Principal neurons in the hippocampus and cerebellum use endocannabinoids to carry out a signalling process that is analogous in mechanism, but opposite in sign, to DSI, called depolarization-induced suppression of excitation. Like DSI, DSE is induced by neuronal depolarization, it consists of a transient depression in neurotransmitter release, and it requires a retrograde endocannabinoid messenger. But unlike DSI, DSE targets glutamatergic rather than GABA axon terminals, and results therefore in reduced excitatory input to the affected cell108 . Do DSI and DSE occur simultaneously in a single neuron and, if so, how are they coordinated? In cerebellar Purkinje cells, the two opposing phenomena can be elicited by similar stimulation protocols and so are likely to coexist. Although they might be topographically segregated along the longitudinal axis of the neuron, the significance of their coexistence is not known. On the other hand, in the hippocampus, the induction of DSE requires longer periods of depolarization than does DSI, and its magnitude is smaller. This could be explained by the lower sensitivity of glutamatergic terminals to endocannabinoid activation, which would indicate that a switch from DSI to DSE might occur when endocannabinoid concentrations at hippocampal synapses attain a certain threshold value. Again, the role of such a switch, if any, is undefined.Inhibition of glutamatergic neurotransmission by cannabinoid agonists has been documented in a variety of brain structures besides the hippocampus and cerebellum. These include the prefrontal cortex, amygdala, nucleus accumbens,trimming cannabis striatum and substantia nigra pars reticulata. Whether such effects reflect the existence of regional DSE-like phenomena is an important question that remains to be addressed.The ability of cannabinoid agonists to inhibit the release of neurotransmitters in the CNS is not restricted to glutamate and GABA.
A particularly convincing case has been made for acetylcholine, the release of which is reduced by cannabinoids both in vitro and in vivo, and is enhanced by inactivation of CB1 receptors. Acetylcholine release in the neocortex and hippocampus facilitates learning and memory, so disruption of this facilitatory process might contribute to the detrimental effects of cannabinoid drugs on cognition. Cannabinoids also reduce the release of the biogenic amines noradrenaline and serotonin136, and the neuropeptide CCK-8 . Analogous, but as yet unknown, actions on peptide release in the hypothalamus might underlie the central involvement of the endocannabinoid system in the secretion of stress hormones and regulation of appetite .High-frequency stimulation of cortical fibres that innervate the striatum leads to a form of persistent synaptic plasticity called long-term depression. Like its hippocampal counterpart, striatal LTD is induced when Ca2+ enters the somatodendritic compartment of projection neurons, and is expressed as a decrease in glutamate release from axon terminals of corticostriatal fibres. These analogies with DSI are suggestive of an endocannabinoiddependent process, an idea that has been confirmed experimentally. Striatal LTD is absent in CB1 -deficient mice and is blocked by the CB1 antagonist rimonabant; moreover, it is induced in a CB1 -dependent manner by anandamide or AM404 . A similar form of endocannabinoid-dependent LTD can be produced by low-frequency stimulation of cortical fibres that innervate the nucleus accumbens. Despite differences in induction protocols in vitro __ one is produced by high-frequency,the other by low-frequency, stimulation __ striatal and accumbal LTD could serve complementary functions. For example, they might both contribute to habit formation, a type of striatumdependent learning that underlies the development of motor skills and is implicated in the pathogenesis of drug addiction. Notably, cannabinoid drugs provoke in rats a relapse to drug-seeking behaviour after prolonged periods of abstinence, whereas CB1 antagonists attenuate the relapse induced by drug-associated cues.
These findings have provided the rationale for current clinical trials of rimonabant as a treatment for alcohol and tobacco addiction .In the hippocampal CA1 field, stimulation protocols that cause long-term potentiation at excitatory synapses onto pyramidal neurons simultaneously produce LTD at adjacent inhibitory synapses. Like striatal LTD, I-LTD might be endocannabinoid-mediated, but its molecular mechanism seems to be remarkably different. According to a current model, glutamate released from excitatory terminals activates metabotropic receptors on dendritesof pyramidal neurons, which in turn stimulates 2-AG formation through the DGL pathway. The newly formed endocannabinoid can then depress GABA release by engaging CB1 receptors on inhibitory nerve endings. How this long-lasting disinhibitory process interacts with other forms of endocannabinoiddependent plasticity and contributes to the overall effects of cannabinoids on hippocampus-dependent learning will surely be the object of future discussion and experiments.We have learned that the brain contains multiple endocannabinoid lipids, and that neurons produce them using membrane constituents as starting material. We have also discovered that these lipids behave differently from traditional transmitters. Rather than being secreted from vesicle stores, they are released in a non-synaptic manner and combine with cannabinoid receptors located near their sites of synthesis. Despite this progress, many crucial pieces of the endocannabinoid puzzle are still missing. For example, we need to map the neuronal circuits that produce anandamide and 2-AG, and this requires in turn the molecular characterization of the synthetic enzymes involved. We also need to understand how classical neurotransmitters and drugs of abuse interact with these circuits, and to explore the functional consequences of such interactions. Last, but not least, we must continue to develop selective pharmacological tools that target not only the different cannabinoid receptor subtypes, but also the mechanisms of endocannabinoid synthesis and deactivation. Although these tasks are far from trivial, what is already known about the endocannabinoid system indicates that they are well worth pursuing.
The use of cannabis by older adults increased sharply over the past two decades in the United States 1 with the legalization for medical and recreational purposes in many states. While there is limited evidence that cannabis may be helpful for specific conditions,older adults are increasingly using cannabis to treat a wide range of symptoms and conditions, including recreationally,and their perceived risk of regular cannabis use is decreasing.However, older adults, due to the physiological changes related to aging, medication use, and increased comorbidity, are at high risk for adverse effects of any psychoactive substance, including cannabis.Cannabis is associated with a range of acute adverse effects that can require emergency care and detrimental for older adults, who are already the most frequent utilizers of the emergency department .Cannabis can slow reaction time and impair attention,leading to injuries including falls. Cannabis use is also associated with increased risk for psychosis, delirium, paranoia, and other acute psychiatric symptoms.The use of cannabis can cause acute physiological changes that can exacerbate cardiovascular and pulmonary diseases.Additionally, there are potential drug interactions that can lead to adverse effects and cannabinoid hyperemesis syndrome is related to cannabis use.Many of these complications have resulted in the need for acute clinical care in EDs.Cannabis-related ED visits have increased in the US, with one study finding a 12.1% average annual increase from 2006 to 2014 in cannabis-associated ED visits.This included a sharp increase among adults aged ≥65 who, while having lower overall rates of cannabis associated ED visits compared to younger adults, had the largest one-year increase from 2017 to 2018 compared to all other age groups.A study focused on adults aged ≥50 found that cannabis use increased the likelihood of ED visits due to injury.Despite the increase in cannabis use and its potential for adverse effects requiring emergency care in this age group, there has been little research focusing on cannabis-related ED visits among older adults. In 1996, California became the first state in the country to legalize medical cannabis and in 2016 passed Proposition 64, which legalized the use, sale, and cultivation of recreational cannabis.We aim to help fill this knowledge gap by examining trends in the rates of cannabis-related ED visits among older adults aged ≥65 and to examine trends among subgroups of older adults in the state of California.This was a retrospective cohort study of adults aged ≥65 using visit-level data from 2005 through 2019 from all non-federal acute care hospitals across the state of California using non-public data from the California Department of Healthcare Access and Information . All licensed hospitals in California are subject to mandatory reporting of utilization data in a standardized format to HCAI. The number of hospitals with EDs ranged from 316 to 335 facilities during the study period. Data presented in this study represent unique ED encounters from hospitals providing emergency medical services licensed by the State of California,gardening rack which were available in two separate non-public HCAI research data sources: Patient Discharge Data and Emergency Department and Ambulatory Surgery Data . ED encounters resulting in admission to the same hospital are combined with the inpatient record and only reported in the PDD; all other ED encounters are reported in the EDAS. For this study, same-hospital ED admissions from the PDD were combined with ED encounters from the EDAS to construct a complete ED utilization database for analysis including all non-duplicative ED encounters reported to HCAI.
Detailed descriptions of these data sources can be found elsewhere.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline for cross-sectional studies. For each calendar year, we determined the number and rate per 100,000 ED visits for overall cannabis-related ED visits among adults aged ≥65 and estimated trends between 2005–2019. We stratified individual trends of cannabis-related ED visits per 100,000 ED visits by age groups , race/ethnicity , sex , and payer/insurance . The Charlson comorbidity index score was calculated with the enhanced coding algorithm provided by Quan et al25 for both ICD-9 and ICD-10 coding and stratified by the following scores: 0, 1, 2, and ≥3. Finally, cannabis diagnoses were divided into three categories: 1. cannabis abuse and unspecified use, 2. cannabis dependence, and 3. poisoning by cannabis, lysergide, and psychodysleptics . Linear trend p-values were calculated for the overall trend and across subgroups. Statistical significance was defined as a p-value <0.05 All statistical analyses were conducted with IBM SPSS Statistics . This study was approved by UCSD’s Human Research Protections Program. Cannabis-related ED visits significantly increased in California among adults aged ≥65 from a total of 366 visits in 2005, a rate of 20.7 per 100,000 ED visits to 12,167 visits in 2019; a rate of 395.0 per 100,000 ED visits , which is an absolute increase of 374.3 and a 1808.2% relative increase. Table 1 presents cannabis related ED visit trends stratified by patient characteristics. There were significant increases for all subgroups. By age group, adults aged 65–74 had the highest rate in 2019 while also having the largest increase in absolute increase compared to adults aged 75–84 and those aged ≥85. Adults aged 75–84, meanwhile had the largest relative percent change with a 2208.3% increase. By race/ethnicity, older Black adults had the highest rate in 2019 and the largest absolute increase compared to older adults of other races/ethnicities. Older males had a higher ED visit rate in 2019 compared to older females although older females had a larger relative percent increase . Older adults without health insurance had the highest rate in 2019 and the largest absolute and relative increases compared to those with health insurance. Older adults with a higher Charlson comorbidity index score also had the highest rate in 2019 and the largest absolute increase compared to those with lower comorbidity scores; however, those with the lowest comorbidity score had the highest relative increase . Finally, the “cannabis abuse and unspecified use” category comprised nearly all cannabis-related ED visits each year with 369.4 per 100,000 ED visits in 2019 with the largest absolute and relative increases compared to the other categories.Cannabis-related ED visits increased sharply in California among older adults over a 15- year period. While there was a significant increase in cannabis-related ED use among all subgroups of older adults, we identified key subgroups with higher rates and larger increases in cannabis-related ED visits . We found that adults aged 65–74, older males, and those with more comorbidities had higher ED visit rates in 2019, while those with marked relative increases included adults aged 75–84, older females, older adults without health insurance, and those with the lowest comorbidity. Older Black adults had the highest rate of ED visits among all subgroups examined during the study period, consistent with a previous study that showed that among older adults who used cannabis, being Black was associated with an increased likelihood of ED visits.