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Release of the brain’s equivalent of THC, marijuana’s active component, reduces seizure activity but leads to post-seizure oxygen deprivation in the brain, Stanford scientists and their collaborators have shown. CBD Products May Help People with Epilepsy Better Tolerate Anti-Seizure Medications Johns Hopkins Medicine researchers have shown that CBD may reduce the adverse effects associated with

Marijuana-like brain substance calms seizures but increases aftereffects, study finds

Release of the brain’s equivalent of THC, marijuana’s active component, reduces seizure activity but leads to post-seizure oxygen deprivation in the brain, Stanford scientists and their collaborators have shown.

August 4, 2021 – By Bruce Goldman

Ivan Soltesz and his colleagues have found that a marijuana-like compound in the brain calms epileptic seizures but also increases memory loss.
Steve Fisch

A marijuana-like chemical in the brain, mirroring its plant-based counterpart, packs both ups and downs.

Epileptic seizures trigger the rapid synthesis and release of a substance mimicked by marijuana’s most psychoactive component, Stanford University School of Medicine investigators have learned. This substance is called 2-arachidonoylglycerol, or 2-AG, and has the beneficial effect of damping down seizure intensity.

But there’s a dark side. The similarly rapid breakdown of 2-AG after its release, the researchers found, trips off a cascade of biochemical reactions culminating in blood-vessel constriction in the brain and, in turn, the disorientation and amnesia that typically follow an epileptic seizure.

The Stanford scientists’ findings, reached in collaboration with colleagues at other institutions in the United States, Canada and China, are described in a study to be published Aug. 4 in Neuron. Ivan Soltesz, PhD, professor of neurosurgery, shares senior authorship with G. Campbell Teskey, PhD, professor of cell biology and anatomy at the University of Calgary in Alberta, Canada. The study’s lead author is Jordan Farrell, PhD, a postdoctoral scholar in Soltesz’s group.

The researchers’ discoveries could guide the development of drugs that both curb seizures’ strength and reduce their aftereffects.

Electrical storm in the brain

About one in every hundred people has epilepsy. Epileptic seizures can be described as an electrical storm in the brain. These storms typically begin at a single spot where nerve cells begin repeatedly firing together in synchrony. The hyperactivity often spreads from that one spot to other areas throughout the brain, causing symptoms such as loss of consciousness and convulsions. It’s typical for the person experiencing a seizure to need tens of minutes before becoming clearheaded again.

The majority of epileptic seizures originate in the hippocampus, a brain structure buried in the temporal lobe, said Soltesz, the James R. Doty Professor of Neurosurgery and Neurosciences. The hippocampus plays an outsized role in short-term memory, learning and spatial orientation. Its ability to quickly adopt new neuronal firing patterns renders it especially vulnerable to glitches that initiate seizures. (Most epileptic seizures in adults begin in or near the hippocampus, Soltesz noted.)

In the study, Soltesz and his associates monitored split-second changes in levels of 2-AG in the hippocampus of mice during periods of normal activity, like walking or running, and in experiments in which brief seizures were induced in the hippocampus.

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2-AG is an endocannabinoid, a member of a family of short-lived signaling substances that are the brain’s internal versions of the psychoactive chemicals in marijuana. 2-AG and these plant-derived psychoactive chemicals share an affinity for a receptor, known as CB1, that’s extremely abundant on the surface of neurons throughout the brain.

“There have been lots of studies providing evidence for a connection between seizures and endocannabinoids,” Soltesz said. “What sets our study apart is that we could watch endocannabinoid production and action unfold in, basically, real time.”

A brake on excitement

Endocannabinoids are understood to play a role in inhibiting excessive excitement in the brain. When excitatory neurons, secreting chemical “go” signals, exceed a threshold, they induce the production and release of endocannabinoids, whose binding to CB1 on an excitatory neuron acts as a brake, ordering that neuron to chill out a little.

While smoking marijuana floods the entire brain with relatively long-lasting THC, endocannabinoids are released in precise spots in the brain under precise circumstances, and their rapid breakdown leaves them in place and active for extremely short periods of time, said Soltesz, who has been studying the connection between endocannabinoids and epilepsy for decades.

But because endocannabinoids are so fragile and break down so quickly, until recently there was no way to measure their fast-changing levels in animals’ brains. “Existing biochemical methods were far too slow,” he said.

The most recent study had its start when Soltesz learned of a new endocannabinoid-visualization method invented by study co-author Yulong Li, PhD, a professor of neuroscience at Peking University in Beijing. The method involves the bioengineering of select neurons in mice so that these neurons express a modified version of CB1 that emits a fluorescent glow whenever a cannabinoid binds to the modified endocannabinoid receptor. The fluorescence can be detected by photosensitive instruments.

Using this new tool, the scientists could monitor and localize sub-second changes in fluorescence that correlate with endocannabinoid levels where that binding was occurring.

Zeroing in on 2-AG

By blocking enzymes critical to the production and breakdown of different endocannabinoids, the researchers proved that 2-AG alone is the endocannabinoid substance whose surges and rapid disappearance track neuronal activity in the mice. Several hundred times as much 2-AG was released when a mouse was having a seizure compared with when it was merely running in place.

The researchers were able to rule out the involvement of an alternative endocannabinoid, anandamide, that many neuroscientists and pharmacologists had assumed was the active substance. Anandamide’s name is derived from the Sanskrit word for “bliss.”

“This previously undetected activity-dependent surge in levels of 2-AG downregulates excitatory neurons’ excessive rhythmic firing during a seizure,” Soltesz said.

But 2-AG is almost immediately converted to arachidonic acid, a building block for inflammatory compounds called prostaglandins. The researchers showed that the ensuing increase in arachidonic acid levels resulted in the buildup of a particular variety of prostaglandin that causes constriction of tiny blood vessels in the brain where the seizure has induced that prostaglandin’s production, cutting off oxygen supply to those brain areas.

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Oxygen deprivation is known to produce the cognitive deficits — disorientation, memory loss — that occur after a seizure, Soltesz said.

“A drug that blocks 2-AG’s conversion to arachidonic acid would kill two birds with one stone,” Soltesz said. “It would increase 2-AG’s concentration, diminishing seizure severity, and decrease arachidonic acid levels, cutting off the production of blood-vessel-constricting prostaglandins.”

Another Stanford co-author of the study is postdoctoral scholar Barna Dudok, PhD.

Other researchers at the University of Calgary, as well as researchers at Vanderbilt University, contributed to the work.

The study was funded by the National Institutes of Health (grants K99NS117795, MH107435, 1S10OD017997-01A1, NS99457 and NS103558), the Canadian Institutes of Health Research, the Beijing Municipal Science & Technology Commission, the National Natural Science Foundation of China, and the Peking University School of Life Sciences.

CBD Products May Help People with Epilepsy Better Tolerate Anti-Seizure Medications

Johns Hopkins Medicine researchers have shown that CBD may reduce the adverse effects associated with anti-seizure medications, and seems to improve other aspects of health and quality of life for patients with epilepsy. Credit: Public domain image

Artisanal (non-pharmaceutical) cannabidiol (CBD) products have become popular in recent years for their apparent therapeutic effects. CBD — a naturally occurring compound of the cannabis plant legally derived from hemp — is used widely as a naturopathic remedy for a number of health conditions, including epilepsy and seizure disorders. Now, Johns Hopkins Medicine researchers, in collaboration with the Realm of Caring Foundation and other institutions, have conducted an observational study with participant-reported data to better understand the impact these products may have on people with epilepsy.

They found that CBD may reduce the adverse effects associated with anti-seizure medications, and seems to improve other aspects of health and quality of life for patients.

“The potential of CBD products for the treatment of seizure disorders goes beyond seizure control alone,” says Ryan Vandrey, Ph.D., professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “In our study, we saw clinically significant improvements in anxiety, depression and sleep when patients with epilepsy initiated therapeutic use of artisanal CBD products.”

Epilepsy, one of the most common nervous system disorders affecting people of all ages, is a neurological condition characterized by recurrent seizures. Treatment for epilepsy includes anti-seizure medications and diet therapy, such as forms of the ketogenic diet. Surgery may be an alternative treatment, especially when medications or diet fail to control seizures, or if drug side effects — including dizziness, nausea, headache, fatigue, vertigo and blurred vision — are too difficult for a patient to tolerate.

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Epidiolex, a pharmaceutical formulation of CBD is approved by the FDA to treat three types of rare seizure disorders (Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex), but is not approved for the many other types of epilepsy. As a result, patients with other forms of epilepsy often seek alternative forms of CBD, including those evaluated in the new study.

For their evaluation, the researchers analyzed data gathered between April 2016 and July 2020 from 418 participants — 230 women and 188 men — with 205 (49%) at least age 18 and 213 (51%) age 18 or younger. The participants included 71 adults with epilepsy who used artisanal CBD products for medicinal purposes and 209 who were caregivers of children or dependent adults to whom artisanal CBD products were given. The control group consisted of 29 adults with epilepsy who were considering the use of CBD products and 109 caregivers who were considering it for a dependent child or adult patient.

Participants completed a web-based survey that included questions regarding quality of life, anxiety and depression, and sleep. They were prompted via email to complete follow-up surveys at three-month intervals for 14 months.

Compared with the control group, artisanal CBD users reported lower epilepsy medication-related adverse effects (13% lower) and had greater psychological health satisfaction (21% greater) at the beginning of the study. They also reported lower anxiety (19% lower) and depression (17% lower).

Both adult and youth (18 years or younger) CBD users reported better quality sleep, compared with their peers in the control groups.

Caregivers of patients currently using CBD products reported significantly less burden and stress, compared with caregivers in the control group (13% less).

Importantly, 27 patients in the control group at the start of the study started using artisanal CBD products later in the study. After starting CBD, these patients reported significant improvements in physical and psychological health, as well as reductions in anxiety and depression.

Participants also were asked about possible adverse effects related to their CBD use. Among the 280 users, the majority (79%) did not report any adverse effects. The remaining reported negative factors such as drowsiness (11%), high or prohibitive product cost (4%), worsening of epilepsy symptoms (4%), concerns about legal issues (3%) and worries about problematic drug interactions (1%).

Vandrey says further research is needed to understand how these findings can best be applied to helping people with epilepsy. In the interim, he says, patients should consult with their physician before trying CBD products.

“Our hope is to do controlled clinical trials to better inform clinical decision making and identify specific formulations that are most beneficial to patients,” he says.

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