope, 1995;Pope et al., 2001;Ramaekers et al., 2006;Shannon et al., 2010), risk of psychosis (Di Forti et al., 2015Schoeler et al., 2016), and poor mental health (Chan et al., 2017). Concentrates may appeal to youth more than flower due to the greater discretion of noncombustion methods, larger variety, and novel devices (Budney et al., 2015;Maccoun & Mello, 2015;Russell et al., 2018). ...
Cannabis users use different forms of cannabis, which are associated with distinct public health concerns. Policies that aim to regulate one specific form may have unintended impacts on other forms. This study examined the behavioral economic relationship between flower and concentrates, the two most common forms of cannabis. We surveyed 605 adult cannabis users (21+) who lived in one of the U.S. states that had legalized recreational cannabis by the time of interview in 2019. The participants completed simulated purchase tasks, which asked how much cannabis flower and concentrates they would purchase in the next 30 days at escalating prices. We estimated (a) demand indices and own-price elasticities using nonlinear exponential demand models and (b) group- and individual-level cross-price elasticities using log-linear demand models. The estimated rate of change in demand elasticity (α) was 0.00066 for cannabis flower (SE = 0.00002, p < .001) and 0.00058 for cannabis concentrate (SE = 0.00002, p < .001). Group-level cross-price elasticity estimate (slope = -0.075, SE = 0.0135, p < .001) indicated that cannabis flower and concentrates were weak complements. Individual-level cross-price elasticity estimates showed that flower and concentrates were treated as independent by 76.2% of the users, as complements by 19.0% of the users, and as substitutes by 4.8% of the users. The findings suggested that cannabis flower and concentrates were overall weak complements and for most adult cannabis users were treated as independent of each other. Price and tax policies regulating either cannabis form may have minimal impacts on the other form. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
... Interestingly, despite the lack of effect of a THC dose, we observed a negative correlation between the amount of cannabis consumed and subjective appeal. Although the biphasic dose responses of cannabinoids have been observed in several studies [65][66][67][68], most of these studies rely on the isolated administration of cannabinoids, rather than the naturalistic consumption of scores of quantifiable analytes, as in the current work. With small amounts of cannabis (0.1-0.25 g), it is possible that THC's effects may have been modulated by the presence of other molecules, an effect that may have been occluded by THC's effects with larger amounts of cannabis. ...
Previous studies have shown that cannabis consumers are willing to pay more money for higher-quality products; however, the definition of “quality” cannabis has not been defined. Despite the known health risks of THC overuse, THC potency has been adopted as the primary market-driving feature of cannabis products. The purpose of this study was to objectively identify features of cannabis that contribute to its appealing subjective effects. In the course of conducting cannabis competitions, commercially available cannabis inflorescences were distributed to healthy volunteers (“judges”) in a randomized, double-blind fashion. Anonymous online survey data about the subjective effects of each cannabis sample were analyzed independently, by researchers not involved with the competitions. Pleasant subjective aroma (but not terpene expression, THC potency, or THC dose) was positively correlated with pleasant subjective effects. There was also a moderate but significant negative association between the amount of cannabis consumed and subjective appeal. These results suggest that, unlike THC potency, pleasant aroma is predictive of pleasant subjective effects. Similar to other agricultural commodities such as coffee and tea, aroma appears to be a robust indicator of the quality of cannabis inflorescence. These findings have wide-reaching public health implications, given the well-established health risks of THC overuse.
... The therapeutic benefits of THC for AD may be impeded by adverse effects including (but not limited to) psychoactivity, dizziness, disorientation, and anxiety (Whiting et al., 2015), particularly relating to high-dose THC administration (e.g., > 10 mg orally for humans, or > 10 mg/kg THC i.p. for mice) (Paronis et al., 2012;Calabrese and Rubio-Casillas, 2018). Importantly, the side effect profile of THC may lessen over time due to tolerance effects (Haney et al., 1999) or may be offset or reduced by using a low-dose regime (e.g., up to ∼3 mg/day orally for humans or < 3 mg/kg i.p. for mice). ...
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by declining cognition and behavioral impairment, and hallmarked by extracellular amyloid-β plaques, intracellular neurofibrillary tangles (NFT), oxidative stress, neuroinflammation, and neurodegeneration. There is currently no cure for AD and approved treatments do not halt or slow disease progression, highlighting the need for novel therapeutic strategies. Importantly, the endocannabinoid system (ECS) is affected in AD. Phytocannabinoids, including cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), interact with the ECS, have anti-inflammatory, antioxidant, and neuroprotective properties, can ameliorate amyloid-β and NFT-related pathologies, and promote neurogenesis. Thus, in recent years, purified CBD and THC have been evaluated for their therapeutic potential. CBD reversed and prevented the development of cognitive deficits in AD rodent models, and low-dose THC improved cognition in aging mice. Importantly, CBD, THC, and other phytochemicals present in Cannabis sativa interact with each other in a synergistic fashion (the “entourage effect”) and have greater therapeutic potential when administered together, rather than individually. Thus, treatment of AD using a multi-cannabinoid strategy (such as whole plant cannabis extracts or particular CBD:THC combinations) may be more efficacious compared to cannabinoid isolate treatment strategies. Here, we review the current evidence for the validity of using multi-cannabinoid formulations for AD therapy. We discuss that such treatment strategies appear valid for AD therapy but further investigations, particularly clinical studies, are required to determine optimal dose and ratio of cannabinoids for superior effectiveness and limiting potential side effects. Furthermore, it is pertinent that future in vivo and clinical investigations consider sex effects.
... Also, one of the most recent studies has determined that smoking cannabis containing the active molecule of tetrahydrocannabinol (THC) disrupts short memory, but unclear evidence of neurogenesis in the hippocampus also has been reported [29]. Alcohol abuse in big quantities can prevent the brain from forming new memories, and after the withdrawal, incapacity to remember correctly what happened when drunk. ...
Neuroplasticity is the brain’s ability to adapt to new stimuli, with the objective to overcome and learn how to deal with novel situations. In this chapter, it will be explained the new neurophysiological mechanism that entitles the processes of brains’ plasticity. The intriguing phenomena that surround cognitive mechanisms will be described on a morphological and molecular scale, aiming to understand some of the brains’ functions. The principal objective is to clarify and explain that neuroplasticity can take place in different complex tasks such as adaptative behaviors, memory, learning, and automatic conducts. Also, the evolutionary advantage of forgetting will be deeply discussed. The work will describe the functioning of the brain when adapting to new circumstances that affect the procedures of memory. It will be explained why applying biotechnology and neurobioethics is crucial for merging basic and clinical sciences.
... This is in accordance with the notion of the dual-effect of ULD-THC; where ULD-THC given to young and healthy mice demonstrates cognitive decline [54], whereas in aged or neurologically impaired mice, ULD-THC shows beneficial effects [23,24]. This age-dependent dual effect of low doses of THC was suggested to be related to CB1 activation, histone acetylation, as well as to the expression of BDNF and TrkB [28] (for an extensive review, see [42,55,56]). ...
Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus. We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC. The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.
The harms associated with substance use represent a public health concern on a global scale, varying according to the substances used, individual characteristics, and contextual factors. This chapter addresses the epidemiology and impacts of substance use in the global context, emphasizing that disorders related to the use of alcohol and other substances affect mental health, quality of life, and well-being, both at micro and macro-social levels. Data from the World Health Organization (WHO) indicate that, in 2016, more than half of the global population aged 15 years or older consumed alcoholic beverages, with a high prevalence of excessive alcohol consumption patterns, such as binge drinking. According to the 2023 World Drug Report by the United Nations Office on Drugs and Crime (UNODC), it is estimated that 36 million people used amphetamines, 22 million used cocaine, and 20 million consumed MDMA, commonly known as “ecstasy”. The excessive use of illicit substances, especially opioids, has been associated with most substance use disorders, with opioids accounting for nearly 70% of deaths related to substance use disorders. Cannabis use among adolescents and young adults also showed high prevalence, with 5.3% of youths aged 15–16 years reporting use in the past year. Health consequences may include impairments in cognitive-socio-emotional development, compromised neurocognitive functions, and long-term health conditions, as well as other psychosocial harms. Prolonged use may be associated with neurobiological alterations, such as changes in synaptic plasticity and inflammatory processes, with effects varying according to genetic, developmental, and sociocultural factors. These variations underscore the importance of a multifactorial understanding of the effects of substance use, without generalizations, taking into account the diversity of neuropsychological profiles and the different contexts in which use occurs.
Adolescent cannabinoid exposure has been implicated in enduring modifications to adult brain circuitry; however, well-controlled, systematic analyses investigating dose-dependent effects of chronic delta-9-tetrahydrocannabinol (THC) exposure on brain connectivity are lacking. It is hypothesized that large-scale intrinsic networks, such as default mode (DMN), central executive (CEN), and salience networks (SN), are critically involved in vulnerability to deficits in cognitive processing often associated with adolescent cannabis use. The present study aimed to elucidate the effects of chronic THC exposure on functional connectivity (FC) of these putative large-scale networks in nonhuman primates. Separate groups of adolescent squirrel monkeys (aged 2.0-yrs [female] and 2.5-yrs [male]) were administered intramuscular injections of vehicle or THC daily (0.32 or 3.2mg/kg) for 6-months during adolescence. Resting state functional connectivity from scans conducted in awake subjects was measured before dosing, at 6-months of chronic dosing, and 60-days following discontinuation of daily THC exposure. Utilizing two distinct analytical methodologies, we observed a non-linear, dosage-dependent alteration in DMN-CEN FC across scan intervals. Specifically, exposure to a low THC dosage increased FC during chronic exposure compared to both the pre-dosing and discontinuation periods. This pattern, however, was not observed in either the vehicle or high THC dosage groups. Dual-regression unveiled a similar non-linear effect within the CEN, but not DMN, suggesting the effect on DMN-CEN FC may be driven by modifications within the CEN. Taken together, these results suggest adolescent THC exposure differentially affects large-scale brain networks and contributes to a nuanced understanding of CEN's role in disrupting brain connectivity following chronic THC exposure.
For a long time, there were many thoughts that cannabis was not a “dangerous” drug, or only a “soft” drug, in the sense that it did not lead to physical withdrawal syndrome—unlike alcohol, opiates, or benzodiazepines. We can be dependent without a physical withdrawal syndrome (even if its presence is of course an aggravating factor). On the other hand, addiction always results in discomfort, lack of any attempt to stop, weaning, the brain suffers and expresses it through general symptoms as we can see, for example, with tobacco: nervousness, tension, restlessness, irritability, and sleep disorders.
This is also the case with cannabis and this is recognized in international classifications since Diagnostic and Statistical Manual of Mental Disorders (DSM) 5. Cannabis addiction has therefore long been contested, but current data indicate that around 10% of cannabis experimenters become addicted to it. This is the case for more than 16% of those who started during adolescence and about 50% of daily users. This addiction is also manifested by a currently well-identified withdrawal syndrome which is expressed in particular by symptoms of irritability, insomnia, dysphoria, anxiety, and craving (irrepressible need to consume). In addition to this addiction problem, cannabis use can be a pathway for psychotic disorders to appear, although it is not yet clear whether it is cannabis that leads to schizophrenia or psychosis that leads to cannabis use.
Background
Neurocognitive deficits have been widely reported in clinical high-risk for psychosis (CHR) populations. Additionally, rates of cannabis use are high among CHR youth and are associated with greater symptom severity. Cannabis use has been sometimes shown to be associated with better neurocognition in more progressed psychosis cohorts, therefore in this study we aimed to determine whether a similar pattern was present in CHR.
Methods
CHR participants ages 12–30 from the North American Prodromal Longitudinal Study (NAPLS-3) (N = 698) were grouped according to: “minimal to no cannabis use” (n = 406), “occasional use” (n = 127), or “frequent use” (n = 165). At baseline, cannabis use groups were compared on neurocognitive tests, clinical, and functional measures. Follow-up analyses were used to model relationships between cannabis use frequency, neurocognition, premorbid, and social functioning.
Results
Occasional cannabis users performed significantly better than other use-groups on measures of IQ, with similar trend-level patterns observed across neurocognitive domains. Occasional cannabis users demonstrated better social, global, and premorbid functioning compared to the other use-groups and less severe symptoms compared to the frequent use group. Follow-up structural equation modeling/path analyses found significant positive associations between premorbid functioning, social functioning, and IQ, which in turn was associated with occasional cannabis use frequency.
Discussion
Better premorbid functioning positively predicts both better social functioning and higher IQ which in turn is associated with a moderate cannabis use pattern in CHR, similar to reports in first-episode and chronic psychosis samples. Better premorbid functioning likely represents a protective factor in the CHR population and predicts a better functional outcome.
Cannabis is one of the oldest and widely used substances in the world. Cannabinoids within the cannabis plant, known as phytocannabinoids, mediate cannabis' effects through interactions with the body's endogenous cannabinoid system. This endogenous system, the endocannabinoid system, has important roles in physical and mental health. These roles point to the potential to develop cannabinoids as therapeutic agents, while underscoring the risks related to interfering with the endogenous system during non-medical use. This scoping narrative review synthesizes the current evidence for both the therapeutic and adverse effects of the major (i.e., Δ9-tetrahydrocannabinol and cannabidiol) and lesser studied minor phytocannabinoids, from nonclinical to clinical research. We pay particular attention to the areas where evidence is well-established, including analgesic effects after acute exposures and neurocognitive risks after acute and chronic use. In addition, drug development considerations for cannabinoids as therapeutic agents within the United States are reviewed. The proposed clinical study design considerations encourage methodological standards for greater scientific rigor and reproducibility, ultimately, to extend our knowledge of the risks and benefits of cannabinoids for patients and providers. Significance Statement This work provides a review of prior research related to phytocannabinoids, including therapeutic potential and known risks in the context of drug development within the United States. We also provide study design considerations for future cannabinoid drug development.
Objective:
Social environment is a key determinant of substance use, but cannabis-related social network analysis is not common, in part due to the assessment burden of comprehensive egocentric social network analysis.
Method:
The current pre-registered secondary analysis assessed the psychometric properties (i.e., convergent, criterion-related, incremental validity) of the Brief Cannabis Social Density Assessment (B-CaSDA) in a cross-sectional sample of adults who use cannabis (N = 310) using a survey-based design. The B-CaSDA assesses the quantity and frequency of cannabis use for the respondent's four closest (non-parent) relationships.
Results:
Cannabis use severity was elevated for each additional person who used cannabis at all or daily in the individual's social network. B-CaSDA indices (i.e., frequency, quantity, total score) were positively correlated with cannabis consumption, cannabis use severity indicators, and established risk factors for harmful cannabis use. B-CaSDA indices also discriminated between those above and below a clinical cutoff on the Cannabis Use Disorder Identification Test - Revised (CUDIT-R). Finally, in omnibus models that included common risk factors for cannabis use severity, the B-CaSDA quantity index contributed additional variance when predicting CUDIT-R total score, and B-CaSDA frequency contributed additional variance in predicting the CUDIT-R quantity-frequency subscale.
Conclusions:
The results suggest that the B-CaSDA has the potential to expand social network research on cannabis use and misuse by increasing its assessment feasibility in diverse designs.
Recent research connecting choline-containing lipids to basal forebrain cholinergic neurons (BFCN) degeneration in neuropathological states highlights a challenge for balancing lipid integrity with optimal acetylcholine (ACh) levels. Warranting an adequate choline source to maintain ACh levels in this pathway is crucial for preserving memory. The endocannabinoid (eCB) system plays a role in modulating learning and memory processes controlled by cholinergic neurotransmission. Consequently, we propose that activation of this system is neuroprotective against cholinergic degeneration. In the present study, we investigated the neuroprotective effect of a subchronic treatment with the CB1 cannabinoid agonist, WIN55,212-2, using both ex vivo and in vivo 192IgG-Saporin models of specific cholinergic damage. Degeneration of baso-cortical cholinergic pathways induced memory deficits and a downregulation of saturated and mono-unsaturated lysophosphatidylcholines (LPC) cortical levels. WIN55,212-2 not only restored memory deficits but also increased cortical ACh levels and modified cortical choline-containing lipids such as sphingomyelins (SM) and LPCs, which are essential for correct memory functioning, in lesioned animals. Given these results, we propose that WIN55,212-2 generates an alternative choline source through the breakdown of SMs, which is enough to increase cortical ACh levels and LPCs. These findings suggest that modification of choline-containing lipids by the activation of CB1 receptors is a promising therapy for dementia associated with cholinergic dysfunction, such as in Alzheimer`s disease (AD).
Background: There is an urgent need for novel therapies to treat Alzheimer's disease. Among others, the use of cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) has been proposed as a putative approach based on their anti-inflammatory effects. Methods: The present work was designed to explore the effects of chronic (28 days) treatment with low doses of cannabinoids: CBD (0.273 mg/kg), THC (0.205 mg/kg) or a combination of both (CBD:THC; 0.273 mg/kg:0.205 mg/kg) in the 5xFAD mouse model of AD. Results: Our data revealed that THC-treated 5xFAD mice (but not other treatment groups) exhibited anxiogenic and depressant-like behavior. A significant improvement in spatial memory was observed only in the CBD:THC-treated group. Interestingly, all cannabinoid-treated groups showed significantly increased cortical levels of the insoluble form of beta amyloid 1-42. These effects were not accompanied by changes in molecular parameters of inflammation at the mRNA or protein level. Conclusions: These data reveal differential effects of chronic, low-dose cannabinoids and point to a role of these cannabinoids in the processing of amyloid peptides in the brains of 5xFAD mice.
Introduction: The effects of cannabidiol (CBD) on cognition has been investigated in recent years to determine the therapeutic potential of this cannabinoid for a broad gamut of medical conditions, including neuropsychiatric disorders. The aim of the present study was to perform a systematic review of studies that analyzed the effects of the acute and chronic administration of CBD on cognition in humans and animals both to assess the cognitive safety of CBD and to determine a beneficial potential of CBD on cognition. Methods: The PubMed, Web of Science, PsycINFO, and Scopus databases were searched in December of 2022 for relevant articles using the following combinations of keywords: ("cannabidiol" OR "CBD") AND ("cognition" OR "processing cognitive" OR "memory" OR "language" OR "attention" OR "executive function" OR "social cognition" OR "perceptual motor ability" OR "processing speed"). Results: Fifty-nine articles were included in the present review (36 preclinical and 23 clinical trials). CBD seems not to have any negative effect on cognitive processing in rats. The clinical trials confirmed these findings in humans. One study found that repeated dosing with CBD may improve cognitive in people who use cannabis heavily but not individuals with neuropsychiatric disorders. Considering the context of neuropsychiatric disorders in animal models, CBD seems to reverse the harm caused by the experimental paradigms, such that the performance of these animals becomes similar to that of control animals. Conclusions: The results demonstrate that the chronic and acute administration of CBD seems not to impair cognition in humans without neuropsychiatric disorders. In addition, preclinical studies report promising results regarding the effects of CBD on the cognitive processing of animals. Future double-blind, placebo-controlled, randomized clinical trials with larger, less selective samples, with standardized tests, and using different doses of CBD in outpatients are of particular interest to elucidate the cognitive effects of CBD.
Cannabis products and Cannabis use are inherently variable. Given the difficulty in standardizing Cannabis products and Cannabis use patterns, studies are often impacted by differences in the participants’ exposure to Cannabis or even specific cannabinoids, especially in medical use. Although it is clear that chronic recreational use impacts brain function, albeit subtly, future researches exploring moderating factors, including the age of onset, recovery of function after abstinence, frequency and magnitude of Cannabis use, high- versus low-potency products, mode of use, and the unique effects of specific cannabinoids, are all needed to understand the impact of Cannabis fully. As legalization efforts expand, overall use rates continue to rise, and questions regarding Cannabis and public policy measures remain crucial.
Aversive memories help us to deal with similar, future threatening situations. Understanding the neural and molecular bases of the learning and memory process provides insights into the physiopathology of memory-related conditions, including posttraumatic stress disorder (PTSD). PTSD patients often present neurochemical dysfunctions, such as noradrenergic hyperactivation, increased glucocorticoid sensitivity, and low endocannabinoid tonus. The individual role of these stress-related neurotransmitters during fear memory formation and maintenance is well documented, but addressing their potential interplay may pave the way for more effective therapeutic approaches. This chapter reviews and discusses animal studies investigating the abovementioned aspect. There is a complex endocannabinoid-noradrenergic-glucocorticoid interplay in fear memory consolidation, reconsolidation, and extinction. Both antagonistic and synergic actions are possible. The outcome depends on neurotransmitter systems targeted by the interventions tested, the brain region considered, and the memory phase studied. Further research will examine still-open questions, such as potential sex-dependent differences.
Δ9-tetrahydrocannabinol (THC) and its sibling, cannabidiol (CBD), are produced by the same Cannabis plant and have similar chemical structures but differ dramatically in their mechanisms of action and effects on brain functions. Both THC and CBD exhibit promising therapeutic properties; however, impairments and increased incidence of mental health diseases are associated with acute and chronic THC use, respectively, and significant side effects are associated with chronic use of high-dose CBD. This review covers recent molecular and preclinical discoveries concerning the distinct mechanisms of action and bioactivities of THC and CBD and their impact on human behavior and diseases. These discoveries provide a foundation for the development of cannabinoid-based therapeutics for multiple devastating diseases and to assure their safe use in the growing legal market of Cannabis-based products.
Cannabis preparations could be an effective reconsolidation-based treatment for post-traumatic stress disorder. However, the effects of Δ9-tetrahydrocannabinol (THC) in fear memory labilization, a critical condition for retrieval-induced reconsolidation, are undetermined. We sought to investigate the effect of a conventional and an ultra-low dose of THC in memory labilization of adult male Wistar rats submitted to contextual fear conditioning. Pretreatment with THC 0.002, but not THC 0.3 mg/kg, i. p., before memory retrieval, did not change memory expression during the retrieval but impaired reconsolidation. No treatment changed freezing expression in an unpaired context. Before retrieval, THC 0.3, but not THC 0.002, decreased GluN2A-NMDA expression and the GluN2A/GluN2B ratio in the dorsal hippocampus (DH) 24 h later. No changes were observed immediately after retrieval. Pretreatment with THC 0.3 abolished the reconsolidation-impairing effect of anisomycin injected into the DH, suggesting an impairment in memory labilization. This effect was associated with an increased freezing expression in the unpaired context and was not observed with the THC ultra-low dose. The GluN2B-NMDA antagonism increased fear generalization in the anisomycin-treated group but restored its reconsolidation-impairing effect and reduced fear generalization when animals were pretreated with THC 0.3. GluN2A-NMDA antagonism or inhibition of the ubiquitin-proteasome system in the DH did not interfere with the effects of THC 0.3. Our findings indicate that THC causes a bidirectional effect on fear memory labilization that depends on hippocampal GluN2B-NMDA receptors' involvement in fear memory generalization.
The organ systems are specialized tissues that perform discrete functions. They are vital and thus have interdependencies. For instance, the heart and renal system both need and influence each other. When deficiency requirements of health and damaging factors lead to a weakened state, then the beginning of disease commences. This is at first hypofunction, then disordered circulation and communication in that tissue or organ. This further leads to inflammation, immune involvement, and eventually, fibrosis and drastic decline of function. Therapy involves addressing deficient requirements of health. More specific therapy involves supporting biochemical function, hormetic stimulation in the low-dose zone, and whole person therapy. These all help to increase adaptive responses of the body. Alternatively and often in combination, there are ways to dampen maladaptive responses and even to introduce some measure of homeostasis by external means. This is why standard medical therapy can often be successful, as it can externally create a balance or at least dampen maladaptive responses. But this may not lead to healing if the body is severely depleted and dysregulated.KeywordsDysfunctionNaturopathic treatmentDiagnosisWhole person approaches
There has been a recent increase in the use of Cannabis-based products containing high levels of Δ⁹-tetrahydrocannabinol (THC) by adolescents. We now know this impacts adolescent cognitive function during this critical period of brain development that results in affecting select brain functions in adulthood. In this chapter, we discuss the relationship between adolescent exposure to cannabinoids, brain development, and adulthood behavioral outcomes, with a focus on mesocorticolimbic function and behaviors. After reviewing how endocannabinoids (eCB) signaling is involved in brain development, we summarize evidence gathered in human adolescents focusing on how THC exposure changes brain anatomy, connectivity, and dopaminergic function in human adults. This evidence is placed in the context of the cognitive aptitude and behaviors of adolescents and their access to high THC products and novel delivery devices. We then summarize evidence in pre-clinical rodent models, including evidence gathered at the molecular and cellular levels showing how THC/cannabinoid exposure impacts the mesocorticolimbic system and reward/addiction-like behaviors in adulthood. These results are discussed in the context of our current understanding of cannabinoid pharmacokinetics (PK) and pharmacodynamics (PD), and the role of eCB signaling in adolescent brain development. Finally, we review novel experimental approaches to study adolescence self-administration of THC in rodents and results suggesting that cannabidiol (CBD) might alleviate the impact of THC on adolescent brains. Together, this chapter emphasizes the urgent need to address the increased use of high THC products by adolescents and study the mechanism by which THC impacts adolescent brain development to help discover viable therapeutic approaches.
A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.
Neurogenesis is influenced by various external factors such as enriched environments. Some researchers had postulated that neurogenesis has contributed to the hippocampal learning and memory. This project was designed to observe the effect of Delta-9-tetrahydrocannabinol (∆9-THC) in cognitive performance that influenced by the neurogenesis. Different doses of ∆9-THC were used for observing the neurogenesis mechanism occurs in the hippocampus of rats. The brains were stained with antibodies, namely BrdU, glial fibrillary acidic protein (GFAP), nestin, doublecortin (DCX) and class III β-tubulin (TuJ-1). The cognitive test was used novel-object discrimination test (NOD) while the proteins involved, DCX and brain-derived neurotrophic factor (BDNF), were measured. Throughout this study, ∆9-THC enhanced the markers involved in all stages of neurogenesis mechanism. Simultaneously, the cognitive behaviour of rat also showed improvement in learning and memory functions observed in behavioural test and molecular perspective. Administration of ∆9-THC was observed to enhance the neurogenesis in the brain, especially in hippocampus thus improved the cognitive function of rats.
Hormesis refers to adaptive responses of biological systems to moderate environmental or self-imposed challenges through which the system improves its functionality and/or tolerance to more severe challenges. The past two decades have witnessed an expanding recognition of the concept of hormesis, elucidation of its evolutionary foundations, and underlying cellular and molecular mechanisms, and practical applications to improve quality of life. To better inform future basic and applied research, we organized and re-evaluated recent hormesis-related findings with the intent of incorporating new knowledge of biological mechanisms, and providing fundamental insights into the biological, biomedical and risk assessment implications of hormesis. As the literature on hormesis is expanding rapidly into new areas of basic and applied research, it is important to provide refined conceptualization of hormesis to aid in designing and interpreting future studies. Here, we establish a working compartmentalization of hormesis into ten categories that provide an integrated understanding of the biological meaning and applications of hormesis.
Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients' antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients' antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients' or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients' cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13-18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.
Several recent findings suggest that targeting the endogenous cannabinoid system can be considered as a potential therapeutic approach to treat Alzheimer's disease (AD). The present study supports this hypothesis demonstrating that delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) botanical extracts, as well as the combination of both natural cannabinoids, which are the components of an already approved cannabis-based medicine, preserved memory in AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Moreover, THC + CBD reduced learning impairment in AβPP/PS1 mice. A significant decrease in soluble Aβ42 peptide levels and a change in plaques composition were also observed in THC + CBD-treated AβPP/PS1 mice, suggesting a cannabinoid-induced reduction in the harmful effect of the most toxic form of the Aβ peptide. Among the mechanisms related with these positive cognitive effects, the anti-inflammatory properties of cannabinoids may also play a relevant role. Here we observed reduced astrogliosis, microgliosis, and inflammatory-related molecules in treated AβPP/PS1 mice, which were more marked after treatment with THC + CBD than with either THC or CBD. Moreover, other cannabinoid-induced effects were uncovered by a genome-wide gene expression study. Thus, we have identified the redox protein thioredoxin 2 and the signaling protein Wnt16 as significant substrates for the THC + CBD-induced effects in our AD model. In summary, the present findings show that the combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD.
The purpose of this study was to investigate the potential therapeutic qualities of Δ⁹-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways.
Previous studies have shown that cannabinoid 1 (CB1) receptor signaling dissociates between reward-associated and aversive memories. The influence of CB1 receptors on the aversion-driven spatial learning in the Morris water maze test is strongly age-dependent: mice with genetic deletion of CB1 receptors (Cnr1(-/-)) show superior learning when young but inferior learning when old compared to age-matched wild-type mice. Whether the reward-driven spatial learning is influenced in the same way by CB1 receptor signaling as the aversion-driven learning remains unclear. Thus, we examined the performance of Cn1(-/-) and their wild-type littermates at ages of 2-, 5-, and 12-months-old in the eight-arm radial maze test-a reward-motivated model of spatial learning. Interestingly, 2-months-old Cnr1(-/-) mice had a superior learning ability to wild-type mice. At the age of 5-months, Cnr1(-/-) mice showed the same performance as the wild-type littermates. However, 12-months-old Cnr1(-/-) mice showed significantly impaired performances in each parameter of the test. Accordingly, this study provides compelling support for our previous result that genetic deletion of CB1 receptor leads to early onset of age-related memory decline, similarly affecting both reward and aversion-driven learning.
Through evolutionary history the primary mechanism by which the cells or tissues of most organisms sense their environment
has been the heptahelical G protein–coupled receptor (GPCR). This prototypic receptive entity has its origins in the earliest
forms of life and often comprises up to 5% of the genome of most unicellular and multicellular life forms. The GPCR system
has adapted to perceive almost all forms of environmental entities, for example, photons, odorants, lipids, carbohydrates,
peptides, and nucleic acids. The GPCR system has also likely adapted to the presence of exogenous compounds that may at some
doses be deleterious but at lower levels may indeed possess beneficial actions. Therefore, with respect to the evolutionary
pressure of diverse environments, it would be an extreme advantage for an organism to adapt multiple components of its primary
receptive system to take advantage of any beneficial effects of agents present in harsh or damaging environments.
KeywordsGprotein–coupled receptor-Dose response-Allosteric-Conformation-Environment-Flavor-Receptive
Impairment of working memory is one of the most important deleterious effects of marijuana intoxication in humans, but its underlying mechanisms are presently unknown. Here, we demonstrate that the impairment of spatial working memory (SWM) and in vivo long-term depression (LTD) of synaptic strength at hippocampal CA3-CA1 synapses, induced by an acute exposure of exogenous cannabinoids, is fully abolished in conditional mutant mice lacking type-1 cannabinoid receptors (CB(1)R) in brain astroglial cells but is conserved in mice lacking CB(1)R in glutamatergic or GABAergic neurons. Blockade of neuronal glutamate N-methyl-D-aspartate receptors (NMDAR) and of synaptic trafficking of glutamate α-amino-3-hydroxy-5-methyl-isoxazole propionic acid receptors (AMPAR) also abolishes cannabinoid effects on SWM and LTD induction and expression. We conclude that the impairment of working memory by marijuana and cannabinoids is due to the activation of astroglial CB(1)R and is associated with astroglia-dependent hippocampal LTD in vivo.
Alzheimer's disease (AD) brain shows an ongoing inflammatory condition and non-steroidal anti-inflammatories diminish the risk of suffering the neurologic disease. Cannabinoids are neuroprotective and anti-inflammatory agents with therapeutic potential.
We have studied the effects of prolonged oral administration of transgenic amyloid precursor protein (APP) mice with two pharmacologically different cannabinoids (WIN 55,212-2 and JWH-133, 0.2 mg/kg/day in the drinking water during 4 months) on inflammatory and cognitive parameters, and on ¹⁸F-fluoro-deoxyglucose (¹⁸FDG) uptake by positron emission tomography (PET).
Novel object recognition was significantly reduced in 11 month old Tg APP mice and 4 month administration of JWH was able to normalize this cognitive deficit, although WIN was ineffective. Wild type mice cognitive performance was unaltered by cannabinoid administration. Tg APP mice showed decreased ¹⁸FDG uptake in hippocampus and cortical regions, which was counteracted by oral JWH treatment. Hippocampal GFAP immunoreactivity and cortical protein expression was unaffected by genotype or treatment. In contrast, the density of Iba1 positive microglia was increased in Tg APP mice, and normalized following JWH chronic treatment. Both cannabinoids were effective at reducing the enhancement of COX-2 protein levels and TNF-α mRNA expression found in the AD model. Increased cortical β-amyloid (Aβ) levels were significantly reduced in the mouse model by both cannabinoids. Noteworthy both cannabinoids enhanced Aβ transport across choroid plexus cells in vitro.
In summary we have shown that chronically administered cannabinoid showed marked beneficial effects concomitant with inflammation reduction and increased Aβ clearance.
Cannabis has long been known to produce cognitive and emotional effects. Research has shown that cannabinoid drugs produce these effects by driving the brain's endogenous cannabinoid system and that this system plays a modulatory role in many cognitive and emotional processes. This review focuses on the effects of endocannabinoid system modulation in animal models of cognition (learning and memory) and emotion (anxiety and depression). We review studies in which natural or synthetic cannabinoid agonists were administered to directly stimulate cannabinoid receptors or, conversely, where cannabinoid antagonists were administered to inhibit the activity of cannabinoid receptors. In addition, studies are reviewed that involved genetic disruption of cannabinoid receptors or genetic or pharmacological manipulation of the endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH). Endocannabinoids affect the function of many neurotransmitter systems, some of which play opposing roles. The diversity of cannabinoid roles and the complexity of task-dependent activation of neuronal circuits may lead to the effects of endocannabinoid system modulation being strongly dependent on environmental conditions. Recent findings are reviewed that raise the possibility that endocannabinoid signaling may change the impact of environmental influences on emotional and cognitive behavior rather than selectively affecting any specific behavior.
Epigenetic mechanisms integrate signals from diverse intracellular transduction cascades and in turn regulate genetic readout. Accumulating evidence has revealed that these mechanisms are critical components of ongoing physiology and function in the adult nervous system, and are essential for many cognitive processes, including learning and memory. Moreover, a number of psychiatric disorders and syndromes that involve cognitive impairments are associated with altered epigenetic function. In this review, we will examine how epigenetic mechanisms contribute to cognition, consider how changes in these mechanisms may lead to cognitive impairments in a range of disorders and discuss the potential utility of therapeutic treatments that target epigenetic machinery. Finally, we will comment on a number of caveats associated with interpreting epigenetic changes and using epigenetic treatments, and suggest future directions for research in this area that will expand our understanding of the epigenetic changes underlying cognitive disorders.
The two main constituents of cannabis, cannabidiol and Δ(9)-tetrahydrocannabinol (THC), have opposing effects both pharmacologically and behaviourally when administered in the laboratory. Street cannabis is known to contain varying levels of each cannabinoid.
To study how the varying levels of cannabidiol and THC have an impact on the acute effects of the drug in naturalistic settings.
Cannabis users (n = 134) were tested 7 days apart on measures of memory and psychotomimetic symptoms, once while they were drug free and once while acutely intoxicated by their own chosen smoked cannabis. Using an unprecedented methodology, a sample of cannabis (as well as saliva) was collected from each user and analysed for levels of cannabinoids. On the basis of highest and lowest cannabidiol content of cannabis, two groups of individuals were directly compared.
Groups did not differ in the THC content of the cannabis they smoked. Unlike the marked impairment in prose recall of individuals who smoked cannabis low in cannabidiol, participants smoking cannabis high in cannabidiol showed no memory impairment. Cannabidiol content did not affect psychotomimetic symptoms, which were elevated in both groups when intoxicated.
The antagonistic effects of cannabidiol at the CB(1) receptor are probably responsible for its profile in smoked cannabis, attenuating the memory-impairing effects of THC. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like 'skunk' and encouraged to use strains containing higher levels of cannabidiol.
As the human life span increases, the number of people suffering from cognitive decline is rising dramatically. The mechanisms
underlying age-associated memory impairment are, however, not understood. Here we show that memory disturbances in the aging
brain of the mouse are associated with altered hippocampal chromatin plasticity. During learning, aged mice display a specific
deregulation of histone H4 lysine 12 (H4K12) acetylation and fail to initiate a hippocampal gene expression program associated
with memory consolidation. Restoration of physiological H4K12 acetylation reinstates the expression of learning-induced genes
and leads to the recovery of cognitive abilities. Our data suggest that deregulated H4K12 acetylation may represent an early
biomarker of an impaired genome-environment interaction in the aging mouse brain.
People who use cannabis have an increased risk of psychosis, an effect attributed to the active ingredient Delta 9-tetrahydrocannabinol (Delta 9-THC). There has recently been concern over an increase in the concentration of Delta 9-THC in the cannabis available in many countries.
To investigate whether people with a first episode of psychosis were particularly likely to use high-potency cannabis.
We collected information on cannabis use from 280 cases presenting with a first episode of psychosis to the South London & Maudsley National Health Service (NHS) Foundation Trust, and from 174 healthy controls recruited from the local population.
There was no significant difference between cases and controls in whether they had ever taken cannabis, or age at first use. However, those in the cases group were more likely to be current daily users (OR = 6.4) and to have smoked cannabis for more than 5 years (OR = 2.1). Among those who used cannabis, 78% of the cases group used high-potency cannabis (sinsemilla, 'skunk') compared with 37% of the control group (OR 6.8).
The finding that people with a first episode of psychosis had smoked higher-potency cannabis, for longer and with greater frequency, than a healthy control group is consistent with the hypothesis that Delta 9-THC is the active ingredient increasing risk of psychosis. This has important public health implications, given the increased availability and use of high-potency cannabis.
Delta-9-tetrahydrocannabinol (Delta-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Delta-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Delta-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Delta-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Delta-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Delta-9-THC. Delta-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Delta-9-tetrahydrocannabinol. Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Delta-9-THC.
This study was designed to test our hypothesis that an ultra-low dose of THC (delta-9 tetrahydrocannabinol) reverses age-dependent cognitive impairments in old mice, and to examine the possible biological mechanisms that underlie this behavioral effect. Old female mice aged 24 months that had been injected once with 0.002 mg/kg THC (3-4 orders of magnitudes lower than doses that induce the conventional cannabinoid effects in mice) performed significantly better than vehicle-treated old mice, and performed similarly to naive young mice aged 2 months, in 6 different behavioral assays that measured various aspects of memory and learning. The beneficial effect of THC lasted for at least 7 weeks. The single injection of THC increased the level of Sirtuin1, an enzyme that has been previously shown to be involved in neuroprotection and neuroplasticity, in the hippocampus and in the frontal cortex of old mice, for at least 7 weeks. Magnetic Resonance Imaging (MRI) demonstrated a larger volume and higher tissue density in various regions of the brain of THC-treated old mice. These findings suggest that extremely low doses of THC that are devoid of any psychotropic effect and do not induce desensitization, may provide a safe and effective treatment for cognitive decline in aging humans.
New evidence in mouse models reveals that exposure to [Delta]9-tetrahydrocannabinol (THC), the main psychoactive component in Cannabis sativa, might improve cognitive performance in aging animals.
The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging. The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated. Here we show that a low dose of Δ(9)-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density. THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC. Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.
Experimental evidence has demonstrated that glutamate is an essential factor for neurogenesis, whereas another line of research postulates that excessive glutamatergic neurotransmission is associated with the pathogenesis of depression. The present review shows that such paradox can be explained within the framework of hormesis, defined as biphasic dose responses. Low glutamate levels activate adaptive stress responses that include proteins that protect neurons against more severe stress. Conversely, abnormally high levels of glutamate, resulting from increased release and/or decreased removal, cause neuronal atrophy and depression. The dysregulation of the glutamatergic transmission in depression could be underlined by several factors including a decreased inhibition (γ-aminobutyric acid or serotonin) or an increased excitation (primarily within the glutamatergic system). Experimental evidence shows that the activation of
A monoclonal antibody to the microtubule-associated protein tau (tau) labeled some neurofibrillary tangles and plaque neurites, the two major locations of paired-helical filaments (PHF), in Alzheimer disease brain. The antibody also labeled isolated PHF that had been repeatedly washed with NaDodSO4. Dephosphorylation of the tissue sections with alkaline phosphatase prior to immunolabeling dramatically increased the number of tangles and plaques recognized by the antibody. The plaque core amyloid was not stained in either dephosphorylated or nondephosphorylated tissue sections. On immunoblots PHF polypeptides were labeled readily only when dephosphorylated. In contrast, a commercially available monoclonal antibody to a phosphorylated epitope of neurofilaments that labeled the tangles and the plaque neurites in tissue did not label any PHF polypeptides on immunoblots. The PHF polypeptides, labeled with the monoclonal antibody to tau, electrophoresed with those polypeptides recognized by antibodies to isolated PHF. The antibody to tau-labeled microtubules from normal human brains assembled in vitro but identically treated Alzheimer brain preparations had to be dephosphorylated to be completely recognized by this antibody. These findings suggest that tau in Alzheimer brain is an abnormally phosphorylated protein component of PHF.
This article provides the first extensive documentation of the dose response features of pre- and postconditioning. Pre- and postconditioning studies with rigorous study designs, using multiple doses/concentrations along with refined dose/concentration spacing strategies, often display hormetic dose/concentration response relationships with considerable generality across biological model, inducing (i.e., conditioning) agent, challenging dose treatment, endpoint, and mechanism. Pre- and postconditioning hormesis dose/concentration-response relationships are reported for 154 diverse conditioning agents, affecting more than 550 dose/concentration responses, across a broad range of biological models and endpoints. The quantitative features of the pre- and postconditioning-induced protective responses are modest, typically being 30-60% greater than control values at maximum, findings that are consistent with a large body (>10,000) of hormetic dose/concentration responses not related to pre- and postconditioning. Regardless of the biological model, inducing agent, endpoint or mechanism, the quantitative features of hormetic dose/concentration responses are similar, suggesting that the magnitude of response is a measure of biological plasticity. This paper also provides the first documentation that hormetic effects account for preconditioning, induced early (1-3h) and delayed (12-72h) windows of protection. These findings indicate that pre- and postconditioning are specific types of hormesis.
In Part I, hormetic doses of a variety of agents stimulated adaptive responses that conditioned and protected cells against the subsequent toxicity resulting from a second, higher dose (called a challenging dose) of the same or different agents. Herein (Part II), the optimal conditioning (hormetic) doses of many agents are documented, cellular mechanisms and temporal profiles are examined from which the conditioning (hormetic) responses are elicited, and the optimal conditioning doses are compared to the levels at which optimal protection occurs in response to the toxic challenge dose. Entry criteria for study evaluation required a conditioning mechanism-induced endpoint response, an hormetic/biphasic dose response for the protective response following the challenging dose, and a mechanistic assessment of how the conditioning dose afforded protection against a toxic challenging dose. The conditioning dose that demonstrated the largest increase in a mechanism-related conditioning (hormetic) response (i.e., prior to administration of the challenging dose) was the same dose that was optimally protective following the challenging dose. Specific receptor antagonists and/or inhibitors of cell signaling pathways which blocked the induction of conditioning (hormetic) effects during the conditioning period abolished the protective effects following the application of a challenge dose, thus identifying a specific and essential component of the hormetic mechanism. Conditioning responses often had sufficient doses to assess the nature of the dose response. In each of the cases these mechanism-based endpoints displayed an hormetic dose response. The present analysis reveals that hormetic biphasic dose responses were associated with both the conditioning process and the protective effects elicited following the challenging dose. Furthermore, based on optimal dosage, temporal relationships and the known mediating actions of receptor-based and/or cell signaling-based mechanisms, the protective effects were shown to be directly linked to the actions of the conditioning (hormetic) doses. These findings indicate that the biological/biomedical effects induced by conditioning represent a specific type of hormetic dose response and thereby contribute significantly to a generalization of the hormetic concept.
Given the lack of effective treatments for late-onset Alzheimer's disease (LOAD) and the substantial burden on patients, families, healthcare systems, and economies, finding an effective therapy is one of the highest medical priorities. The past few years have seen a growing interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, including the treatment of LOAD and other physical conditions that are common in older people. Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. Also, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances). The current article provides an overview of the potential of cannabinoids in the treatment of LOAD and related neuropsychiatric symptoms in older people. We also discuss the efficacy, safety and pharmacokinetics of cannabinoid-based drugs in older people with dementia. This article is protected by copyright. All rights reserved.
© 2015 American Society for Clinical Pharmacology and Therapeutics.
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Basic research on high dilution effects started with homeopathic therapy. So many models have been tested that we have tried to classify them according to the general concept of regulation. Firstly, succussed dilutions must be separated from unsuccussed very low doses from a physical point of view. This leads us to discuss the validity of the controls in high dilution research. Then, following a classification according to regulating effects, one can consider that some research in the field of "homeopathic research" can be relevant to cybernetic regulation and, in some cases, very low dose effects can be described as cybernetic regulatory signals. Hormetic models and application of the Arndt-Schultz law are based on the identity principle and are related to variations of concentration. They are presented and differentiated from the self recovery process which exists as a function of time. By using unsuccussed molecular and succussed non-molecular dilutions, the hormetic model supports a learning process which must be related to informative concepts. Starting from this primary level of informative process and by comparison with the phylogenic evolution of the immune system as an informative system, we can elaborate a progressive information organisation of the high dilution effects. Endogenous molecules have a specific regulatory function while highly diluted exogenous molecules will only be informative in the framework of the similia principle.
In our previous studies, we found that a single ultralow dose of tetrahydrocannabinol (THC; 0.002 mg/kg, three to four orders of magnitude lower than the conventional doses) protects the brain from different insults that cause cognitive deficits. Because various insults may trigger a neuroinflammatory response that leads to secondary damage to the brain, the current study tested whether this extremely low dose of THC could protect the brain from inflammation-induced cognitive deficits. Mice received a single injection of THC (0.002 mg/kg) 48 hr before or 1–7 days after treatment with lipopolysccharide (LPS; 10 mg/kg) and were examined with the object recognition test 3 weeks later. LPS caused long-lasting cognitive deficits, whereas the application of THC before or after LPS protected the mice from this LPS-induced damage. The protective effect of THC was blocked by the cannabinoid (CB) 1 receptor antagonist SR14176A but not by the CB2 receptor antagonist SR141528 and was mimicked by the CB1 agonist ACEA but not by the CB2 agonist HU308. The protective effect of THC was also blocked by pretreatment with GW9662, indicating the involvement of peroxisome proliferator-activated receptor-γ. Biochemical examination of the brain revealed a long-term (at least 7 weeks) elevation of the prostaglandin-producing enzyme cyclooxygenase-2 in the hippocampus and in the frontal cortex following the injection of LPS. Pretreatment with the extremely low dose of THC tended to attenuate this elevation. Our results suggest that an ultralow dose of THC that lacks any psychotrophic activity protects the brain from neuroinflammation-induced cognitive damage and might be used as an effective drug for the treatment of neuroinflammatory conditions, including neurodegenerative diseases. © 2014 Wiley Periodicals, Inc.
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.
Abstract This article provides the first extensive documentation of mechanisms of hormetic dose/concentration responses. The mechanisms selected were principally those mediated via receptor and/or cell signaling pathways. Mechanisms are reported for greater than 100 agents affecting nearly 400 dose/concentration responses from a wide range of chemical classes, affecting a broad range of cell types and endpoints. Regardless of the model (i.e. in vitro or in vivo), inducing agent, endpoint, or receptor/cell signaling pathway mediated mechanism, the quantitative features of the hormetic dose/concentration responses are similar, suggesting that the magnitude of the response is a measure of biological plasticity, within a broad range of biological contexts. These findings represent an important advance in the understanding of the hormetic dose/concentration response, its generalizability and potential biomedical applications, including drug discovery/efficacy assessment and the risk assessment process.
The distribution in the rat brain of fatty acid amide hydrolase (FAAH) an enzyme that catalyzes the hydrolysis of the endogenous cannabinoid anandamide was studied by immunohistochemistry. An immunopurified, polyclonal antibody to the C terminal region of FAAH was used in these studies. The large principal neurons, such as pyramidal cells in the cerebral cortex, the pyramidal cells the hippocampus, Purkinje cells in the cerebellar cortex and the mitral cells in the olfactory bulb, showed the strongest FAAH immunoreactivity. These FAAH-containing principal neurons except the mitral cells in the olfactory bulb are in close proximity with cannabinoid CB1 receptors as revealed by our previous immunohistochemical study. Moderately or lightly stained FAAH-containing neurons were also found in the amygdala, the basal ganglia, the deep cerebellar nuclei, the ventral posterior nuclei of the thalamus, the optic layer and the intermediate white layer of the superior colliculus and the red nucleus in the midbrain, and motor neurons of the spinal cord. These data demonstrate that FAAH is heterogeneously distributed and this distribution exhibits considerable, although not complete, overlap with the distribution of cannabinoid CB1 receptors in rat brain.
Cannabis is associated with psychotic outcomes in numerous studies, an effect that is commonly attributed to Δ (9)-tetrahydrocannabinol (Δ 9-THC). An increasing number of authors identify cannabidiol, another component of the cannabis plant, as an antipsychotic agent. The objective of the current study is to investigate the role of cannabidiol content in the association between cannabis use and psychiatric symptoms in a large non-clinical population of cannabis users.
In a web-based cross-sectional study we obtained detailed information about cannabis use and subclinical psychiatric experiences using the Community Assessment of Psychic Experiences (CAPE). Different types of cannabis (i.e. marijuana, hashish etc.) have distinctive proportions of Δ 9-THC and cannabidiol. Since average concentrations of Δ 9-THC and cannabidiol in the most popular types of cannabis sold on the Dutch market are annually measured, we were able to estimate exposure to Δ 9-THC and cannabidiol.
We included 1877 subjects (mean age 23, SD 6.0) who used the same type of cannabis in the majority of the occasions (in >60% of occasions). We found a significant inverse relationship (F(1,1877): 14.577, p<0.001) between cannabidiol content and self-reported positive symptoms, but not with negative symptoms or depression. The estimated effect size of cannabidiol content was small.
Although the observed effects are subtle, using high cannabidiol content cannabis was associated with significantly lower degrees of psychotic symptoms providing further support for the antipsychotic potential of cannabidiol.
Extensive in vitro and in vivo studies have shown that cannabinoid drugs have neuroprotective properties and suggested that the endocannabinoid system may be involved in endogenous neuroprotective mechanisms. On the other hand, neurotoxic effects of cannabinoids in vitro and in vivo were also described. Several possible explanations for these dual, opposite effects of cannabinoids on cellular fate were suggested, and it is conceivable that various factors may determine the final outcome of the cannabinoid effect in vivo . In the current review, we focus on one of the possible reasons for the dual neuroprotective/neurotoxic effects of cannabinoids in vivo , namely, the opposite effects of low versus high doses of cannabinoids. While many studies reported neuroprotective effects of the conventional doses of cannabinoids in various experimental models for acute brain injuries, we have shown that a single administration of an extremely low dose of Δ ⁹ ‐tetrahydrocannabinol (THC) (3–4 orders of magnitude lower than the conventional doses) to mice induced long‐lasting mild cognitive deficits that affected various aspects of memory and learning. These findings led to the idea that this low dose of THC, which induces minor damage to the brain, may activate preconditioning and/or postconditioning mechanisms and thus will protect the brain from more severe insults. Indeed, our recent findings support this assumption and show that a pre‐ or a postconditioning treatment with extremely low doses of THC, several days before or after brain injury, provides effective long‐term cognitive neuroprotection. The future therapeutical potential of these findings is discussed.
LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
Preconditioning, a phenomenon where a minor noxious stimulus protects from a subsequent more severe insult, and post-conditioning, where the protective intervention is applied following the insult, offer new insight into the neuronal mechanism(s) of neuroprotection and may provide new strategies for the prevention and treatment of brain damage. We have previously reported that a single administration of an extremely low dose of Δ(9)-tetrahydrocannabinol (THC; the psychoactive ingredient of marijuana) to mice induced minor long-lasting cognitive deficits. In the present study we examined the possibility that such a low dose of THC will protect the mice from more severe cognitive deficits induced by the epileptogenic drug pentylenetetrazole (PTZ). THC (0.002 mg/kg, a dose that is 3-4 orders of magnitude lower than the doses that induce the conventional effects of THC) was administered 1-7 days before, or 1-3 days after the injection of PTZ (60 mg/kg). The consequences of this treatment were studied 3-7 weeks later by various behavioral tests that evaluated different aspects of memory and learning. We found that a single administration of THC either before or after PTZ abolished the PTZ-induced long-lasting cognitive deficits. Biochemical studies indicated a concomitant reduction in phosphorylated-ERK (extracellular signal-regulated kinase) in the cerebella of mice 7 weeks following the injection of THC. Our results suggest that a pre- or post-conditioning treatment with extremely low doses of THC, several days before or after brain injury, may provide safe and effective long-term neuroprotection.
The basal forebrain cholinergic complex comprising medial septum, horizontal and vertical diagonal band of Broca, and nucleus basalis of Meynert provides the mayor cholinergic projections to the cerebral cortex and hippocampus. The cholinergic neurons of this complex have been assumed to undergo moderate degenerative changes during aging, resulting in cholinergic hypofunction that has been related to the progressing memory deficits with aging. However, the previous view of significant cholinergic cell loss during aging has been challenged. Neuronal cell loss was found predominantly in pathological aging, such as Alzheimer's disease, while normal aging is accompanied by a gradual loss of cholinergic function caused by dendritic, synaptic, and axonal degeneration as well as a decrease in trophic support. As a consequence, decrements in gene expression, impairments in intracellular signaling, and cytoskeletal transport may mediate cholinergic cell atrophy finally leading to the known age-related functional decline in the brain including aging-associated cognitive impairments. However, in pathological situations associated with cognitive deficits, such as Parkinsons's disease, Down-syndrome, progressive supranuclear palsy, Jakob-Creutzfeld disease, Korsakoff's syndrome, traumatic brain injury, significant degenerations of basal forebrain cholinergic cells have been observed. In presenile (early onset), and in the advanced stages of late-onset Alzheimer's disease (AD), a severe loss of cortical cholinergic innervation has extensively been documented. In contrast, in patients with mild cognitive impairment (MCI, a prodromal stage of AD), and early forms of AD, apparently no cholinergic neurodegeneration but a loss of cholinergic function occurs. In particular imbalances in the expression of NGF, its precursor proNGF, the high and low NGF receptors, trkA and p75NTR, respectively, changes in acetylcholine release, high-affinity choline uptake, as well as alterations in muscarinic and nicotinic acetylcholine receptor expression may contribute to the cholinergic dysfunction. These observations support the suggestion of a key role of the cholinergic system in the functional processes that lead to AD. Malfunction of the cholinergic system may be tackled pharmacologically by intervening in cholinergic as well as neurotrophic signaling cascades that have been shown to ameliorate the cholinergic deficit at early stages of the disease, and slow-down the progression. However, in contrast to many other, dementing disorders, in AD the cholinergic dysfunctions are accompanied by the occurrence of two major histopathological hallmarks such as β-amyloid plaques and neurofibrillary tangles, provoking the question whether they play a particular role in inducing or mediating cholinergic dysfunction in AD. Indeed, there is abundant evidence that β-amyloid may trigger cholinergic dysfunction through action on α7 nicotinic acetylcholine receptors, affecting NGF signaling, mediating tau phosphorylation, interacting with acetylcholinesterase, and specifically affecting the proteome in cholinergic neurons. Therefore, an early onset of an anti β-amyloid strategy may additionally be potential in preventing aging-associated cholinergic deficits and cognitive impairments.
Either protective or toxic effects of cannabinoids on cell survival have been reported extensively in the literature; however, the factors that determine the direction of the effect are still obscured. In this study we have used the neuroblastoma cell line N18TG2 that expresses CB1 cannabinoid receptors to investigate several factors that may determine the consequences of exposure to cannabinoid agonists. Cells that were grown under optimal, stressful, or differentiating conditions were exposed to cannabinoid agonists and then assayed for cell viability by measuring MTT, LDH, and caspase-3 activity. Various cannabinoid agonists (CP 55,940, ∆9-THC, HU-210, and WIN 55,212-2) failed to affect cell viability when the cells were grown under optimal conditions. On the other hand, the same agonists significantly reduced cell viability when the cells were grown under stressful conditions (glucose- and serum-free medium), while enhancing the viability of cells grown in differentiation medium (0.5% serum and 1.5% DMSO). The toxic/protective profile was not dependent on the type or the concentration of the cannabinoid agonist that was applied. The cannabinoid agonist CP 55,940 similarly affected the non-neuronal HEK-293 cells that were grown under stressful conditions only when they expressed CB1 receptors. Our results shed light on the conflicting reports regarding the protective or toxic effects of cannabinoids in vitro and indicate that cannabinoids may activate different intracellular signaling mechanisms, depending on the state of the cell, thus leading to different physiological consequences.