We already know that humans have our own endocannabinoid systems, made to regulate a number of bodily functions with a number of cannabinoid receptors that interact with compounds like THC and CBD in cannabis.
Brain activity patterns and neural circuits regulated by these cannabinoids derived in the brain were not well known, but new research has revealed our bodies may actually release their own cannabinoid molecules in specific circumstances, independent of external cannabinoid use.
According to a new mice study from Northwestern Medicine published in the journal Cell Reports, the brain’s key emotional center, the amygdala, releases its own cannabinoid molecules under stress. When released, these molecules work to decrease incoming stress alarms from the hippocampus, which controls memory and emotions in the brain.
The study results add further evidence to the assertion that the brain contains innate cannabinoid molecules, key to our body’s natural coping response to stress. Further, the study may indicate that impairments to this endogenous (the body’s own) cannabinoid signaling system in the brain could result in higher susceptibility to developing psychiatric disorders related to stress, like depression and post-traumatic stress disorder (PTSD).
Still, further research is needed to determine exactly how these mechanisms work in the human brain, said corresponding study author Dr. Sachin Patel.
The Human Body’s Self-Made Cannabinoids and Understanding Stress
“Stress exposure confers risk for the development or exacerbation of psychiatric disorders: from generalized anxiety and major depression to post-traumatic stress disorder,” authors state in the introduction. “Understanding stress-induced molecular-, cellular-, and circuit-level adaptations could provide critical insight into how stress is translated into affective pathology and may reveal novel therapeutic targets for the treatment of stress-related disorders.”
Scientists at Northwestern Medicine used a new protein sensor that can detect the presence of these cannabinoid molecules in real time at specific brain synapses, which show that specific high-frequency patterns of amygdala activity can generate the molecules. Additionally, the sensor showed that mice brains released these molecules in response to several different types of stress.
Scientists also removed the target of these cannabinoids, the cannabinoid receptor type 1, which resulted in a worsened ability to cope with stress and motivational deficits in mice. After scientists removed the receptor target of the endogenous cannabinoids at hippocampal-amygdala synapses, mice adopted more passive and immobile responses to stress. They also had a lower preference to drink sweetened sucrose water after stress exposure.
Findings Hold Potential in Treating Stress-Related Disorders
“Understanding how the brain adapts to stress at the molecular, cellular and circuit level could provide critical insight into how stress is translated into mood disorders and may reveal novel therapeutic targets for the treatment of stress-related disorders,” according to Patel and Lizzie Gilman, Professor of Psychiatry and Behavioral Sciences and a Northwestern Medicine psychiatrist.
The endocannabinoid system is one of the leading signaling systems identified as a prominent drug-development candidate for stress-related psychiatric disorders, Patel said. This system is an active, complex cell signaling network, involving a combination of endocannabinoids, enzymes and cannabinoid receptors helping to regulate a number of biological functions — like eating, anxiety, learning, memory, reproduction, metabolism, growth and development — through an array of actions across the nervous system.
This hypothesis is crucial in determining where future research guides this continued conversation, Patel said.
“Determining whether increasing levels of endogenous cannabinoids can be used as potential therapeutics for stress-related disorders is a next logical step from this study and our previous work,” Patel said. “There are ongoing clinical trials in this area that may be able to answer this question in the near future.”
The study, published in this month’s issue of Neuropsychopharmacology, looked at the effects of 5-MeO-DMT, a psychedelic “which has been associated with improvement in depression and anxiety symptoms in early phase clinical studies,” the authors said.
5-MeO-DMT is “short for 5-methoxy-N,N-dimethyltryptamine,” and “is a psychedelic substance found naturally in certain species of toads, plants, and seeds,” according to PsyPost.
“It has been used for centuries in traditional shamanic and spiritual practices by indigenous cultures in parts of South America and other regions. When consumed, inhaled, or smoked, 5-MeO-DMT induces intense and often short-lived psychedelic experiences, characterized by profound changes in perception, ego dissolution, and altered sensory perceptions. Users commonly report feelings of unity with the universe and intense spiritual insights,” the outlet explained.
“Neural plasticity” is “defined as the ability of the nervous system to change its activity in response to intrinsic or extrinsic stimuli by reorganizing its structure, functions, or connections after injuries, such as a stroke or traumatic brain injury (TBI),” according to the National Library of Medicine.
The authors of the study noted that “serotonergic psychedelics are gaining increasing interest as potential therapeutics for a range of mental illnesses,” and that compounds “with short-lived subjective effects may be clinically useful because dosing time would be reduced, which may improve patient access.”
But they said that “relatively little is known about the behavioral and neural mechanisms of 5-MeO-DMT, particularly the durability of its long-term effects.”
To that end, the researchers set out to characterize “the effects of 5-MeO-DMT on innate behaviors and dendritic architecture in mice.”
“We showed that 5-MeO-DMT induces a dose-dependent increase in head-twitch response that is shorter in duration than that induced by psilocybin at all doses tested. 5-MeO-DMT also substantially suppresses social ultrasonic vocalizations produced during mating behavior. 5-MeO-DMT produces long-lasting increases in dendritic spine density in the mouse medial frontal cortex that are driven by an elevated rate of spine formation,” the researchers wrote.
But, in contrast to psilocybin, the researchers observed that “5-MeO-DMT did not affect the size of dendritic spines.”
“These data provide insights into the behavioral and neural consequences underlying the action of 5-MeO-DMT and highlight similarities and differences with those of psilocybin,” they wrote.
The research community has only scratched the surface of the potential for psychedelics to treat mental health conditions, but some insights have already been profound.
A book published earlier this year called I Feel Love, written by Rachel Nuwer, highlighted the extraordinary example of a white supremacist who said that his experience with MDMA drove him away from his bigoted ideology.
The white supremacist, identified only as Brendan, described his experience as part of a double-blind trial at the University of Chicago.
“Strangely, at the very bottom of the form, Brendan had written in bold letters: ‘This experience has helped me sort out a debilitating personal issue. Google my name. I now know what I need to do,’” Nuwer wrote in the book.
“MDMA does not seem to be able to magically rid people of prejudice, bigotry, or hate on its own. But some researchers have begun to wonder if it could be an effective tool for pushing people who are already somehow primed to reconsider their ideology toward a new way of seeing things. While MDMA cannot fix societal-level drivers of prejudice and disconnection, on an individual basis it can make a difference. In certain cases, the drug may even be able to help people see through the fog of discrimination and fear that divides so many of us,” Nuwer continued.
Newly published research suggests that psilocybin––the main ingredient in magic mushrooms––could be an effective treatment option for individuals with obsessive-compulsive disorder (OCD).
The study, published last month in Translational Psychiatry, examined the effects of psilocybin on a group of male mice, with the researchers curious how it would influence the rodents’ propensity for burying marbles.
The researchers explained that the “marble burying test” was “performed in transparent cages containing ~4.5 cm fine sawdust.”
“Twenty glass marbles were placed equidistant from each other in a 5 × 4 pattern. The experiment was done under dim light in a quiet room to reduce the influence of anxiety on behavior. The mice were left in the cage with the marbles for a 30-min period, after which the test was terminated by removing the mice,” they said. “A marble was considered buried when two-thirds or more of its size was covered with burying substrate, and the number of buried marbles was counted after 30 min.”
“All mice underwent a pretest without any injection, and the number of marbles buried was counted. Only mice that buried at least 15 marbles were selected to perform the test after drug administration. Eighty percent of pretested mice fulfilled this criterion and were used in the definitive experiment, which took place at least a week following the pretest,” they continued.
Immediately following the marble burying test, the researchers carried out the “open field test” in order “to evaluate the effects of the drug treatments on locomotor activity.”
“The apparatus consisted of a square wooden arena (50 × 50 × 40 cm) with white walls and a black floor. Mice were placed individually in the center of the open field and allowed to freely explore the apparatus for 30 min. A camera was used to monitor movement. The total distance traveled (centimeters) was measured by the Ethovision XT-12 Video Tracking System (Noldus Information Technology BV),” they continued.
Ultimately, the researchers observed that the mice that were “administered psilocybin buried 32.84% fewer marbles over 30 min” than mice that were treated differently.
Bernard Lerer, a psychiatry professor at Hebrew University and an author of the study, said that his team is “very interested in the potential of psychedelic drugs to treat psychiatric disorders, particularly in patients who do not respond well to standard medications.”
“For that reason, we founded the Hadassah BrainLabs Center for Psychedelic Research where we do extensive research on psychedelic drugs. Obsessive-compulsive disorder (OCD) is one of the conditions in which a high proportion of patients do not respond well to standard treatment – at least a third,” Lerer told PsyPost.
“There is preliminary evidence from studies in patients that psilocybin can help patients with OCD. But psilocybin induces a psychedelic trip and this requires special management. We think that psilocybin could help patients with OCD without the trip. How do we achieve this?” Lerer continued. “We have shown in a different study that the medication, buspirone, which is used to treat anxiety, blocks a mouse equivalent of the psychedelic trip and another researcher has shown that it does so in humans. We wanted to find out whether psilocybin would be effective in a mouse model for anti-obsessional effects – marble burying – and whether it would do so even in the presence of buspirone, which blocks the trip.”
As PsyPost explained, the results of Lerer’s study “showed that mice treated with psilocybin buried significantly fewer marbles compared to the control group,” and that the “reduction in marble burying was similar to the effect observed with escitalopram, indicating that psilocybin may have a similar therapeutic effect as antidepressant medication in the treatment of OCD.”
Why are cannabis consumers skinny? Of course, not every connoisseur is slim. Cannabis stimulates appetite, so we tend to consume more calories than the average person. But in general, cannabis connoisseurs are thinner than, say, recreational alcohol drinkers sporting a beer gut. Researchers at the University of California, Irvine, think they’ve discovered why. But, they warn, this “pseudo-health” benefit comes at a price. Is this true? Or is reefer madness sneaking its way into a scientific research paper? What’s the […]
A recent study claimed to show vaped CBD is more harmful than vaped nicotine, and while several news outlets have reported on it, they all missed numerous flaws in the methodology. As a result of numerous confounding variables, there is no way to actually show that any of the harms they found were from CBD, and not one of the many other chemicals in the oil. High Times spoke to several cannabis vaping experts in an effort to nip this story in the bud, and stop it before it can spread further.
Seeing Through the Hazy Cloud of Vaped Variables
Rather than test a range of CBD and nicotine products, Dr. Yasmin Thanavala and her colleagues only looked at one CBD and one nicotine product, using the same Juul device to aerosolize both. The study was done on groups of ten mice, and rather than direct inhalation, the mice were in chambers filled with vapor. Things got off to a rocky start, with Table 1 showing the CBD sample used propylene glycol (PG) and vegetable glycerin (VG) and the nicotine sample used medium chain triglycerides (MCT), yet every other part of the study reported the CBD sample used MCT and the nicotine sample used PG/VG.
Source: “Not All Vaping is the Same: Differential Pulmonary Effects of Vaping Cannabidiol Versus Nicotine”
Dr. Thanavala told High Times “that is an error in Table 1,” confirming the CBD sample used MCT oil, which is banned by five legal cannabis states due to concerns over EVALI-like symptoms. Despite being “aware that ~ 5 states have banned MCT oil as a vape additive,” Dr. Thanavala and her colleagues used a CBD sample with MCT. Paradoxically, given their choice to use samples with MCT, VG, and PG, the researchers noted that “any respiratory toxic effects of vaping could potentially be exacerbated by the presence of other constituents,” like MCT, VG, PG, and terpenes.
Dr. Jeff Raber is the CEO, CVO, and a co-founder of the cannabis analytical laboratory, the Werc Shop, and is an expert on vaped cannabis and common vape additives. “VG/PG blends can be irritating to the vapor pathway,” which is one reason why they are not widely used in the cannabis industry today. Dr. Raber said “the concern with MCT is that it could stay in the lungs and lead to lipid pneumonia,” which is normally caused by “long chain fats” with over 40 carbons in their chain, cautioning “we don’t know the ‘magic number’ on what is safe to inhale.” Dr. Raber is an advocate for using alternatives that are “naturally in the plant” like terpenes or cannabinoids, and thinks terpenes are a great alternative to PG, VG, or MCT.
Dr. Peter Grinspoon is a primary care doctor, cannabis specialist at Harvard Medical School, and author of the upcoming book Seeing Through the Smoke. Dr. Grinspoon echoed some of Dr. Raber’s concerns, “I can’t see the rationale for dissolving them in different solvents, as the solvents themselves could be responsible for some of the findings.” Dale Gieringer Ph.D. is the Director of Cal NORML and a vaporizer research pioneer, who told High Times, “It’s impossible to draw meaningful conclusions about vaped CBD from this study.”
The next thing you see in Table 1 is there are a dozen terpenes in the CBD sample and seven terpenes in the nicotine sample, which all are “confounding variables,” in other words, potential sources for the supposed harm of CBD which were not controlled for by their study. When asked about their attempts to limit the myriad of confounding variables, Dr. Thanavala said, “Our goal was to test commercial pods the way a user would.”
“That’s a fair point to test the pods consumers buy,” said Dr. Raber “but they did not clearly delineate that the CBD was the culprit.” Dr. Raber then fired off some questions for the researchers: “How pure was the CBD? Could it be the combination of that formula with that hardware? How consistent was the hardware made? How was it stored? Did they use a new battery or an old one?” Dr. Raber noted the “time and cost limitation to studies” but would have preferred to see “2-3 different CBD and tobacco samples tested to see if they all behaved the same way.”
When pressed about the variables clouding their data, Dr. Thanavala told High Times, “Our goal was not to dissect out the effects of the individual components.” As that was their goal, one major question remains: Why did they “dissect out” the CBD and blame all the reported harms on it? If they truly wanted their study to demonstrate real-world harms of consumer-available products, they should have reported on that, rather than singling out CBD, which their study was not constructed to control for.
Designing a Better Study
Dr. Raber had an easy solution to control for the numerous confounding variables,“they could have gotten rid of concerns by just filling the cartridges themselves.” That would allow them to test terpene and solvent free samples, limiting confounding variables significantly. As a result, Dr. Raber was “disappointed” and felt they didn’t run “the right blanks and controls.” He also brought up a meta level issue of risks vs. rewards. Any potential harms need to be weighed against the potential benefits in what Dr. Raber called a “medicinal cost benefit risk analysis.” Considering the benefits of cannabis will be one way to improve a follow up study.
Another confounding variable they did not properly control for was the temperature samples were heated to. When asked if they knew how hot their samples got, Dr. Thanavala pointed to their supplemental section, which only had information on the room temperature, not device temperature. A 2021 study found that some “vape pens” heated to temperatures far above the point of combustion (450 °F, 232 °C), in worst cases as high as 633 °F/334 °C when containing liquids or 1000 °C when dry heating the coils. “Temperature is a key parameter but very hard to determine,” said Dr. Raber, because the temperature around the coil is hotter than the vapor stream.“The rate of molecular change doubles every 10 degrees celsius you go up,” said Dr. Raber, “a jump of 50 degrees can lead to a lot of changes.” The study hinted to these concerns saying, “Numerous potential degradation byproducts were detected … suggesting that both products are susceptible to high temperatures.” The CBD sample “may have been more susceptible to thermal degradation compared with nicotine product.”
One final way to improve their methodology is to use more accurate puff topography. “At present there is no information on CBD user topography,” said Dr. Thalanavala, so their study “followed the same puffing protocols for both products.” They did note that “users of cannabis-based vaping products may use these products in a very different way than nicotine vapers.”
Arnaud Dumas DeRauly is the CEO of the Blinc Group, and Chair of the ISO & CEN Vaping Standards Committees, and has researched cannabis user puff topography. DeRauly told High Times that this study used a puffing regime similar to Coresta Recommended Method 81, which “is totally different” than what Blinc’s research showed. In the study, “Animals were exposed … to a total of 20 puffs generated over 1 hour (1 puff every 3 min), 5 days/week.” Blinc’s research found that, while rates were different for U.S. and Canadian cannabis consumers, most needed only 20 puffs per day rather than 20 puffs per hour like the mice. Beyond puff topography, DeRauly was critical of the decision to use the Juul atomizer for both samples, and said “the Juul coil is not compatible with lipids like CBD oil.” Finally, DeRauly pointed out that one of the researchers, Maciej L Goniewicz, received funding from Pfizer and Johnson & Johnson, which the study noted was “outside of this work.”
Source: “Blinc Group and Labstat”
Mice: Nice Animals, Definitely Not Humans
As previously mentioned, this was a study done on small groups of mice, which means the results might not even be generalizable to the broader population of rodents, let alone, humans. While Dr. Thanavala said that ten mice per group is an “adequate group size,” the study’s discussion section said “larger numbers of mice could have further strengthened our study conclusions.” Dr. Raber viewed the findings as “not generalizable” and said, when it came to rodent lungs and humans, “It is a model, it is not an exact replica.” The mouse lung is not just smaller than human lungs, it “is considerably different in structure,” namely, while both mice and humans have five lobes in their right lung, “unlike the human the mouse has only a single left lung.” Research on mouse lungs also shows they lack “mast cells in the peripheral lung” and “extensive pulmonary circulation.”
Another way this study could be improved is to actually do it on humans, which currently is very difficult due to the federal ban on cannabis research with a positive hypothesis. If a researcher sought to prove the claim that vaped CBD is more harmful than nicotine, they could be eligible for funding, but if they wanted to disprove that claim, they would not. While a lot of research is done on mice, in the words of the recently deceased Father of Cannabis Research, Raphael Mechoulam, “Mice are nice animals but they are definitely not humans.”
A bunch of highly trained scientists in China are, right hand to God, sending macaque monkeys and mice into space so they can study how they reproduce in space-like conditions.
“Some studies involving mice and macaques will be carried out to see how they grow or even reproduce in space,” a researcher with the Chinese Academy of Sciences, Zhang Lu, said in a speech Monday. “These experiments will help improve our understanding of an organism’s adaptation to microgravity and other space environments.”
According to an article by the South China Morning Post, the study will take place aboard the Wentian Lab Module on the Chinese Space Station Tiangong. The space station is currently outfitted with small test cabinets intended for fish or snails but they will be reconfigured to house the monkeys, who were presumably still on Earth as of the publication of this article.
Anyone with a pulse is currently wondering the following: is it even possible to make monkeys have sex in space? Have humans had sex in space? If you have sex in space but give birth to the baby on Earth is the baby an earthling or an alien? Would that very same baby be barred from entering the United States under Trump’s immigration laws?
The history here is interesting, actually. Fruit flies were the first living creatures officially sent into space in 1947. Then the Soviets and the U.S. sent a bunch of animals including monkeys, mice, and dogs into orbit in the late 40s and 50s. I’ve seen some reports that mating may have occurred but the Soviets weren’t big on sharing notes so it’s hard to say.
In terms of the present day space monkeys, a Beijing college professor told the SCMP that their large size presents more issues, but studying larger animals is crucial for understanding if humans can create colonies on other planets.
“The astronauts will need to feed them and deal with the waste,” Professor Kehkooi Kee of Tsinghua University told the SCMP. “These experiments will be necessary.”
As far as humans go, NASA has clearly stated that as far as they know, no humans have ever had sex in space. No reports of space sex have ever been confirmed, though it is a surprisingly hotly-debated issue. An American astronaut couple married in secret before joining each other on a mission to the International Space Station in the 90s but the official story is basically that everyone is always too busy doing astronaut shit to think about screwing. I call shenanigans on that but I’ve also never been to space.
Our nation’s top scientists say the physics of space sex would be quite difficult as you’d need a third person, or a lot of velcro, to properly hold you in place. Not only that, the increased radiation levels in space and the effects of zero gravity on blood circulation present equally challenging issues for sexual and reproductive success.
According to a 2014 study: “Relative to other organ systems, the gonads are highly sensitive to radiation exposure. In men and women, temporary infertility is associated with high-dose, acute radiation exposure.”
Many scientists have also proposed that the way low gravity affects blood circulation might make it difficult for men to produce or maintain an erection. All this, coupled with the lack of privacy on a spacecraft has thus far made it very difficult for astronauts to, dare I say, experiment in this department.
Which brings us back to the Chinese launching monkeys into space. If the monkeys can successfully reproduce without any issues, or if we can at least develop an understanding of any issues that do occur, it may be key to understanding if humans can maintain future colonies in space or on other planets.
On September 28, a large team of scientists from different universities published results of the study in the peer-reviewed journal Nature, in which mice diagnosed with depression were given these novel compounds found in LSD.
According to the study, the mice showed signs of decreased depression without showing any physical indicators that they were high on acid. Apparently, when placed into an uncomfortable or life-threatening situation mice with depression will stop struggling to survive quicker than mice without depression. However, depressed mice will struggle for much longer when given substances like ketamine, psilocybin, and LSD.
“These molecules are potential leads for the development of therapeutics against disorders that have withstood long-term treatment including depression, anxiety, and post traumatic stress disorder,” a portion of the study said.
You might be asking yourself the same question I asked, how can anyone tell if a mouse is high? According to the paper, mice on LSD have a signature type of twitch they do with their nose so the scientists can tell if the mouse feels anything. Thus, if you ever see a mouse twitching its nose it could mean he’s tripping his cute little mouse balls off and it would be polite to offer him some water or a granola bar.
In all seriousness, the study represents a potentially monumental breakthrough in mental health treatment for millions of people who suffer from depression but are afraid of, or otherwise unable to handle a psychedelic trip. One of the authors of the study told High Times that the particular compounds used in the study will likely not make it to clinical trials but similar compounds potentially could.
“The particular compounds in the paper are not clinical candidates,” said Dr. Bryan Roth, a professor of pharmacology at UNC Chapel Hill School of Medicine. “As you might not appreciate, the compounds in the paper were discovered some time ago and since then we have evaluated many hundreds of additional compounds to find a potential candidate.”
Regardless of how early in the game it may be, this discovery begs the question of exactly where the therapeutic benefits of psychedelics are found, as a lot of people (myself not included) would likely skip the intense experience if it wasn’t necessarily needed in order for the patient to feel better.
“With hallucination remaining a liability, A goal in this area is the development of drug leads that retain the antidepressant and anxiolytic properties without psychedelic activity,” the study said. “There is much interest in finding agonists that retain antidepressive actions without the hallucinogenic effects of classic psychedelics such as LSD and psilocin.”
“Society would like a molecule that you can get prescribed and just take and you don’t need a guided tour for your trip,” another author of the study, Professor Brian Shoichet, told NPR.
The scientists and doctors involved in the study generally expressed optimism in their reporting that since the antidepressive benefits of drugs like LSD and psilocybin kick in almost immediately and can often last a year or more, these novel compounds may carry the same benefit without the wild ride.
Tripless therapeutics are not a brand new idea, however. A similar study in 2020 had some reported success with derivatives of ibogaine which appeared to produce the same antidepressive properties ibogaine is known for in mice without the presence of any physical symptoms that would indicate the mice were tripping.
Good news America, you may one day be able to easily experience relief from countless ailments through the power of non-psychoactive psychedelics. For those of you in more of a hurry, regular acid is worth the trouble, I assure you.
