Living inside each of us are hundreds of species of bacteria that comprise the gut microbiome, which has a huge impact on our well-being, affecting many physiological processes, including our immunity, metabolism, and neurological function. Medical scientists have shown that an imbalance in the gut microbiome, known as dysbiosis, can lead to depression and other adverse health outcomes. But the specific molecular pathways that link gut dysbiosis to mood disorders is still largely unchartered territory.
A recent report by French scientists in Nature Communications (Chevalier, 2020) breaks new ground in exploring how the endocannabinoid system mediates the impact of gut microbiota on mood and brain function. This paper builds upon previous research into the pathophysiology of depression that focuses on changes in the hippocampus, an area of the brain where cannabinoid (CB1) receptors are concentrated.
Several studies indicate that activation of CB1 receptor signaling produces antidepressant effects by stimulating neurogenesis in the hippocampus. Tetrahydrocannabinol (THC) and cannabidiol (CBD) are both neurogenic compounds that promote the formation of neurons in the adult brain. Physical exercise also boosts neurogenesis by priming the endocannabinoid system – whereas chronic stress has the opposite effect.
Chronic stress, a risk factor for many diseases, has been shown to decrease cannabinoid signaling and neurogenesis in the brain. Alterations in gut microbiota composition following chronic stress are also well documented.
In an effort to shed light on the mechanisms whereby chronic stress induces dysbiosis, researchers at the Pasteur Institute in Paris transplanted gut microbiota from a stressed-out, depressed mouse to naive, unstressed mice. The naive mice that received the fecal transplant became anxious and exhibited depressive behavior, much like the donor mouse.
Furthermore, the dysbiotic fecal transplant from the chronically stressed mouse resulted in reduced neurogenesis in the hippocampus of the receiving mouse. And the reduction in adult hippocampal neurogenesis was associated with a dysregulation of the endocannabinoid system in the recipient rodent’s brain. These changes were not seen in the laboratory animals that received a “control microbiota” transplant from a normal, unstressed mouse.
Probing further, the French scientists discovered that the dysbiotic fecal transplant altered the fatty acid metabolism of the recipient mice, leading to a “systemic decrease in endocannabinoid precursors.”
Specifically, the researchers identified a paucity of diacylglycerol (DAG) compounds, which are an essential building block of 2-AG [2-Arachidonoyglycerol], the most prevalent endocannabinoid in the brain and body.
“In the hippocampus, we observed a decrease in 2-AG” in mice receiving the dysbiotic fecal transplant “but not with control microbiota,” according to the French team, which noted that serum levels of DAG “were inversely correlated with the severity of depressive-like behaviors.” Depleted DAG means less 2-AG, diminished cannabinoid receptor activity, and more intense mood disorders.
The fecal transplant experiment proved that “intestinal microbiota [are] sufficient to initiate a pathological feed-forward loop for depressive disorders by impairing the endocannabinoid system in the hippocampus, a brain region strongly involved in the development of depressive symptoms.”
Lactobacilli & Endocannabinoid Precursors
Medical researchers have identified key changes in the microbiome that contribute to gut dysbiosis. Fecal transfer data involving mice revealed that stress-induced “perturbations of gut bacterial composition were characterized by loss of Lactobacilli, an alteration that was maintained after microbiota transplantation to naive hosts.” Beyond animal models, gut microbiota dysbiosis characterized by low Lactobacilli frequency has also been detected in depressed humans.
The next step was obvious: ascertain whether probiotic treatment with Lactobacilli would ameliorate depressive-like behavior in mice that received a dysbiotic fecal transplant. Sure enough, that did the trick. A Lactobacillus strain was shown to alleviate microbiota-induced anxiety and depression while boosting endocannabinoid brain levels and hippocampal neurogenesis. “We have found that one of the mechanisms by which Lactobacilli promote these effects is through regulation of the bioavailability of endocannabinoid precursors,” the French study asserted.
This finding adds a new dimension to the significant body of scientific literature, which demonstrates that “Lactobacilli treatment, as well as the administration of other probiotics, are beneficial in significantly lowering depression and anxiety scores in patients.”
It’s reasonable to postulate that in addition to probiotic intervention, a diet rich in endocannabinoid precursor compounds, such as arachidonic acid, will raise 2-AG levels in the brain. Milk and meat are rich sources of arachidonic acid, which combines with DAG to create 2-AG. (Sorry, vegans, but that’s what the science says.) 2-AG activates CB1 cannabinoid receptors in the brain, and this produces anxiolytic and anti-depressant effects by modulating hippocampal neurogenesis in people as well as lab animals.
A Key Pathway
Of course, there are other ways to enhance cannabinoid tone. Consuming resin-rich cannabis is a popular, time-tested option. But this was not the focus of the French study, which identified what seems to be a key pathway linking microbiota dysbiosis to mood disorders.
“In sum,” the authors conclude, “our data show that microbiota dysbiosis induced by chronic stress affects lipid metabolism and the generation of endocannabinoids, leading to decreased signaling in the endocannabinoid system and reduced adult neurogenesis in the hippocampus… Because we were able to interrupt this pathological feed-forward loop by administering arachidonic acid or a Lactobacillus probiotic strain, our study supports the concept that dietary or probiotic interventions might be effective levers in the therapeutic arsenal to fight stress-associated depressive syndromes.”
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RICHMOND, VA — Virginia lawmakers gave final approval Saturday to a bill that will legalize cannabis for adult use, but not until 2024, when retail sales of the drug would begin.
With a compromise bill having cleared the state House and Senate, Virginia becomes the first Southern state to vote to legalize marijuana, joining 15 other states and the District of Columbia. The legislation now goes to Democratic Gov. Ralph Northam, who supports legalization.
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The bill was a top priority for Democrats, who framed legalization as a necessary step to end the disparate treatment of people of color under current marijuana laws.
But talks between Democrats in the House and Senate grew tense in recent days as the two chambers wrangled over significant differences between their versions of the legislation.
Negotiations continued into Saturday when, late in the afternoon, details of a compromise agreement were made publicly available.
Possession not legal until Jan. 1, 2024
Under the legislation that passed, possession of up to an ounce (28.3 grams) of marijuana will become legal beginning Jan. 1, 2024, at the same time sales will begin and regulations will go into effect to control the marijuana marketplace in Virginia.
Under a provision Senate Democrats insisted on, the legislation will include a reenactment clause that will require a second vote from the General Assembly, but only on the regulatory framework and criminal penalties for several offenses, including underage use and public consumption of marijuana. A second vote will not be required on legalization.
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The Senate had sought to legalize simple possession this year to immediately end punishments for people with small amounts of marijuana, but House Democrats argued that legalization without a legal market for marijuana could promote the growth of the black market.
Lawmakers last year decriminalized marijuana, making simple possession a civil penalty that can be punished by a fine of no more than $25.
Why the three-year delay?
The three-year delay in legalizing simple possession drew sharp criticism from the American Civil Liberties Union of Virginia, Marijuana Justice, and other racial justice advocacy groups.
“This bill does not advance the cause of equal justice or racial justice in Virginia. It is the product of a closed-door legislative process that has prioritized the interests of recreational marijuana smokers over people and communities of color,” the groups said in a statement before the vote.
But Sen. Adam Ebbin, the chief sponsor of the Senate bill, said the compromise agreement is a good start on legalization.
“It’s been a lot of work to get here, but I would say that we’re on the path to an equitable law allowing responsible adults to use cannabis” he said during the debate.
Groups that opposed legalization entirely have said they are concerned that it could result in an increase in drug-impaired driving crashes and the use of marijuana among youth.