Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid ...medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except
in vitro
at supraphysiological concentrations. Thus, as further evidence for CBD’s beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in
in vitro
assays only manifest at high concentrations, which may be difficult to achieve
in vivo
, particularly given CBD’s relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug’s action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD’s effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD’s therapeutic mechanism of action.
Summary
Objective
Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol (CBD) in a ...battery of acute seizure models. Additionally, we defined the disease‐modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus–spontaneous recurrent seizures (RISE‐SRS) model of temporal lobe epilepsy (TLE).
Methods
We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure, 6‐Hz psychomotor seizure, and pentylenetetrazol acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective or behavioral toxic dose was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg single dose) in a rat model of pilocarpine‐induced status epilepticus. We defined the effect of chronic CBD administration (200 mg/kg orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE‐SRS model of TLE.
Results
CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine‐induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD's acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time‐dependent increase in seizure burden and improved TLE‐associated motor comorbidities of epileptic rats in the RISE‐SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task.
Significance
The present study illustrates that CBD is a well‐tolerated and effective antiseizure agent and illustrates a potential disease‐modifying effect of CBD on reducing both seizure burden and associated comorbidities well after the onset of symptomatic seizures in a model of TLE.
Abstract Objectives: To test the association between childhood IQ and mortality over the normal human lifespan. Design: Longitudinal cohort study. Setting: Aberdeen. Subjects: All 2792 children in ...Aberdeen born in 1921 and attending school on 1 June 1932 who sat a mental ability test as part of the Scottish mental survey 1932. Main outcome measure: Survival at 1 January 1997. Results: 79.9% (2230) of the sample was traced. Childhood mental ability was positively related to survival to age 76 years in women (P<0.0001) and men (P<0.0001). A 15 point disadvantage in mental ability at age 11 conferred a relative risk of 0.79 of being alive 65 years later (95% confidence interval 0.75 to 0.84); a 30 point disadvantage reduced this to 0.63 (0.56 to 0.71). However, men who died during active service in the second world war had a relatively high IQ. Overcrowding in the school catchment area was weakly related to death. Controlling for this factor did not alter the association between mental ability and mortality. Conclusion: Childhood mental ability is a significant factor among the variables that predict age at death. What is already known on this topic People in deprived conditions tend to have more illness and die younger The reasons for this inequality in health are not fully established What this study adds IQ at age 11 years was significantly associated with survival up to 76 years in an Aberdeen cohort The association was unaffected by adjustment for overcrowding Men with high IQ were more likely to die in active service in the second world war
To examine the association between intellectual engagement and cognitive ability in later life, and determine whether the maintenance of intellectual engagement will offset age related cognitive ...decline.
Longitudinal, prospective, observational study.
Non-clinical volunteers in late middle age (all born in 1936) living independently in northeast Scotland.
Sample of 498 volunteers who had taken part in the Scottish Mental Health Survey of 1947, from one birth year (1936).
Cognitive ability and trajectory of cognitive decline in later life. Typical intellectual engagement was measured by a questionnaire, and repeated cognitive measurements of information processing speed and verbal memory were obtained over a 15 year period (recording more than 1200 longitudinal data points for each cognitive test).
Intellectual engagement was significantly associated with level of cognitive performance in later life, with each point on a 24 point scale accounting for 0.97 standardised cognitive performance (IQ-like) score, for processing speed and 0.71 points for memory (both P<0.05). Engagement in problem solving activities had the largest association with life course cognitive gains, with each point accounting for 0.43 standardised cognitive performance score, for processing speed and 0.36 points for memory (both P<0.05). However, engagement did not influence the trajectory of age related decline in cognitive performance. Engagement in intellectual stimulating activities was associated with early life ability, with correlations between engagement and childhood ability and education being 0.35 and 0.22, respectively (both P<0.01).
These results show that self reported engagement is not associated with the trajectory of cognitive decline in late life, but is associated with the acquisition of ability during the life course. Overall, findings suggest that high performing adults engage and those that engage more being protected from relative decline.
The Xylariaceae and its relatives rank as one of the best-known members of the Ascomycota. They are now well recognized for their diversity, global distribution, ecological activities and their ...outstanding novel metabolites with wide ranging bioactivity.
The functional networks of cultured neurons exhibit complex network properties similar to those found in vivo. Starting from random seeding, cultures undergo significant reorganization during the ...initial period in vitro, yet despite providing an ideal platform for observing developmental changes in neuronal connectivity, little is known about how a complex functional network evolves from isolated neurons. In the present study, evolution of functional connectivity was estimated from correlations of spontaneous activity. Network properties were quantified using complex measures from graph theory and used to compare cultures at different stages of development during the first 5 weeks in vitro. Networks obtained from young cultures (14 days in vitro) exhibited a random topology, which evolved to a small-world topology during maturation. The topology change was accompanied by an increased presence of highly connected areas (hubs) and network efficiency increased with age. The small-world topology balances integration of network areas with segregation of specialized processing units. The emergence of such network structure in cultured neurons, despite a lack of external input, points to complex intrinsic biological mechanisms. Moreover, the functional network of cultures at mature ages is efficient and highly suited to complex processing tasks.
Background and Purpose
Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first ...time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models.
Experimental Approach
The effect of CBDV (1–100 μM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4‐aminopyridine (4‐AP) application or Mg2+‐free conditions was assessed by in vitro multi‐electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50–200 mg·kg−1) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ) and pilocarpine‐induced seizures in rats. The effects of CBDV in combination with commonly used antiepileptic drugs on rat seizures were investigated. Finally, the motor side effect profile of CBDV was investigated using static beam and grip strength assays.
Key Results
CBDV significantly attenuated status epilepticus‐like epileptiform LFPs induced by 4‐AP and Mg2+‐free conditions. CBDV had significant anticonvulsant effects on the mES (≥100 mg·kg−1), audiogenic (≥50 mg·kg−1) and PTZ‐induced seizures (≥100 mg·kg−1). CBDV (200 mg·kg−1) alone had no effect against pilocarpine‐induced seizures, but significantly attenuated these seizures when administered with valproate or phenobarbital at this dose. CBDV had no effect on motor function.
Conclusions and Implications
These results indicate that CBDV is an effective anticonvulsant in a broad range of seizure models. Also it did not significantly affect normal motor function and, therefore, merits further investigation as a novel anti‐epileptic in chronic epilepsy models.
Linked Articles
This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue‐8
Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and ...reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude in CA1 and dentate gyrus (DG) regions and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in (35)Sguanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.
The Scottish Mental Surveys of 1932 and 1947 collected valid IQ-type test scores for almost everyone born in 1921 and 1936 and attending school on June 1, 1932 (
N
= 89,498) and June 4, 1947 (
N
= ...70,805). These surveys are described. This research, using the surveys' data, examined (a) the stability of intelligence differences across the life span, (b) the determinants of cognitive change from childhood to old age, and (c) the impact of childhood intelligence on survival and health in old age. Surviving participants of the Scottish Mental Surveys were tested, and the surveys' data were linked with public and health records. Novel findings on the stability of IQ scores from age 11 to age 80; sex differences in cognitive aging; the dedifferentiation hypothesis of cognitive aging; and the effect of childhood IQ on all-cause and specific mortality, morbidity, and frailty in old age are presented.
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