cannabidiol and Memory-Disorders

Medical marijuana continues to gain acceptance and become legalized in many states. Various species of the marijuana plant have been cultivated, and this plant can contain up to 100 active compounds known as cannabinoids. Two cannabinoids seem the most clinically relevant: Δ9-tetrahydrocannabinol (THC), which tends to produce the psychotropic effects commonly associated with marijuana, and cannabidiol (CBD), which may produce therapeutic effects without appreciable psychoactive properties. Smoking marijuana, or ingesting extracts from the whole plant orally (in baked goods, teas, and so forth), introduces variable amounts of THC, CBD, and other minor cannabinoids into the systemic circulation, where they ultimately reach the central and peripheral nervous systems. Alternatively, products containing THC, CBD, or a combination of both compounds, can be ingested as oral tablets or via sprays applied to the oral mucosal membranes. These products may provide a more predictable method for delivering a known amount of specific cannabinoids into the body. Although there is still a need for randomized controlled trials, preliminary studies have suggested that medical marijuana and related cannabinoids may be beneficial in treating people with chronic pain, inflammation, spasticity, and other conditions seen commonly in physical therapist practice. Physical therapists, therefore, should be aware of the options that are available for patients considering medical marijuana and should be ready to provide information for these patients. Clinicians also should be aware that marijuana can produce untoward effects on cognition, coordination, balance, and cardiovascular and pulmonary function and should be vigilant for any problems that may arise if patients are using cannabinoids during physical rehabilitation.

Topics: Cannabidiol; Cognition Disorders; Confusion; Controlled Substances; Depression; Dronabinol; Drug Administration Routes; Hallucinations; Heart; Humans; Lung; Marijuana Abuse; Medical Marijuana; Memory Disorders; Muscle Spasticity; Nausea; Pain; Physical Therapists; Postural Balance; Professional Role; Vomiting

Community-based studies suggest that cannabis products that are high in Δ⁹-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600 mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥ 3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ²=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6 ± 18.9%) compared with the CBD group (-0.4% ± 9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Topics: Adult; Cannabidiol; Cannabis; Cognitive Dysfunction; Double-Blind Method; Dronabinol; Drug Interactions; Female; Hippocampus; Humans; Learning; Male; Memory Disorders; Paranoid Disorders

Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA. In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood-brain barrier (BBB) and affect the central nervous system. The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer's disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Cannabidiol; Cannabinoids; Cannabis; Dronabinol; Memory Disorders; Mice; Neuroprotective Agents

Growing evidence indicates that cannabidiol (CBD), a substance present in the Cannabis sativa plant, has potential therapeutic value to regulate abnormal emotional memories associated with post-traumatic stress and drug use disorders. CBD can attenuate their valence after retrieval (i.e., during reconsolidation) or potentiate their suppression by extinction. Pharmacological research has now focused on elucidating how it acts. Systemic antagonism of cannabinoid type-1 (CB1) receptors has often prevented the abovementioned effects of CBD. However, it is unknown in which brain regions CBD stimulates CB1 receptors and how it interferes with local activity-related plasticity to produce these effects. The present study addressed these questions considering the reconsolidation of contextual fear memories in rats. We focused on the medial prefrontal cortex (mPFC), which comprises the anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) subregions, as local activity or plasticity has been associated with the process to-be-investigated. Animals that received post-retrieval systemic CBD treatment presented relatively fewer cells expressing Zif268/Egr1 protein, a proxy for synaptic plasticity related to reconsolidation, in the AC and PL. At the same time, there were no significant differences in the IL. Pretreatment with the CB1 receptor antagonist/inverse agonist AM251 into the AC, PL, or IL prevented the impairing effects of systemic CBD treatment on reconsolidation. CBD also caused reconsolidation impairments when injected directly into the AC or PL but not the IL. Together, these findings show complementary mechanisms through which CBD may hinder the reconsolidation of destabilized aversive memories along the dorsoventral axis of the mPFC.

Topics: Animals; Behavior, Animal; Cannabidiol; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Male; Memory Consolidation; Memory Disorders; Neuronal Plasticity; Prefrontal Cortex; Rats; Receptor, Cannabinoid, CB1

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) share the pathological hallmark of intracellular neurofibrillary tangles, which result from the hyperphosphorylation of microtubule associated protein tau. The P301S mutation in human tau carried by TAU58/2 transgenic mice results in brain pathology and behavioural deficits relevant to FTD and AD. The phytocannabinoid cannabidiol (CBD) exhibits properties beneficial for multiple pathological processes evident in dementia. Therefore, 14-month-old female TAU58/2 transgenic and wild type-like (WT) littermates were treated with 100 mg/kg CBD or vehicle i.p. starting three weeks prior to conducting behavioural paradigms relevant to FTD and AD. TAU58/2 females exhibited impaired motor function, reduced bodyweight and less anxiety behaviour compared to WT. Impaired spatial reference memory of vehicle-treated transgenic mice was restored by chronic CBD treatment. Chronic CBD also reduced anxiety-like behaviours and decreased contextual fear-associated freezing in all mice. Chronic remedial CBD treatment ameliorated several disease-relevant phenotypes in 14-month-old TAU58/2 transgenic mice, suggesting potential for the treatment of tauopathy-related behavioural impairments including cognitive deficits.

Topics: Alzheimer Disease; Animals; Cannabidiol; Disease Models, Animal; Female; Frontotemporal Dementia; Memory Disorders; Mice; Mice, Transgenic; Spatial Memory; tau Proteins; Tauopathies

Clinical and preclinical evidence has indicated that estrogen depletion leads to memory impairments and increases the susceptibility to neural damage. Here, we have sought to investigate the effects of Cannabidiol (CBD) a non-psychotomimetic compound from Cannabis sativa, on memory deficits induced by estrogen depletion in rats, and its underlying mechanisms. Adult rats were subjected to bilateral ovariectomy, an established estrogen depletion model in rodents, or sham surgery and allowed to recover for three weeks. After that, they received daily injections of CBD (10 mg/kg) for fourteen days. Rats were tested in the inhibitory avoidance task, a type of emotionally-motivated memory. After behavioral testing they were euthanized, and their hippocampi were isolated for analysis of components of the Akt/GSK3β survival pathway and the antiapoptotic protein Bcl2. Results revealed that ovariectomy impaired avoidance memory, and CBD was able to completely reverse estrogen depletion-induced memory impairment. Ovariectomy also reduced Akt/GSK3β pathway's activation by decreasing the phosphorylation levels of Akt and GSK3β and Bcl2 levels, which were ameliorated by CBD. The present results indicate that CBD leads to a functional recovery accompanied by the Akt/GSK3β survival pathway's activation, supporting its potential as a treatment for estrogen decline-induced deterioration of neural functioning and maintenance.

Topics: Animals; Behavior, Animal; Brain; Cannabidiol; Estrogens; Female; Glycogen Synthase Kinase 3 beta; Hippocampus; Memory Disorders; Models, Theoretical; Ovariectomy; Proto-Oncogene Proteins c-akt; Rats; Signal Transduction

Schizophrenia is a chronic mental disorder that disturbs feelings and behavior. The symptoms of schizophrenia fall into three categories: positive, negative, and cognitive. Cognitive symptoms are characterized by memory loss or attentional deficits, and are especially difficult to treat. Thus, there is intense research into the development of new treatments for schizophrenia-related responses. One of the possible strategies is connected with cannabidiol (CBD), a cannabinoid compound. This research focuses on the role of CBD in different stages of memory (acquisition, consolidation, retrieval) connected with fear conditioning in the passive avoidance (PA) learning task in mice, as well as in the memory impairment typical of cognitive symptoms of schizophrenia. Memory impairment was provoked by an acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (animal model of schizophrenia). Our results revealed that an acute injection of CBD (30 mg/kg; intraperitoneally (i.p.) improved all phases of long-term fear memory in the PA test in mice. Moreover, the acute injection of non-effective doses of CBD (1 or 5 mg/kg; i.p.) attenuated the memory impairment provoked by MK-801 (0.6 mg/kg; i.p.) in the consolidation and retrieval stages of fear memory, but not in the acquisition of memory. The present findings confirm that CBD has a positive influence on memory and learning processes in mice, and reveals that this cannabinoid compound is able to attenuate memory impairment connected with hypofunction of glutamate transmission in a murine model of schizophrenia.

Topics: Animals; Avoidance Learning; Behavior, Animal; Cannabidiol; Disease Models, Animal; Dizocilpine Maleate; Locomotion; Male; Memory; Memory Disorders; Mice; Schizophrenia

Neuropsychiatric disorders, such as addiction, are associated with cognitive impairment, including learning and memory deficits. Previous research has demonstrated that the chronic use of methamphetamine (METH) induces long-term cognitive impairment and cannabidiol (CBD), as a neuroprotectant, can reverse spatial memory deficits induced by drug abuse. The study aimed to evaluate the effect of CBD on METH-induced memory impairment in rats chronically exposed to METH (CEM). For the induction of CEM, animals received METH (2 mg/kg, twice/day) for 10 days. Thereafter, the effect of intracerebroventricular (ICV) administration of CBD (32 and 160 nmol) during the (10 days) abstinence period on spatial memory was evaluated using the Y-Maze test, while recognition memory was examined using the novel object recognition (NOR) test. The results revealed a significant increase in the motor activity of METH-treated animals compared with the control group and, after the 10-day abstinence period, motor activity returned to baseline. Notably, the chronic administration of METH had impairing effects on spontaneous alternation performance and recognition memory, which was clearly observed in the NOR test. Additionally, although the ICV administration of CBD (160 nmol) could reverse long-term memory, a lower dose (32 nmol) did not result in any significant increase in exploring the novel object during short-term memory testing. These novel findings suggest that the chronic administration of METH induces memory impairment and presents interesting implications for the potential use of CBD in treating impairment deficits after chronic exposure to psychostimulant drugs such as METH.

Topics: Animals; Cannabidiol; Infusions, Intraventricular; Male; Maze Learning; Memory Disorders; Methamphetamine; Neuroprotective Agents; Rats; Recognition, Psychology

We aimed to determine changes in working memory and functional connectivity via functional magnetic resonance imaging (fMRI)-modified Sternberg task after treatment with highly purified cannabidiol (CBD, Epidiolex®; 100 mg/mL) in patients with treatment-resistant epilepsy (TRE).. Twenty patients with TRE (mean age: 35.8 years; 7 male) performed fMRI Sternberg task before receiving CBD ("PRE") and after reaching stable dosage of CBD (15-25 mg/kg/day; "ON"). Each patient performed 2 runs of the modified Sternberg task during PRE and ON fMRI. Twenty-three healthy controls (HCs; mean age: 25 years; 11 M) also completed the task. All were presented with a sequence of 2 or 6 letters and instructed to remember them (encoding). After a delay, a single letter was shown, and participants recalled if letter was shown in sequence (retrieval). Paired t-tests were used to analyze accuracy/response times. For each subject, event-related modeling of encoding (2 and 6 letters) and retrieval was performed. Paired t-tests controlling for seizure frequency change and scanner type were performed to assess changes in neural recruitment during encoding and retrieval in key regions of interest.. There was nonsignificant increase in mean modified Sternberg task accuracy from PRE to ON-CBD (28.6 vs. 32.1%). PRE and ON accuracy was worse than HCs (75.5%, p < 0.001). ON-PRE comparison revealed increased activation in the right inferior frontal gyrus (IFG) during 6-letter encoding. ON-HC comparison revealed increased activation in bilateral IFG and insula during 2-letter encoding. PRE-HC comparison revealed decreased activation in the left middle frontal gyrus during 6-letter encoding. None of these activations were associated with working memory performance.. Treatment-resistant epilepsy results in poorer working memory performance and lower neural recruitment compared with HCs. Treatment with CBD results in no significant changes in working memory performance and in significant increases in neural activity in regions important for verbal memory and attention compared with HCs during memory encoding.

Topics: Adult; Cannabidiol; Epilepsy; Humans; Magnetic Resonance Imaging; Male; Memory Disorders; Memory, Short-Term

Nicotine withdrawal is associated with cognitive deficits including attention, working memory, and episodic memory impairments. These cognitive deficits are a hallmark of nicotine abstinence which could be targeted in order to prevent smoking relapse. The underlying mechanisms, however, are poorly understood. In this study, memory impairment was observed in mice 4 days after the precipitation of nicotine withdrawal by the nicotinic antagonist mecamylamine. The presence of cognitive deficits correlated with microglial activation in the hippocampus and the prefrontal cortex. Moreover, an increased expression of neuroinflammatory markers including IL1β, TNFα and IFNγ was found in both memory-related brain regions. Notably, flow cytometric analysis also revealed an enhancement of TNFα and IFNγ plasmatic levels at the same time point during nicotine withdrawal. Impaired neurogenesis, as shown by reduction in the expression of the endogenous cell proliferation marker Ki67 and the early neuron marker doublecortin, was also associated with nicotine abstinence. Treatment with the non-psychoactive cannabinoid cannabidiol abolished memory impairment of nicotine withdrawal and microglia reactivity, reduced the expression of IL1β and IFNγ in the hippocampus and the prefrontal cortex, respectively, and normalized Ki67 levels. The nonsteroidal anti-inflammatory drug indomethacin also prevented cognitive deficits and microglial reactivity during withdrawal. These data underline the usefulness of anti-inflammatory agents to improve cognitive performance during early nicotine abstinence.

Topics: Animals; Anti-Inflammatory Agents; Attention; Brain; Cannabidiol; Cognition; Cognition Disorders; Cognitive Dysfunction; Hippocampus; Male; Memory Disorders; Memory, Short-Term; Mice; Mice, Inbred C57BL; Microglia; Nicotine; Nicotinic Agonists; Prefrontal Cortex; Smoking; Smoking Cessation; Tobacco Use Disorder

Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats. In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction. Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed. Male rats received vehicle or iron carbonyl (30 mg/kg) from the 12th to the 14th postnatal days and were treated with vehicle or CBD (10 mg/kg) for 14 days in adulthood. Iron increased Caspase 9, Cytochrome c, APAF1, Caspase 3 and cleaved PARP, without affecting cleaved Caspase 8 levels. CBD reversed iron-induced effects, recovering apoptotic proteins Caspase 9, APAF1, Caspase 3 and cleaved PARP to the levels found in controls. These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action.

Topics: Animals; Animals, Newborn; Apoptosis; Cannabidiol; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Iron; Iron Compounds; Iron Overload; Male; Memory Disorders; Rats; Rats, Wistar; Signal Transduction

Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection that might cause permanent neurological deficits. Cannabidiol (CBD) is a nonpsychotomimetic compound of Cannabis sativa with neuroprotective properties. In the present work, we evaluated the effects of CBD in a murine model of CM. Female mice were infected with Plasmodium berghei ANKA (PbA) and treated with CBD (30mg/kg/day - 3 or 7days i.p.) or vehicle. On 5th day-post-infection (dpi), at the peak of the disease), animals were treated with single or repeated doses of Artesunate, an antimalarial drug. All groups were tested for memory impairment (Novel Object Recognition or Morris Water Maze) and anxiety-like behaviors (Open field or elevated plus maze test) in different stages of the disease (at the peak or after the complete clearance of the disease). Th1/Th2 cytokines and neurotrophins (brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)) were measured in the prefrontal cortex and hippocampus of experimental groups. PbA-infected mice displayed memory deficits and exhibited increase in anxiety-like behaviors on the 5dpi or after the clearance of the parasitemia, effects prevented by CBD treatment. On 5dpi, TNF-α and IL-6 increased in the hippocampus, while only IL-6 increased in the prefrontal cortex. CBD treatment resulted in an increase in BDNF expression in the hippocampus and decreased levels of proinflammatory cytokines in the hippocampus (TNF-α) and prefrontal cortex (IL-6). Our results indicate that CBD exhibits neuroprotective effects in CM model and might be useful as an adjunctive therapy to prevent neurological symptoms following this disease.

Topics: Animals; Antimalarials; Anxiety; Artemisinins; Artesunate; Brain-Derived Neurotrophic Factor; Cannabidiol; Cognition; Disease Models, Animal; Drug Therapy, Combination; Female; Hippocampus; Malaria, Cerebral; Memory Disorders; Mice, Inbred C57BL; Nerve Growth Factor; Neuroprotective Agents; Plasmodium berghei; Prefrontal Cortex; Survival Analysis; Treatment Outcome

Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients.

Topics: Analysis of Variance; Animals; Cannabidiol; Disease Models, Animal; Dose-Response Relationship, Drug; Dronabinol; Drug Combinations; Fear; Male; Maze Learning; Memory; Memory Disorders; Rats; Rats, Wistar; Time Factors

Cannabidiol (CBD) has been investigated in a wide spectrum of clinical approaches due to its psychopharmacological properties. CBD has low affinity for cannabinoid neuroreceptors and agonistic properties to 5-HT receptors. An interaction between cannabinoid and purinergic receptor systems has been proposed. The purpose of this study is to evaluate CBD properties on memory behavioral and locomotor parameters and the effects of pre-treatment of adenosine receptor blockers on CBD impacts on memory using adult zebrafish. CBD (0.1, 0.5, 5, and 10mg/kg) was tested in the avoidance inhibitory paradigm and anxiety task. We analyzed the effect of a long-term caffeine pre-treatment (~20mg/L - four months). Also, acute block of adenosine receptors was performed in co-administration with CBD exposure in the memory assessment. CBD promoted an inverted U-shaped dose-response curve in the anxiety task; in the memory assessment, CBD in the dose of 5mg/Kg promoted the strongest effects without interfering with social and aggressive behavior. Caffeine treatment was able to prevent CBD (5mg/kg) effects on memory when CBD was given after the training session. CBD effects on memory were partially prevented by co-treatment with a specific A2A adenosine receptor antagonist when given prior to or after the training session, while CBD effects after the training session were fully prevented by adenosine A1 receptor antagonist. These results indicated that zebrafish have responses to CBD anxiolytic properties that are comparable to other animal models, and high doses changed memory retention in a way dependent on adenosine.

Topics: Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Animals; Avoidance Learning; Behavior, Animal; Caffeine; Cannabidiol; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Memory Disorders; Motor Activity; Receptor, Adenosine A2A; Zebrafish

Impairments in cognitive ability and widespread pathophysiological changes caused by neurotoxicity, neuroinflammation, oxidative damage, and altered cholesterol homeostasis are associated with Alzheimer's disease (AD). Cannabidiol (CBD) has been shown to reverse cognitive deficits of AD transgenic mice and to exert neuroprotective, anti-oxidative, and anti-inflammatory properties in vitro and in vivo. Here we evaluate the preventative properties of long-term CBD treatment in male AβPPSwe/PS1ΔE9 (AβPP × PS1) mice, a transgenic model of AD. Control and AD transgenic mice were treated orally from 2.5 months of age with CBD (20 mg/kg) daily for 8 months. Mice were then assessed in the social preference test, elevated plus maze, and fear conditioning paradigms, before cortical and hippocampal tissues were analyzed for amyloid load, oxidative damage, cholesterol, phytosterols, and inflammation. We found that AβPP × PS1 mice developed a social recognition deficit, which was prevented by CBD treatment. CBD had no impact on anxiety or associative learning. The prevention of the social recognition deficit was not associated with any changes in amyloid load or oxidative damage. However, the study revealed a subtle impact of CBD on neuroinflammation, cholesterol, and dietary phytosterol retention, which deserves further investigation. This study is the first to demonstrate CBD's ability to prevent the development of a social recognition deficit in AD transgenic mice. Our findings provide the first evidence that CBD may have potential as a preventative treatment for AD with a particular relevance for symptoms of social withdrawal and facial recognition.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cannabidiol; Cerebral Cortex; Disease Models, Animal; Hippocampus; Humans; Male; Memory Disorders; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neuroimmunomodulation; Nootropic Agents; Presenilin-1; Recognition, Psychology; Social Behavior

Recent human studies suggest that recreational cannabis strains that are relatively high in cannabidiol (CBD) content produce less cognitive impairment than do strains with negligible CBD and similar Δ(9) tetrahydrocannabinol (THC) content. Self-selection in such studies means it is impossible to rule out additional variables which may determine both cannabis strain selection and basal cognitive performance level. Controlled laboratory studies can better determine a direct relationship.. In this study, adult male rhesus monkeys were assessed on visuospatial Paired Associates Learning and Self-Ordered Spatial Search memory tasks, as well as additional tests of motivation and manual dexterity. Subjects were challenged with THC (0.2, 0.5 mg·kg(-1) , i.m.) in randomized order and evaluated in the presence or absence of 0.5 mg·kg(-1) CBD.. CBD attenuated the effects of THC on paired associates learning and a bimanual motor task without affecting the detrimental effects of THC on a Self-Ordered Spatial Search task of working memory. CBD did not significantly reverse THC-induced impairment of a progressive ratio or a rotating turntable task.. This study provides direct evidence that CBD can oppose the cognitive-impairing effects of THC and that it does so in a task-selective manner when administered simultaneously in a 1:1 ratio with THC. The addition of CBD to THC-containing therapeutic products may therefore help to ameliorate unwanted cognitive side-effects.. This article is commented on by Mechoulam and Parker, pp 1363-1364 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12400.

Topics: Animals; Behavior, Animal; Cannabidiol; Cognition; Dronabinol; Functional Laterality; Macaca mulatta; Male; Memory; Memory Disorders; Models, Animal; Molecular Sequence Data; Motivation; Motor Activity; Time Factors

This commentary discusses the importance of a new study entitled 'Cannabidiol attenuates deficits of visuo-spatial associative memory induced by Δ(9) -tetrahydrocannabinol' by Wright et al. from the Scripps Institute in La Jolla, California. The results in this study show that the non-psychoactive cannabis constituent cannabidiol opposes some, but not all, forms of behavioural and memory disruption caused by Δ(9) -tetrahydrocannabinol in male rhesus monkeys.. This article is a commentary on the research paper by Wright et al., pp 1365-1373 of this issue. To view this paper visit http://dx.doi.org/10.1111/bph.12199.

Topics: Animals; Behavior, Animal; Cannabidiol; Cognition; Dronabinol; Male; Memory; Memory Disorders

Cannabidiol, the main nonpsychotropic constituent of Cannabis sativa, possesses a large number of pharmacological effects including anticonvulsive, sedative, hypnotic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective, as demonstrated in clinical and preclinical studies. Many neurodegenerative disorders involve cognitive deficits, and this has led to interest in whether cannabidiol could be useful in the treatment of memory impairment associated to these diseases.. We used an animal model of cognitive impairment induced by iron overload in order to test the effects of cannabidiol in memory-impaired rats.. Rats received vehicle or iron at postnatal days 12-14. At the age of 2 months, they received an acute intraperitoneal injection of vehicle or cannabidiol (5.0 or 10.0 mg/kg) immediately after the training session of the novel object recognition task. In order to investigate the effects of chronic cannabidiol, iron-treated rats received daily intraperitoneal injections of cannabidiol for 14 days. Twenty-four hours after the last injection, they were submitted to object recognition training. Retention tests were performed 24 h after training.. A single acute injection of cannabidiol at the highest dose was able to recover memory in iron-treated rats. Chronic cannabidiol improved recognition memory in iron-treated rats. Acute or chronic cannabidiol does not affect memory in control rats.. The present findings provide evidence suggesting the potential use of cannabidiol for the treatment of cognitive decline associated with neurodegenerative disorders. Further studies, including clinical trials, are warranted to determine the usefulness of cannabidiol in humans suffering from neurodegenerative disorders.

Topics: Animals; Cannabidiol; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Iron Overload; Male; Memory Disorders; Neurodegenerative Diseases; Rats; Rats, Wistar

Oxidative stress plays an important role in the development of cognitive impairment in sepsis. Here we assess the effects of acute and extended administration of cannabidiol (CBD) on oxidative stress parameters in peripheral organs and in the brain, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent either sham operation or CLP. Rats subjected to CLP were treated by intraperitoneal injection with "basic support" and CBD (at 2.5, 5, or 10mg/kg once or daily for 9days after CLP) or vehicle. Six hours after CLP (early times), the rats were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus, striatum, and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day (late times), the rats were submitted to the inhibitory avoidance task. After the test, the animals were killed and samples from lung, liver, kidney, heart, spleen, and brain (hippocampus) were obtained and assayed for TBARS formation and protein carbonyls. The acute and extended administration of CBD at different doses reduced TBARS and carbonyl levels in some organs and had no effects in others, ameliorated cognitive impairment, and significantly reduced mortality in rats submitted to CLP. Our data provide the first experimental demonstration that CBD reduces the consequences of sepsis induced by CLP in rats, by decreasing oxidative stress in peripheral organs and in the brain, improving impaired cognitive function, and decreasing mortality.

Topics: Analysis of Variance; Animals; Avoidance Learning; Brain; Cannabidiol; Cecum; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Memory Disorders; Protein Carbonylation; Punctures; Rats; Rats, Wistar; Sepsis; Stress, Psychological; Thiobarbituric Acid Reactive Substances; Time Factors

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.

Topics: Adolescent; Alcohol Drinking; Analysis of Variance; Cannabidiol; Cannabinoids; Dronabinol; Female; Humans; Male; Marijuana Smoking; Memory; Memory Disorders; Mental Recall; Psychiatric Status Rating Scales; Receptor, Cannabinoid, CB1; Saliva; United Kingdom; Verbal Learning; Young Adult

Cannabidiol, a non-psychoactive component of cannabis, has been reported to have interactions with Delta(9)-tetrahydrocannabinol (Delta(9)-THC). However, such interactions have not sufficiently been clear and may have important implications for understanding the pharmacological effects of marijuana. In the present study, we investigated whether cannabidiol modulates the pharmacological effects of Delta(9)-THC on locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory in the eight-arm radial maze task in mice. In addition, we measured expression level of cannabinoid CB(1) receptor at striatum, cortex, hippocampus and hypothalamus. Delta(9)-THC (1, 3, 6 and 10 mg/kg) induced hypoactivity, catalepsy-like immobilisation and hypothermia in a dose-dependent manner. In addition, Delta(9)-THC (1, 3 and 6 mg/kg) dose-dependently impaired spatial memory in eight-arm radial maze. On the other hand, cannabidiol (1, 3, 10, 25 and 50 mg/kg) did not affect locomotor activity, catalepsy-like immobilisation, rectal temperature and spatial memory on its own. However, higher dose of cannabidiol (10 or 50 mg/kg) exacerbated pharmacological effects of lower dose of Delta(9)-THC, such as hypoactivity, hypothermia and impairment of spatial memory. Moreover, cannabidiol (50 mg/kg) with Delta(9)-THC (1 mg/kg) enhanced the expression level of CB(1) receptor expression in hippocampus and hypothalamus. Cannabidiol potentiated pharmacological effects of Delta(9)-THC via CB(1) receptor-dependent mechanism. These findings may contribute in setting the basis for interaction of cannabinoids and to find a cannabinoid mechanism in central nervous system.

Topics: Animals; Body Temperature; Brain; Cannabidiol; Catalepsy; Dose-Response Relationship, Drug; Dronabinol; Drug Synergism; Hypothermia; Male; Maze Learning; Memory Disorders; Mice; Motor Activity; Psychotropic Drugs; Receptor, Cannabinoid, CB1