Marijuana use while pregnant boosts risk of children's sleep problems

Negative effects seen as much as a decade later

July 2, 2020

Science Daily/University of Colorado at Boulder

As many as 7% of moms-to-be use marijuana while pregnant, and that number is rising fast as more use it to quell morning sickness. But new research suggests such use could have a lasting impact on the fetal brain, influencing children's sleep for as much as a decade.

Use marijuana while pregnant, and your child is more likely to suffer sleep problems as much as a decade later, according to a new University of Colorado Boulder study of nearly 12,000 youth.

Published in Sleep Health: The Journal of The National Sleep Foundation, the paper is the latest to link prenatal cannabis use to developmental problems in children and the first to suggest it may impact sleep cycles long-term.

It comes at a time when -- while the number of pregnant women drinking alcohol and smoking cigarettes has declined in the United States -- It has risen to 7% of all pregnant women as legalization spreads and more dispensaries recommend it for morning sickness.

"As a society, it took us a while to understand that smoking and drinking alcohol are not advisable during pregnancy, but it is now seen as common sense," said senior author John Hewitt, director of the Institute for Behavioral Genetics at CU Boulder. "Studies like this suggest that it is prudent to extend that common sense advice to cannabis, even if use is now legal."

A landmark study

For the study, Hewitt and lead author Evan Winiger analyzed baseline data from the landmark Adolescent Brain and Cognitive Development (ABCD) study, which is following 11,875 youth from age 9 or 10 into early adulthood.

As part of an exhaustive questionnaire upon intake, participants' mothers were asked if they had ever used marijuana while pregnant and how frequently. (The study did not assess whether they used edibles or smoked pot). The mothers were also asked to fill out a survey regarding their child's sleep patterns, assessing 26 different items ranging from how easily they fell asleep and how long they slept to whether they snored or woke up frequently in the night and how sleepy they were during the day.

About 700 moms reported using marijuana while pregnant. Of those, 184 used it daily and 262 used twice or more daily.

After controlling for a host of other factors, including the mother's education, parent marital status and family income and race, a clear pattern emerged.

"Mothers who said they had used cannabis while pregnant were significantly more likely to report their children having clinical sleep problems," said Winiger, a graduate student in the Department of Psychology and Neuroscience.

Those who used marijuana frequently were more likely to report somnolence symptoms (symptoms of excess sleepiness) in their children, such as trouble waking in the morning and being excessively tired during the day.

The authors note that, while their sample size is large, the study has some limitations.

"We are asking mothers to remember if they smoked marijuana 10 years ago and to admit to a behavior that is frowned upon," said Winiger, suggesting actual rates of prenatal use may have been higher.

While the study doesn't prove that using cannabis while pregnant causes sleep problems, it builds on a small but growing body of evidence pointing to a link.

For instance, one small study found that children who had been exposed to marijuana in-utero woke up more in the night and had lower sleep quality at age 3. Another found that prenatal cannabis use impacted sleep in infancy.

And, in other previous work, Hewitt, Winiger and colleagues found that teenagers who frequently smoked marijuana were more likely to develop insomnia in adulthood.

The fetal brain on THC

Researchers aren't sure exactly how cannabis exposure during vulnerable developmental times might shape future sleep. But studies in animals suggest that THC and other so-called cannabinoids, the active ingredients in pot, attach to CB1 receptors in the developing brain, influencing regions that regulate sleep. The ABCD study, which is taking frequent brain scans of participants as they age, should provide more answers, they said.

Meantime, mothers-to-be should be wary of dispensaries billing weed as an antidote for morning sickness. According to CU research, about 70% of Colorado dispensaries recommend it for that use. But mounting evidence points to potential harms, including low birth weight and later cognitive problems. With marijuana on the market today including far higher THC levels than it did a decade ago, it's impacts on the fetal brain are likely more profound than they once were.

"This study is one more example of why pregnant women are advised to avoid substance use, including cannabis," said Hewitt. "For their children, it could have long-term consequences."

https://www.sciencedaily.com/releases/2020/07/200702153700.htm

Curbing your enthusiasm for overeating

Mouse study focuses on cannabis-like molecules that augment feeding behavior

June 11, 2019

Science Daily/University of California - Riverside

Signals between our gut and brain control how and when we eat food. But how the molecular mechanisms involved in this signaling are affected when we eat a high-energy diet and how they contribute to obesity are not well understood.

Using a mouse model, a research team led by a biomedical scientist at the University of California, Riverside, has found that overactive endocannabinoid signaling in the gut drives overeating in diet-induced obesity by blocking gut-brain satiation signaling.

Endocannabinoids are cannabis-like molecules made naturally by the body to regulate several processes: immune, behavioral, and neuronal. As with cannabis, endocannabinoids can enhance feeding behavior.

The researchers detected high activity of endocannabinoids at cannabinoid CB1 receptors in the gut of mice that were fed a high-fat and sugar -- or Western -- diet for 60 days. This overactivity, they found, prevented the food-induced secretion of the satiation peptide cholecystokinin, a short chain of amino acids whose function is to inhibit eating. This resulted in the mice overeating. Cannabinoid CB1 receptors and cholecystokinin are present in all mammals, including humans.

Study results appear in the journal Frontiers in Physiology, an open-access journal.

"If drugs could be developed to target these cannabinoid receptors so that the release of satiation peptides is not inhibited during excessive eating, we would be a step closer to addressing the prevalence of obesity that affects millions of people in the country and around the world," said Nicholas V. DiPatrizio, an assistant professor of biomedical sciences in the UCR School of Medicine who led the research team.

DiPatrizio explained that previous research by his group on a rat model showed that oral exposure to dietary fats stimulates production of the body's endocannabinoids in the gut, which is critical for the further intake of high-fat foods. Other researchers, he said, have found that levels of endocannabinoids in humans increased in blood just prior to and after eating a palatable high-energy food, and are elevated in obese humans.

"Research in humans has shown that eating associated with a palatable diet led to an increase in endocannabinoids -- but whether or not endocannabinoids control the release of satiation peptides is yet to be determined," said Donovan A. Argueta, a doctoral student in DiPatrizio's lab and the first author of the research paper.

Previous attempts at targeting the cannabinoid CB1 receptors with drugs such as Rimonabant -- a CB1 receptor blocker -- failed due to psychiatric side effects. However, the DiPatrizio lab's current study suggests it is possible to target only the cannabinoid receptors in the gut for therapeutic benefits in obesity, greatly reducing the negative side effects.

The research team plans to work on getting a deeper understanding of how CB1 receptor activity is linked to cholecystokinin.

"We would also like to get a better understanding of how specific components of the Western diet -- fat and sucrose -- lead to the dysregulation of the endocannabinoid system and gut-brain signaling," DiPatrizio said. "We also plan to study how endocannabinoids control the release of other molecules in the intestine that influence metabolism."

https://www.sciencedaily.com/releases/2019/06/190611081915.htm

Bodyguard for the brain: Researchers identify mechanism that seems to protect brain from aging

July 13, 2011

Science Daily/University of Bonn

Researchers from the Universities of Bonn and Mainz have discovered a mechanism that seems to protect the brain from aging. In experiments with mice, they switched off the cannabinoid-1 receptor. As a consequence, the animals showed signs of degeneration -- as seen in people with dementia -- much faster.

The research results are presented in a current issue of the Proceedings of the National Academy of Sciences (PNAS).

Humans are getting older and older, and the number of people with dementia is increasing. The factors controlling degeneration of the brain are still mostly unknown. However, researchers assume that factors such as stress, accumulation of toxic waste products as well as inflammation accelerate aging. But, vice versa, there are also mechanisms that can -- like a bodyguard -- protect the brain from degenerating, or repair defective structures.

Researchers from the Universities of Bonn and Mainz have now discovered a hitherto unknown function of the cannabinoid-1 receptor (CB1). A receptor is a protein that can bind to other substances, triggering a chain of signals. Cannabinoids such as THC -- the active agent in cannabis sativa -- and endocannabinoids formed by the body bind to the CB1 receptors. The existence of this receptor is also the reason for the intoxicating effect of hashish and marijuana.

Not only does the CB1 receptor have an addictive potential, but it also plays a role in the degeneration of the brain. "If we switch off the receptor using gene technology, mouse brains age much faster," said Önder Albayram, principal author of the publication and a doctoral student on the team of Professor Dr. Andreas Zimmer from the Institut für Molekulare Psychiatrie at the University of Bonn. "This means that the CB1 signal system has a protective effect for nerve cells."

Mice prove their brain power in a pool

The researchers studied mice in different age categories -- young six week old animals, middle-aged ones at five months, and those of an advanced age at 12 months. The animals had to master various tasks -- first, they had to find a submerged platform in the pool. Once the mice knew its location, the platform was moved, and the animals had to find it again. This was how the researchers tested how well the rodents learned and remembered.

The animals in which the CB1 receptor had been switched off (the knock-out mice) clearly differed from their kind. "The knock-out mice showed clearly diminished learning and memory capacity," said Privatdozent Dr. Andras Bilkei-Gorzo from Professor Zimmer's team, who led the study. So, animals that did not have the receptor were less successful in their search for the platform. "In addition, they showed a clear loss of nerve cells in the hippocampus," he explained further. This part of the brain is the central area for forming and storing information. In addition, the researchers found inflammation processes in the brain. As the mice advanced in age, the degenerative processes became increasingly noticeable.

Amazing parallels with the human brain

The animals with the intact CB1 receptor, to the contrary, did clearly better with regard to their learning and memory capabilities, as well as the health of their nerve cells. "The root cause of aging is one of the secrets of life," commented Albayram. This study has begun to open the door to solving this enigma. The processes in the mouse brains have a surprising number of parallels with age-related changes in human brains. So, the endocannabinoid system may also present a protective mechanism in the aging of the human brain.

The principal author cautioned, "This will require additional research." The scientists would like to better understand the mechanism by which CB1 receptors protect the brain from inflammation processes. And based on these signal chains, it might then be possible to develop substances for new therapies.

https://www.sciencedaily.com/releases/2011/07/110712093856.htm

Chronic marijuana smoking affects brain chemistry, molecular imaging shows

June 13, 2011

Science Daily/Society of Nuclear Medicine

Definitive proof of an adverse effect of chronic marijuana use revealed at SNM's 58th Annual Meeting could lead to potential drug treatments and aid other research involved in cannabinoid receptors, a neurotransmission system receiving a lot of attention. Scientists used molecular imaging to visualize changes in the brains of heavy marijuana smokers versus non-smokers and found that abuse of the drug led to a decreased number of cannabinoid CB1 receptors, which are involved in not just pleasure, appetite and pain tolerance but a host of other psychological and physiological functions of the body.

"Addictions are a major medical and socioeconomic problem," says Jussi Hirvonen, MD, PhD, lead author of the collaborative study between the National Institute of Mental Health and National Institute on Drug Abuse, Bethesda, Md. "Unfortunately, we do not fully understand the neurobiological mechanisms involved in addiction. With this study, we were able to show for the first time that people who abuse cannabis have abnormalities of the cannabinoid receptors in the brain. This information may prove critical for the development of novel treatments for cannabis abuse. Furthermore, this research shows that the decreased receptors in people who abuse cannabis return to normal when they stop smoking the drug."

According to the National Institute on Drug Abuse, marijuana is the number-one illicit drug of choice in America. The psychoactive chemical in marijuana, or cannabis, is delta-9-tetrahydrocannabinol (THC), which binds to numerous cannabinoid receptors in the brain and throughout the body when smoked or ingested, producing a distinctive high. Cannabinoid receptors in the brain influence a range of mental states and actions, including pleasure, concentration, perception of time and memory, sensory perception, and coordination of movement. There are also cannabinoid receptors throughout the body involved in a wide range of functions of the digestive, cardiovascular, respiratory and other systems of the body. Currently two subtypes of cannabinoid receptors are known, CB1 and CB2, the former being involved mostly in functions of the central nervous system and the latter more in functions of the immune system and in stem cells of the circulatory system.

For this study, researchers recruited 30 chronic daily cannabis smokers who were then monitored at a closed inpatient facility for approximately four weeks. The subjects were imaged using positron emission tomography (PET), which provides information about physiological processes in the body. Subjects were injected with a radioligand, 18F-FMPEP-d2, which is a combination of a radioactive fluorine isotope and a neurotransmitter analog that binds with CB1 brain receptors.

Results of the study show that receptor number was decreased about 20 percent in brains of cannabis smokers when compared to healthy control subjects with limited exposure to cannabis during their lifetime. These changes were found to have a correlation with the number of years subjects had smoked. Of the original 30 cannabis smokers, 14 of the subjects underwent a second PET scan after about a month of abstinence. There was a marked increase in receptor activity in those areas that had been decreased at the outset of the study, an indication that while chronic cannabis smoking causes downregulation of CB1 receptors, the damage is reversible with abstinence.

Information gleaned from this and future studies may help other research exploring the role of PET imaging of CB1 receptors -- not just for drug use, but also for a range of human diseases, including metabolic disease and cancer.

https://www.sciencedaily.com/releases/2011/06/110606131705.htm

Study overturns decade-old findings in neurobiology: Research suggests potential target for drugs to combat alcohol addiction

May 13, 2010

Science Daily/Scripps Research Institute

In findings that should finally put to rest a decade of controversy in the field of neurobiology, a team at The Scripps Research Institute has found decisive evidence that a specific neurotransmitter system -- the endocannabinoid system -- is active in a brain region known to play a key role in the processing of memory, emotional reactions, and addiction formation. The new study also shows that this system can dampen the effects of alcohol, suggesting an avenue for the development of drugs to combat alcohol addiction.

The research was published in the journal Neuropsychopharmacology on May 12.

"This study will change a lot in the field," said Scripps Research Associate Professor Marisa Roberto, who was first author of the paper. "I'm confident it will have a big impact."

"This is very new," said Paul Schweitzer, associate professor of the neurobiology of addiction at Scripps Research and corresponding author of the paper. "It is the first time a study has shown a direct cellular interaction between endocannabinoids and alcohol in the brain."

The Missing Link?

The new research overturns the conclusions of a paper published by a European group in the Journal of Neuroscience in 2001. This paper claimed that endocannabinoid receptors, in particular the most common type called CB1, did not exist in the brain region called the central amygdala.

"Yet CB1 receptors are very abundant," said Schweitzer. "They are almost everywhere in the brain and there are lots of them. The endocannabinoid system acts on appetite, mood, memory -- and addiction. Addiction is why we started to study it in the central amygdala."

The Scripps Research scientists began to suspect that the 2001 study, whose conclusions had been widely accepted in the field, might have missed the CB1 receptors in the brain's central amygdala. Indirect evidence from a number of subsequent studies -- including one by Scripps Research Associate Professor Loren "Larry" Parsons -- had suggested that the endocannabinoid system (and by implication its receptors) were indeed active in this brain region.

The Scripps Research team decided to take a fresh look at the whole question, and set out to conduct a new physiological study specifically looking for signs of the missing CB1 receptors in the central amygdala.

"There wasn't much physiology done before this," said Roberto. "There were a lot of behavioral studies, but very few on physiology and, aside from the 2001 study, none on the physiology in the central amygdala -- this brain region that is so important for drugs of abuse."

Back on Track

Using electrophysiological techniques in brain slices to test the response of brain cells from the rat central amygdala, the scientists indeed found compelling evidence that CB1 receptors were active there.

The cells responded to a substance (agonist) mimicking the action of endocannabinoids in the brain. Up to a point, the more of the agonist the scientists applied, the bigger the effect. An inhibitor (antagonist) reversed this response.

"We saw a big and consistent physiological effect," said Roberto. "It was beautiful. The receptor had to be there or otherwise it wouldn't have worked."

With this major milestone achieved, the researchers extended their investigation to their primary area of interest -- the brain's response to alcohol. Alcohol abuse can lead to devastating consequences for individuals and families. It is also associated with direct and indirect public health costs estimated to be in the hundreds of billions of dollars yearly in the United States alone.

To learn more about the effect of alcohol on the biology of the brain, the scientists focused on the transmission of one particular neurotransmitter called gamma amino butyric acid (GABA). GABA is the main inhibitory neurotransmitter in the brain, and neurons in every brain region use GABA to fine-tune signaling throughout the nervous system. Previous studies by the Scripps Research scientists indicated that GABA plays a critical role in alcohol dependence and other addictions.

"We knew ethanol in these neurons increase GABA transmission, and that cannabinoids decrease GABA transmission," said Roberto. "So the question was what happens if we activate the cannabinoid system and we put ethanol on it."

When the scientists first applied the CB1 agonist on cells from the central amygdala, it decreased GABA transmission; when the scientists proceeded to put ethanol on top, the effect of ethanol was abolished. When the team reversed the order of application, GABA transmission first went up with the application of ethanol, then down with the application of the CB1 agonist.

"Alcohol and CB1 agonists have opposing effects on GABA," summarized Schweitzer. "Our feeling is that since the CB1 system is so widely expressed, there's a big role there in dampening the effect of alcohol."

While the team's research points to the endocannibinoid system as a potential target in the development of drugs to treat alcoholism, Schweitzer notes there are still many questions to be answered: Do CB1 agonists work the same way in brains that have become addicted to alcohol? What is the mechanism for this action? Can the effects of CB1 on alcohol metabolism be separated from its many other effects on mood, appetite, and memory?

Schweitzer also cautions against equating CB1 agonists and cannabis in interpreting the study's results. "This study does not have to do with marijuana, but the endocannabinoid system," he said. "On this level of analysis, the two don't have much in common."

The work was supported by National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health.

https://www.sciencedaily.com/releases/2010/05/100512151549.htm

Cannabinoid-blocking Weight-loss Drug Might Fight Alcoholic Fatty Liver

March 6, 2008

Science Daily/Cell Press

The cannabinoid receptors best known for delivering the psychological effects of marijuana also explain the connection between chronic alcohol use and a buildup of fat in the liver, according to a report in the March issue of Cell Metabolism. Alcoholic fatty liver can progress to more serious disease, and alcoholism is a leading cause of liver disease in Western societies.

The researchers also found that mice treated with rimonabant, a drug designed to block cannabinoid receptors, become resistant to alcohol's fat-building effects in the liver. Rimonabant is now in use for weight loss in several European countries but has not received FDA approval for use in the United States.

"What makes these findings particularly interesting from our perspective is that they may have practical implications," said George Kunos of the National Institute on Alcohol Abuse and Alcoholism. "Treatment of animals with a [cannabinoid receptor] antagonist largely prevented alcohol's effect. It suggests that the development of fatty liver in those who use alcohol could be interfered with, or perhaps reversed, with such treatment."

In addition to alcoholism, obesity can also lead to the development of fatty liver disease. Scientists have shown that natural cannabinoids, so-called endocannabinoids, and CB1 cannabinoid receptors in the livers of mice are increased when animals are fed a high-fat diet. Studies have also shown that mice lacking CB1 receptors and mice treated with drugs that block these receptors are protected from obesity and fatty liver.

"Similar to high-fat diet, chronic ethanol exposure can increase endocannabinoid levels, at least in the brain," the researchers said. The apparent similarities between diet- and ethanol-induced changes in fat metabolism and endocannabinoid activity in the liver suggested that endocannabinoids might also be a culprit in ethanol-induced fatty liver.

Kunos's team now shows that mice fed a low-fat diet and ethanol show an increase in the gene encoding the CB1 receptor and in liver levels of one endocannabinoid, 2-arachidonoylglycerol (2-AG). These mice also developed fatty livers. In contrast, the livers of mice fed the ethanol diet plus rimonabant did not differ in fat content from those of mice fed a control diet. Similarly, mice lacking CB1 receptors, either throughout the body or only in the liver, gained protection from alcoholic fatty liver.

"Although alcoholic fatty liver is reversible in its early stages by cessation of drinking, this is often not feasible," the researchers concluded. "The present findings suggest that treatment with a CB1 antagonist may slow the development of fatty liver and thus prevent or delay its progression to more severe and irreversible forms of liver disease."

Drugs designed to selectively act on CB1 receptors found outside of the brain might fight fatty liver with less risk of adverse side effects, including anxiety and depression, they added. "Rimonabant has recently been introduced in Europe for the treatment of visceral obesity and the metabolic syndrome, which themselves are known risk factors for [liver disease]. Clinical trials testing the effectiveness of CB1 receptor blockers in the treatment of both alcoholic and nonalcoholic fatty liver and their more severe sequelae may be warranted."

https://www.sciencedaily.com/releases/2008/03/080304124345.htm

Mouse Model Links Alcohol Intake to Marijuana-like Brain Compounds

January 21, 2003

Science Daily/NIH/National Institute On Alcohol Abuse And Alcoholism

Brain molecules similar to the active compound in marijuana help to regulate alcohol consumption, according to new reports by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland, and a separate NIAAA-supported group at several New York state research institutions.

In studies conducted with a strain of mice known to have a high preference for alcohol, the scientists found greatly reduced alcohol intake in mice specially bred to lack CB1, the brain receptor for innate marijuana-like substances known as endocannabinoids. The effect was age dependent, the Bethesda group found. The New York scientists showed that the endocannabinoid system activates a brain region known as the nucleus accumbens, which plays a major role in mediating the rewarding effects of alcohol. Both groups had shown that alcohol intake among normal mice of the same alcohol-preferring strain could be reduced by treating the animals with a drug that blocks CB1 receptors in the brain.

The new reports appear in the early online versions of the Proceedings of the National Academy of Sciences, Volume 20, Number 3, at www.pnas.org and the Journal of Neurochemistry, Volume 24, Number 4, at www.blackwell-synergy.com/servlet/useragent?func=showIssues&code=jnc in the week beginning January 20, 2003 (specific dates to be determined).

"These are important findings," notes NIAAA Director Ting-Kai Li, M.D. "Implicating yet another neurochemical mechanism in alcohol consumption opens another potential avenue for the development of new pharmacologic agents to prevent and treat alcohol problems."

The brain's multiple communication pathways employ a wide variety of signaling molecules known as neurotransmitters to relay messages from one brain cell to another. Researchers have found that alcohol affects numerous neurotransmitters and that a variety of brain pathways are involved in alcohol abuse and dependence. Determining precisely how alcohol interacts with brain cells and affects brain chemistry is an ongoing focus of research. Knowledge gained through this research helps scientists develop drugs to diminish the desire to consume alcohol and to counteract alcohol's effects.

Since their discovery in the early 1990's, endocannabinoids and endocannabinoid receptors have been studied intensely by alcohol and drug abuse researchers. Recent animal studies have suggested that the so-called "endocannabinoid system" is involved in some of the pharmacologic effects of alcohol and in drinking behavior.

In one of the current studies, researchers led by George Kunos, M.D., Ph.D., Scientific Director of NIAAA's Division of Intramural Biological and Clinical Research, found that, among the normal, alcohol-preferring mice–that is, those with intact CB1 receptors–the animals' appetite for both alcohol and food decreased with age. This occurred even though levels of endocannabinoids and the density of CB1 receptors were found to be similar in the brains of young and old mice.

"Although unexpected," says Dr. Kunos, "the observed age-dependent decline in alcohol preference in mice parallels observations in humans, in that only some teenage binge drinkers become alcoholics as adults, and that the onset of alcoholism declines with age."

The researchers found a possible explanation for this phenomenon by comparing the efficiency of the signal sent by the CB1 receptors in different regions of the brain in young and old mice. In old mice, they found diminished CB1 signaling in an area known as the limbic forebrain. The part of the limbic forebrain known as the nucleus accumbens plays a major role in mediating the rewarding properties of alcohol and cannabinoids and also is thought to help regulate appetite. The nucleus accumbens exerts its effects through the release of the neurotransmitter dopamine. Alcohol ingestion typically elicits a robust release of dopamine from the nucleus accumbens.

The second report by NIAAA-supported scientists led by Basalingappa L. Hungund, Ph.D., of the New York State Psychiatric Institute and Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York, complements the findings of the Kunos research team. Dr. Hungund and colleagues found that, in addition to showing a dramatic reduction in alcohol intake, alcohol-preferring mice that lack CB1 receptors release no dopamine from the nucleus accumbens after they drink alcohol. In mice with intact CB1 receptors, the researchers were able to abolish alcohol-induced release of dopamine from the nucleus accumbens by treating the animals with a drug that blocks CB1 receptors.

"Our results," says coauthor Balapal Basavarajappa, Ph.D., "clearly suggest that the CB1 receptor system is involved in ethanol-induced dopamine release in the nucleus accumbens and indicate that activation of the limbic dopamine system is required for the reinforcing effects of alcohol. They further suggest an interaction between the cannabinoidergic and dopaminergic systems in the reinforcing properties of drugs of abuse, including alcohol."

"Taken together," adds Dr. Kunos, "these findings provide unequivocal evidence for the role of endocannabinoids and CB1 in alcohol drinking behavior in rodents, and suggest that the CB1 receptor may be a promising pharmacotherapy target."

The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA disseminates research findings to scientists, practitioners, policy makers, and the general public.

https://www.sciencedaily.com/releases/2003/01/030121080758.htm

Light-sensitive THC: Intoxicatingly light-sensitive

January 10, 2018

Science Daily/ETH Zurich

Chemists have synthesized several variants of THC, the active ingredient in cannabis. Its structure can be altered with light, and the researchers have used this to create a new tool that can be used to more effectively study the body's own cannabinoid system.

When many people hear the abbreviation THC (tetrahydrocannabinol), they immediately think of smoking marijuana and intoxication. But the substance is also of interest to medicine -- when given to people suffering from serious illnesses, it relieves muscle cramps, pain, loss of appetite and nausea.

THC works by binding to the corresponding cannabinoid-1 (CB1) receptors, which are located in the cell membrane and are present in large numbers in the central and peripheral nervous system. CB1 receptors play a major role in memory, motor coordination, mood and cognitive processes.

Receptors key to signal transmission

When a THC molecule binds to one of these CB1 receptors, it changes form, triggering a cascade of various signals inside the cell. However, it is still hard to study CB1 receptors and their manifold functions, because cannabinoids such as THC are highly lipophilic, so they frequently embed themselves in the membranes made of fat molecules in an uncontrolled manner. To be able to use THC or variants of it more precisely for pharmaceutical and medical applications, it is therefore important to gain a better understanding of CB1 receptors.

To study the diverse interactions between CB1 receptors and cannabinoids, a group of chemists headed by ETH professor Erick Carreira synthesised THC molecules. Their structure can be altered with light. The researchers published their findings in the latest issue of the Journal of the American Chemical Society.

Light-sensitive THC derivatives

The scientists synthesised four variants, or derivatives, of THC by attaching a light-sensitive "antenna" to the THC molecule. This antenna makes it possible to use light of a specific wavelength to precisely manipulate the altered molecule. Ultraviolet light changes the spatial structure of the antenna, and this change can be reversed again with blue light.

The researchers tested two of these derivatives in a living cell culture. The derivatives docked with CB1 receptors in the same way as naturally occurring THC. When the researchers irradiated the THC derivative with ultraviolet light, its structure altered just as the researchers expected, consequently activating the CB1 receptor. This triggers reactions such as the opening of the potassium ion channels located in the cell membrane, which causes potassium ions to flow out of the cell. The researchers were able to measure this with an electrode inserted into the cell.

When irradiated with blue light, the THC derivative returned to its original form, disabling the CB1 receptor as a result. The ion channels closed and the flow of potassium stopped. The researchers were able to activate and deactivate these processes using the corresponding coloured pulses of light.

A basis for light-controlled applications

"This work is our successful proof of principle: light-sensitive THC variants are a suitable tool for controlling and influencing CB1 receptors," says Michael Schafroth, a doctoral student with ETH professor Carreira and major contributor to the study. He added that they have now laid an important foundation for further projects that are already in progress; for example, another doctoral student in Carreira's group, Roman Sarott, is working on synthesising additional THC derivatives that react to long-wavelength red light. "Red light penetrates deeper into tissue than blue light," says Sarott. "If we want to study CB1 receptors in a living organism, we need molecules that are sensitive to red light."

In addition to the researchers from Carreira's group, leading scientists from New York University (NYU), the Indiana University Bloomington (IUB) and the University of Southern California (USC) as well as the Ludwig-Maximilian University in Munich were involved in the interdisciplinary project. The biological experiments were conducted by James Frank and Dirk Trauner.

A starting point for medicine

Many cultures have long known of the intoxicating and therapeutic effect of THC. The identification of THC eventually led to the discovery of the endocannabinoid system, which involves the body's native as well as exogenous substances in the cannabinoids class as well as their receptors in the body.

The pharmaceutical industry is also interested in gaining a better understanding of the endocannabinoid system so that it can better use specific components for pharmaceutical purposes. The system is considered a possible starting point for treatments for addiction, obesity, depression and even Alzheimer's and Parkinson's.

https://www.sciencedaily.com/releases/2018/01/180110112944.htm

An alternative to medical marijuana for pain?

March 4, 2015

Science Daily/Elsevier

Medical marijuana is proliferating across the country due to the ability of cannabis ingestion to treat important clinical problems such as chronic pain. However, negative side effects and the development of tolerance limit the widespread therapeutic use of Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive ingredient in cannabis.

THC's side effects are produced via its actions at cannabinoid CB1 receptors in the brain. Thus, scientists theorized that an agent with similar mechanistic actions, but that activate CB2 receptors instead, may eliminate the unwanted side effects while maintaining an equivalent level of efficacy.

Dr. Andrea Hohmann and her colleagues at Indiana University tested this strategy and found that, unlike Δ9-THC, repeated dosing with the cannabinoid CB2 agonist AM1710 suppresses chemotherapy-induced pain in mice without producing tolerance, physical withdrawal, motor dysfunction, or hypothermia. Moreover, the therapeutic effects of AM1710 were preserved in mice lacking CB1 receptors but absent in mice lacking CB2 receptors.

Their findings are reported in the current issue of Biological Psychiatry.

"Our study is important because it demonstrates beyond doubt that activation of cannabinoid CB2 receptors suppresses neuropathic pain without producing signs of physical dependence (i.e., a withdrawal syndrome) or other unwanted side effects associated with activation of CB1 receptors in the brain," said Hohmann.

Their studies used animals that were treated with a chemotherapeutic agent (paclitaxel) to produce pain. When animals were given AM1710, a CB2 agonist, its pain-suppressive effects were fully preserved and its therapeutic effects were maintained even after repeated dosing.

Alternatively, and as expected, when animals were given Δ9-THC, they developed complete tolerance to the pain-suppressing effects of THC and with repeated dosing, THC was no longer effective in suppressing neuropathic pain.

When the THC-treated animals were challenged with a drug that blocks CB1 receptors in the brain, the animals showed a prominent withdrawal syndrome, indicating signs of physical dependence following removal of THC. Strikingly, this was not the case with the CB2 agonist; blocking either CB1 or CB2 receptors produced no signs of withdrawal in animals treated chronically with the CB2 agonist.

Hohmann added, "We think our data suggests that CB2 receptors are an important target for suppressing chronic pain without unwanted side effects (e.g. psychoactivity, addiction)."

"It is important to know whether the benefits of cannabis ingestion for pain could be attributed in large part to the stimulation of CB2 receptors," commented Dr. John Krystal, Editor of Biological Psychiatry. "CB2 agonists, in theory, would present less risk regarding addiction and intoxication than the ingestion of cannabis or THC."

More work will be necessary before CB2 receptor agonists could be prescribed for use in humans, but for now, these data support the therapeutic potential of CB2 agonists for managing pain without the adverse effects associated with cannabis.

https://www.sciencedaily.com/releases/2015/03/150304075336.htm