Psychedelics improve mental health, cognition in special ops veterans

Chart review reports effects of 2-drug treatment at Mexico clinic

October 5, 2023

Science Daily/Ohio State University

One treatment each of two psychedelic drugs lowered depression and anxiety and improved cognitive functioning in a sample of U.S. special operations forces veterans who sought care at a clinic in Mexico, according to a new analysis of the participants' charts.

The treatment included a combination of ibogaine hydrochloride, derived from the West African shrub iboga, and 5-MeO-DMT, a psychedelic substance secreted by the Colorado River toad. Both are designated as Schedule I drugs under the U.S. Controlled Substances Act.

In addition to relieving symptoms of post-traumatic stress disorder (PTSD), the combined treatment also alleviated cognitive impairment linked to traumatic brain injury -- which stood out to researchers from The Ohio State University who led the chart-review analysis. Many special operations forces veterans seeking treatment for complex psychiatric symptoms do not respond to more traditional therapies.

"What sets this group apart from some other veterans and civilians is that often, they are exposed to repeated traumatic events as a routine part of their jobs. This build-up of exposure to these difficulties seems to produce a cluster of challenges that include traumatic brain injury, which we know in and of itself predisposes people to mental health problems," said lead author Alan Davis, associate professor and director of the Center for Psychedelic Drug Research and Education (CPDRE) in Ohio State's College of Social Work.

"So the fact that we saw that there were improvements in cognitive functioning linked to brain injury were probably the most striking results, because that's something we didn't predict and it's very new and novel in terms of how psychedelics might help in so many different domains."

The study is published in the American Journal of Drug and Alcohol Abuse.

Most of the veterans attending the clinic retreat program had been on active duty after 9/11 and reported seeking care for memory problems, brain injury, depression, anxiety, PTSD, sleep problems, anger and fatigue. Head injuries were reported by 86% of attendees, most of whom attributed memory problems, irritability, disordered sleep and ringing in the ears to those long-ago head traumas.

Eighty-six veterans completed pre-treatment questionnaires assessing a range of mental health symptoms as well as satisfaction with life, anger levels and suicidality. Each attendee received a single oral ibogaine hydrochloride dose and, on a separate day, at least three incremental inhalation doses adding up to 50 milligrams of 5-MeO-DMT, also commonly called Five or Bufo. Preparation and reflection sessions preceded and followed each treatment.

Overall, participants reported large improvements in self-reported PTSD symptoms, depression, anxiety, insomnia severity and anger, as well as a significant increase in satisfaction with life, from pre-treatment to the one-month follow-up, and sustained benefits at the three- and six-month follow-ups. Additional reported improvements that continued for six months included reductions in disability and post-concussive symptoms, and very large increases in psychological flexibility and cognitive functioning.

Davis said the improved cognitive functioning warrants more research into whether better thinking results from lowered mental health symptoms or biological changes to signaling in the brain, or a mixture of both types of effects. And they noted that changes to psychological flexibility -- one's capacity to act in ways that are consistent with their values regardless of whatever internal or external experience they might have -- have been found in previous research to be connected to insightful and mystical psychedelic experiences.

"I think we're seeing a similar picture emerging here where the more one is psychologically flexible, the more likely it is that one's mental health symptoms will be reduced or ameliorated," Davis said.

Most attendees also reported moderate to strong desirable changes across a range of attitudes, behaviors and relationships. One month after treatment, almost half reported the psychedelic experience was the most spiritually significant (48.6%) or psychologically insightful (42.9%) of their lives, and 17.1% called it the most difficult or challenging experience in their life.

Davis and colleagues took a conservative approach to analyzing outcome data, building in an assumption that attendees who didn't complete all of the follow-up surveys may not have gotten the relief they had hoped for from the treatment. But they said finding that a population of veterans with complicated trauma histories can benefit from psychedelic therapy supports the importance of continuing to test psychedelic-assisted therapies in U.S. clinical trials.

Psilocybin-assisted therapy is currently being studied at Ohio State for the treatment of PTSD among military veterans.

https://www.sciencedaily.com/releases/2023/10/231005110741.htm

Your body's own cannabinoid molecules calm you during stress

Scientists discover how stress activates the same receptors as THC

September 12, 2023

Science Daily/Northwestern University

When you are under stress, your brain may release its own cannabinoid molecules to calm you down, activating the same brain receptors as THC derived from cannabis plants.

But the brain activity patterns and neural circuits that are regulated by these brain-derived cannabinoid molecules were not well known.

A new Northwestern Medicine study in mice has discovered that a key emotional brain center, the amygdala, releases endogenous (the body's own) cannabinoid molecules under stress, and these molecules dampen the incoming stress alarm from the hippocampus, a memory and emotion center in the brain. These results provide more support for the hypothesis that these endogenous cannabinoid molecules are a body's natural coping response to stress.

Stress exposure heightens risk for the development or worsening of psychiatric disorders from generalized anxiety and major depression to post-traumatic stress disorder (PTSD).

"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," said corresponding study author Dr. Sachi Patel, chair of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine and a Northwestern Medicine psychiatrist.

The study could indicate that impairments in this endogenous cannabinoid signaling system in the brain could lead to a greater susceptibility to developing stress-related psychiatric disorders including depression and PTSD, although this remains to be determined in humans, Patel said.

The study will be published Sept. 12 in Cell Reports.

For the study, Northwestern scientists used a new protein sensor that can detect the presence of these cannabinoid molecules at specific brain synapses in real time to show that specific high-frequency patterns of amygdala activity can generate these molecules. The sensor also showed that these molecules were released as a result of several different types of stress in mice.

When scientists removed the target of these cannabinoids, the cannabinoid receptor type 1, it resulted in poorer ability to cope with stress and motivational deficits in the mice. Specifically, when the receptor target of these endogenous cannabinoids was removed at hippocampal-amygdala synapses, mice adopted more passive and immobile responses to stress and had a lower preference to drink a sweetened sucrose water after stress exposure. The latter finding may relate to anhedonia, or the decrease in pleasure, often experienced by patients with stress-related disorders such as depression and PTSD.

One of the leading signaling systems that has been identified as a prominent drug-development candidate for stress-related psychiatric disorders is the endocannabinoid system, 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," said Patel, also the Lizzie Gilman Professor of Psychiatry and Behavioral Sciences. "There are ongoing clinical trials in this area that may be able to answer this question in the near future."

Other Northwestern authors include Farhana Yasmin, Amanda Morgan and Keenan Johnson.

The title of the article is "Endocannabinoid release at ventral hippocampal-amygdala synapses regulates stress-induced behavioral adaptation."

https://www.sciencedaily.com/releases/2023/09/230912113528.htm

How psychedelic drugs affect a rat's brain

August 9, 2023

Science Daily/Lund University

Researchers at Lund University have developed a technique for simultaneously measuring electrical signals from 128 areas of the brain in awake rats. They have then used the information to measure what happens to the neurons when the rats are given psychedelic drugs. The results show an unexpected and simultaneous synchronisation among neurons in several regions of the brain.

The idea that electrical oscillations in the brain could be used to teach us more about our experiences was conceived several years ago. Pär Halje and the research team was studying rats with Parkinson's disease that had problems with involuntary movements. The researchers discovered a tone -- an oscillation or wave in the electrical fields -- of 80 hertz in the brains of the rats with Parkinson's disease. It turned out that the wave was closely connected to the involuntary movements.

"A Polish researcher had observed similar waves after giving rats the anaesthetic ketamine. The ketamine was given at a low dose so that the rats were conscious, and the equivalent dose in a human causes psychedelic experiences. The waves they saw were in more cognitive regions of the brain than in the rats with Parkinson's, and the frequency was higher, but that still made us consider whether there were links between the two phenomena. Perhaps excessive brain waves in the motor regions of the brain cause motor symptoms, while excessive waves in cognitive regions give cognitive symptoms," says Pär Halje, researcher in neurophysiology at Lund University.

The research team that Pär Halje belongs to has developed a method that uses electrodes to simultaneously measure oscillations from 128 separate areas of the brain in awake rats. The electrical waves are caused by the cumulative activity in thousands of neurons, but the researchers also succeeded in isolating signals from individual neurons.

"For several of these areas, it is the first time anyone has successfully shown how individual neurons are affected by LSD in awake animals. When we gave the rats the psychedelic substances LSD and ketamine, the waves were clearly registered."

Collective wave patterns 

Despite ketamine and LSD affecting different receptors in the brain -- they have completely different ways into the nervous system -- they resulted in the same wave patterns even if the signals from individual cells differed. When the rats were given LSD, researchers saw that their neurons were inhibited -- they signalled less -- in all parts of the brain. Ketamine seemed to have a similar effect on the large neurons -- pyramidal cells -- which saw their expression inhibited, while interneurons, which are smaller neurons that are only collected locally in tissue, increased their signalling.

Pär Halje interprets the results seen in the study, which is published in Communication Biology, to mean that the wave phenomenon is connected to the psychedelic experience.

"Activity in the individual neurons caused by ketamine and LSD looks quite different, and as such cannot be directly linked to the psychedelic experience. Instead, it seems to be this distinctive wave phenomenon -- how the neurons behave collectively -- that is most strongly linked to the psychedelic experience."

Research model for psychoses

Even if what is happening in individual cells is interesting, Pär Halje argues that the whole is bigger and more exciting than the individual parts.

"The oscillations behave in a strange way. One might think that a strong wave starts somewhere, which then spreads to other parts of the brain. But instead, we see that the neurons' activity synchronises itself in a special way -- the waves in the brain go up and down essentially simultaneously in all parts of the brain where we are able to take measurements. This suggests that there are other ways in which the waves are communicated than through chemical synapses, which are relatively slow."

Pär Halje emphasises that it is difficult to know whether the waves cause hallucinations or are merely an indication of them. But, he argues, it opens up the possibility that this could be used as a research model for psychoses, where no good models exist today.

"Given how drastically a psychosis manifests itself, there ought to be a common pattern that we can measure. So far, we have not had that, but we now see a very specific oscillation pattern in rats that we are able to measure."

Can the waves reveal more about consciousness?

There is also a dream -- that the model will help us in the hunt for the mechanisms behind consciousness and that the measurements may be a way to study how consciousness is shaped.

"In light of the development of AI, it is becoming increasingly important to clarify what we mean by intelligence and what we mean by consciousness. Can self-awareness occur spontaneously, or is it something that needs to be built in? We do not know this today, because we do not know what the required ingredients for consciousness in our brains are. This is where it is exciting, the synchronised pattern we see, and whether this can help us to track down the neural foundations of consciousness," says Pär Halje.

https://www.sciencedaily.com/releases/2023/08/230809130726.htm

Ketamine effective for treatment-resistant depression

July 14, 2023

Science Daily/University of New South Wales

Promising results in a trial of ketamine for severe depression could lead to treatment becoming more affordable.

A low-cost version of ketamine to treat severe depression has performed strongly in a double-blind trial that compared it with placebo.

In research published today in the British Journal of Psychiatry, researchers led by UNSW Sydney and the affiliated Black Dog Institute found that more than one in five participants achieved total remission from their symptoms after a month of bi-weekly injections, while a third had their symptoms improve by at least 50 per cent. The study was a collaboration between six academic clinical mood disorder units in Australia and one in New Zealand and was funded by the Australian National Health and Medical Research Council (NHMRC).

"For people with treatment-resistant depression -- so those who have not benefitted from different modes of talk-therapy, commonly prescribed antidepressants, or electroconvulsive therapy -- 20 per cent remission is actually quite good," lead researcher Professor Colleen Loo says.

"We found that in this trial, ketamine was clearly better than the placebo -- with 20 per cent reporting they no longer had clinical depression compared with only 2 per cent in the placebo group. This is a huge and very obvious difference and brings definitive evidence to the field which only had past smaller trials that compared ketamine with placebo."

How the trial worked

The researchers recruited 179 people with treatment-resistant depression. All were given an injection of either a generic form of ketamine that is already widely available in Australia as a drug for anaesthesia and sedation -- or placebo. Participants received two injections a week in a clinic where they were monitored for around two hours while acute dissociative and sedative effects wore off -- usually within the first hour. The treatment ran for a month and participants were asked to assess their mood at the end of the trial and one month later.

As a double-blind trial, neither participants nor researchers administering the drug were aware which patients received generic ketamine or placebo, to ensure psychological biases were minimised. Importantly, a placebo was chosen that also causes sedation, to improve treatment masking. Midazolam is a sedative normally administered before a general anaesthetic, while in many previous studies the placebo was saline.

"Because there are no subjective effects from the saline, in previous studies it became obvious which people were receiving the ketamine and which people received placebo," Prof. Loo says.

"In using midazolam -- which is not a treatment for depression, but does make you feel a bit woozy and out of it -- you have much less chance of knowing whether you have received ketamine, which has similar acute effects."

Other features of the recent trial that set it apart from past studies included accepting people into the trial who had previously received electroconvulsive therapy (ECT).

"People are recommended ECT treatment for their depression when all other treatments have been ineffective," Prof. Loo says.

"Most studies exclude people who have had ECT because it is very hard for a new treatment to work where ECT has not."

Another difference about this trial was that the drug was delivered subcutaneously (injected into the skin) rather than by drip, thus greatly reducing time and medical complexity. The study is also the largest in the world to date that compares generic ketamine with placebo in treating severe depression.

Much more affordable

Apart from the positive results, one of the standout benefits of using generic ketamine for treatment-resistant depression is that it is much cheaper than the patented S-ketamine nasal spray currently in use in Australia. Where S-ketamine costs about $800 per dose, the generic ketamine is a mere fraction of that, costing as little as $5, depending on the supplier and whether the hospital buys it wholesale. On top of the cost for the drug, patients need to pay for the medical care they receive to ensure their experience is safe -- which at Black Dog Institute clinics, comes to $350 per session.

"With the S-ketamine nasal spray, you are out of pocket by about $1200 for every treatment by the time you pay for the drug and the procedure, whereas for generic ketamine, you're paying around $300-350 for the treatment including the drug cost," Prof. Loo says.

She adds that for both S-ketamine and generic ketamine treatments, the positive effects often wear off after a few days to weeks, so ongoing treatment may be required, depending on someone's clinical situation. But the prohibitive costs of the drug and procedure make this an unsustainable proposition for most Australians.

"This is why we're applying for a Medicare item number to fund this treatment now, because it's such a powerful treatment.

"And if you consider that many of these people might spend many months in hospital, or be unable to work and are often quite suicidal, it's quite cost effective when you see how incredibly quickly and powerfully it works. We've seen people go back to work, or study, or leave hospital because of this treatment in a matter of weeks."

The researchers will next be looking at larger trials of generic ketamine over longer periods, and refining the safety monitoring of treatment.

https://www.sciencedaily.com/releases/2023/07/230714114752.htm

Psychedelic drugs reopen 'critical periods' for social learning

June 14, 2023

Science Daily/Johns Hopkins Medicine

Neuroscientists have long searched for ways to reopen "critical periods" in the brain, when mammals are more sensitive to signals from their surroundings that can influence periods of brain development. Now, researchers at Johns Hopkins Medicine say a new study in mice shows that psychedelic drugs are linked by their common ability to reopen such critical periods, but differ in the length of time the critical period is open -- from two days to four weeks with a single dose.

The findings, published June 16 in the journal Nature, provide a new explanation for how psychedelic drugs work, say the scientists, and suggest potential to treat a wider range of conditions, such as stroke and deafness, beyond those in current studies of the drugs, such as depression, addiction and post-traumatic stress disorder. The scientists also provide a new look at molecular mechanisms impacted by psychedelics.

Critical periods have been demonstrated to perform such functions as help birds learn to sing and help humans learn a new language, relearn motor skills after a stroke and establish dominance of one eye over the other eye.

"There is a window of time when the mammalian brain is far more susceptible and open to learning from the environment," says Gül Dölen, M.D., Ph.D., associate professor of neuroscience at the Johns Hopkins University School of Medicine. "This window will close at some point, and then, the brain becomes much less open to new learning."

Building on her laboratory's experience studying social behavior, Dölen's team has been researching how psychedelic drugs work by reopening these critical periods. In 2019, her team found that MDMA, a psychedelic drug that arouses feelings of love and sociability, opens a critical period in mice.

At the time, Dölen thought MDMA's prosocial properties smooth the way for opening the critical period, but her team was surprised, she says, to find in the current study that other psychedelic drugs without prosocial properties could also reopen critical periods.

For the current study, Dölen's team looked at the reopening potential of five psychedelic drugs -- ibogaine, ketamine, LSD, MDMA and psylocibin -- shown in numerous studies as able to change normal perceptions of existence and enable a sense of discovery about one's self or the world.

The research team conducted a well-established behavioral test to understand how easily adult male mice learn from their social environment. They trained mice to develop an association between an environment linked with social interaction versus another environment connected with being by themselves. By comparing time spent in each environment after giving the psychedelic drug to the mice, the researchers were able to see if the critical period opened in the adult mice, enabling them to learn the value of a social environment -- a behavior normally learned as juveniles.

For mice given ketamine, the critical period of social reward learning stayed open in the mice for 48 hours. With psilocybin, the open state lasted two weeks. For mice given MDMA, LSD and ibogaine, the critical period remained open for two, three and four weeks, respectively.

The researchers say the length of time that the critical period stayed open in mice seems to roughly parallel the average length of time that people self-report the acute effects of each psychedelic drug.

"This relationship gives us another clue that the duration of psychedelic drugs' acute effects may be the reason why each drug may have longer or shorter effects on opening the critical period," says Dölen.

"The open state of the critical period may be an opportunity for a post-treatment integration period to maintain the learning state," she adds. "Too often, after having a procedure or treatment, people go back to their chaotic, busy lives that can be overwhelming. Clinicians may want to consider the time period after a psychedelic drug dose as a time to heal and learn, much like we do for open heart surgery."

Next, the scientists looked at psychedelic drugs' impact on molecular mechanisms. First, in mouse brain cells, they examined a binding point, known as a receptor, for the neurotransmitter serotonin. The researchers found that while LSD and psilocybin use the serotonin receptor to open the critical period, MDMA, ibogaine and ketamine do not.

To explore other molecular mechanisms, the research team turned to ribonucleic acid (RNA), a cousin to DNA that represents which genes are being expressed (producing proteins) in the mice's cells. The researchers found expression differences among 65 protein-producing genes during and after the critical period was opened.

About 20% of these genes regulate proteins involved in maintaining or repairing the extracellular matrix -- a kind of scaffolding that encases brain cells located in the nucleus accumbens, an area associated with social learning behaviors that are responsive to rewards.

https://www.sciencedaily.com/releases/2023/06/230614220630.htm

Researchers analyze THC in breath of cannabis smokers

Distinguishing between recent use and past use remains an elusive goal

May 22, 2023

Science Daily/National Institute of Standards and Technology (NIST)

Researchers analyzed THC levels in the breath of people who use cannabis regularly, both before and after they smoked marijuana. The researchers found that THC levels spanned a similar range across pre- and post-use samples. 'In many cases, we would not have been able to tell whether the person smoked within the last hour based on the concentration of THC in their breath,' said study author.

Most states in the U.S. allow people to use cannabis for medical or recreational purposes. Yet all states want their roadways to be safe. A breathalyzer that can accurately identify people who recently smoked cannabis might help them keep impaired drivers off the road -- if such a device existed.

But developing a breathalyzer for cannabis is far more difficult than for alcohol, which people exhale in large amounts when drinking. In contrast, the intoxicating component of cannabis, called THC, is thought to be carried inside aerosol particles that people exhale. The total volume of aerosols can be very small, making it difficult to accurately measure their THC content. Currently, there is no standard method for doing this.

Now, researchers at the National Institute of Standards and Technology (NIST) and the University of Colorado Boulder have conducted a study in which they collected breath samples from people both before and after they smoked high-THC cannabis, aka marijuana, and used laboratory instruments (not a handheld device) to measure the amount of THC in their breath. The goal of this study, published in the Journal of Breath Research, was to begin developing a protocol that yields reproducible results -- a necessary step toward a reliable, validated field-based method.

The samples collected before people smoked were important because THC can persist in the bodies of people who frequently use cannabis for a month or more, long after the effects of the drug have worn off.

"One key question that we cannot yet answer is whether breath measurements can be used to distinguish between a person who uses cannabis regularly but hasn't done so lately, and someone who consumed an hour ago," said NIST supervisory chemical engineer and study author Tara Lovestead. "Having a reproducible protocol for breath measurements will help us and other researchers answer that question."

The breath samples were collected in a mobile lab -- a comfortably appointed white van that would park conveniently outside participants' homes. This mobile pharmacology lab was developed by researchers at University of Colorado Boulder, including Cinnamon Bidwell, an assistant professor of psychology and neuroscience and a co-author of the study. In addition, all participants purchased and used a consistent kind of high-THC cannabis prepared by a licensed dispensary in Boulder, Colorado. This study design allowed the authors to conduct their research without handling high-THC cannabis or otherwise running afoul of federal laws.

At the appointed time, participants popped into the van, gave their pre-use breath sample and also provided a blood sample. They then went back into their residence, smoked cannabis according to their usual custom and returned immediately to the van to provide a second blood sample. Since THC concentrations in blood spike immediately after consuming the drug, researchers compared the before-and-after blood samples to confirm that the participants had in fact just used it. An hour later, the participants gave their second breath sample.

Participants provided breath samples by blowing into a tube containing an "impaction filter" that captured aerosols from their breath. Later in the lab, the researchers extracted the material caught in the filter and measured the concentration of THC and other cannabis compounds using liquid chromatography with tandem mass spectrometry, a laboratory technique that identifies compounds and measures their amount.

Because this was a protocol development study that involved only 18 participants, the results of the analysis do not carry statistical weight. However, they do highlight the need for further study.

"We expected to see higher THC concentrations in the breath samples collected an hour after people used," Lovestead said. However, THC levels spanned a similar range across pre-use and post-use samples. "In many cases, we would not have been able to tell whether the person smoked within the last hour based on the concentration of THC in their breath."

This study was funded by a grant from the Department of Justice's National Institute of Justice. NIJ has also awarded the research team an additional grant of $1.5 million over three years to continue its research. The next study will involve at least 40 participants providing more than a thousand breath samples. That should give the results more statistical heft.

"A lot more research is needed to show that a cannabis breathalyzer can produce useful results," said NIST materials research engineer and co-author Kavita Jeerage. "A breathalyzer test can have a huge impact on a person's life, so people should have confidence that the results are accurate."

https://www.sciencedaily.com/releases/2023/05/230522131310.htm

Is there a common path to the psychedelic experience?

April 25, 2023

Science Daily/Michigan Medicine - University of Michigan

A new study takes a closer look at the neurobiology of psychedelic experiences caused by nitrous oxide, ketamine and LSD.

Nitrous oxide, colloquially known as laughing gas, has been used clinically as an anesthetic to dull pain since the 19th century. However, in smaller amounts, it can induce mind-altered experiences, including feelings of bliss, spirituality, and the feeling of being outside of one's body -- much like those induced by the psychedelic substances LSD and ketamine.

A study led by George Mashour, M.D., Ph.D. and Richard Harris, Ph.D., of the recently founded Michigan Psychedelic Center at the University of Michigan Medical School takes a closer look at the neurobiology of psychedelic experiences.

Using fMRI, the team examined the brain activity of healthy people who were administered nitrous oxide and compared that activity to data collected from participants in different studies who were given ketamine and LSD to see whether the neurobiology of the psychedelic experience was similar.

In addition, this data was compared to a control group comprised of participants administered propofol, a commonly used anesthesia drug, to distinguish between brain changes not related to the psychedelic experience.

The team noted that participants under the influence of each psychedelic drug had decreased connectivity within a particular network but increased connectivity across various networks. Although there were notable differences, each psychedelic increased connectivity between the right temporoparietal junction and intraparietal sulcus in both hemispheres of the brain and between precuneus and left intraparietal sulcus.

These nodes, they note, are located in the so-called cortical "hot zone" of the brain, an area proposed to be critical for determining the content of conscious experience. This could help explain the altered states of consciousness described by people administered these psychedelic substances.

The fact that the patterns of activity associated with nitrous oxide, ketamine, and LSD overlapped hints at common underlying biology, they add. Further research to determine the specifics of this biology could help researchers determine how best to use psychedelics as therapeutics.

https://www.sciencedaily.com/releases/2023/04/230425111218.htm

Cannabinoids give worms the munchies, too

April 20, 2023

Science Daily/Cell Press

Marijuana (cannabis) is well known for giving people the "munchies." Not only does it make people want to eat more, but it also makes them crave the tastiest, most high-calorie foods. Now a new study in the journal Current Biology on April 20 shows that well-studied nematode worms (C. elegans) react to those chemicals known as cannabinoids in precisely the same way.

"Cannabinoids make nematodes hungrier for their favored foods and less hungry for their non-favored foods," says Shawn Lockery from the University of Oregon in Eugene. "Thus, the effects of cannabinoids in nematodes parallels the effects of marijuana on human appetites.

"Nematodes diverged from the lineage leading to mammals more than 500 million years ago," he added. "It is truly remarkable that the effects of cannabinoids on appetite are preserved through this length of evolutionary time."

Lockery explained that the new study was inspired in 2015, when cannabis became legal in Oregon. "At the time, our laboratory at the University of Oregon was deeply involved in assessing nematode food preferences as part of our research on the neuronal basis of economic decision-making," he said. "In almost literally a 'Friday afternoon experiment' -- read: 'let's dump this stuff on to see what happens' -- we decided to see if soaking worms in cannabinoids alters existing food preferences. It does, and the paper is the result of many years of follow-up research."

Cannabinoids are known to act by binding to cannabinoid detector proteins called cannabinoid receptors in the brain, nervous system, and other parts of the body. Those receptors in the body normally respond to related molecules that are naturally present in the body, known as endocannabinoids. The endocannabinoid system plays important roles in eating, anxiety, learning and memory, reproduction, metabolism, and more.

At the molecular level, the cannabinoid system in nematodes looks a lot like that in people and other animals. It begged the question as to whether the so-called hedonic feeding effects of cannabinoids also would be conserved across species.

In the new study, the researchers first showed that worms react to the endocannabinoid anandamide by eating more. They also ate more of their favorite food. The researchers found that those effects of the endocannabinoids depended on the presence of the worms' cannabinoid receptors.

In further studies, they genetically replaced the C. eleganscannabinoid receptor with the human cannabinoid receptor to see what would happen, and they found that the animals responded normally to cannabinoids. The discovery emphasizes the commonality of cannabinoid effects in nematodes and humans, the researchers say. They report that the effects of anandamide also depend on neurons that play a role in food detection.

"We found that the sensitivity of one of the main food-detecting olfactory neurons in C. elegans is dramatically altered by cannabinoids," Lockery said. "Upon cannabinoid exposure, it becomes more sensitive to favored food odors and less sensitive to non-favored food odors. This effect helps explain changes in the worm's consumption of food, and it is reminiscent of how THC makes tasty food even tastier in humans."

The findings in worms are not only entertaining, Lockery says, but they also have significant practical implications.

"Cannabinoid signaling is present in the majority of tissues in our body," he said. "It therefore could be involved in the cause and treatment of a wide range of diseases. The fact that the human cannabinoid receptor gene is functional in C. elegans food-choice experiments sets the stage for rapid and inexpensive screening for drugs that target a wide variety of proteins involved in cannabinoid signaling and metabolism, with profound implications for human health."

The researchers note that big outstanding questions remain, including how cannabinoids change the sensitivity of C. elegansolfactory neurons, which don't have cannabinoid receptors. They're also curious to study the effects of psychedelics on nematodes.

"Perhaps we can find a new set of similarities between humans and worms, now in the case of drugs that alter perception and psychological well-being," Lockery says.

https://www.sciencedaily.com/releases/2023/04/230420135331.htm

Peek of how ketamine acts as 'switch' in the brain

December 1, 2022

Science Daily/University of Pennsylvania School of Medicine

Ketamine, an established anesthetic and increasingly popular antidepressant, dramatically reorganizes activity in the brain, as if a switch had been flipped on its active circuits, according to a new study by Penn Medicine researchers. In a Nature Neuroscience paper released this month, the team described starkly changed neuronal activity patterns in the cerebral cortex of animal models after ketamine administration -- observing normally active neurons that were silenced and another set that were normally quiet suddenly springing to action. This ketamine-induced activity switch in key brain regions tied to depression may impact our understanding of ketamine's treatment effects and future research in the field of neuropsychiatry.

"Our surprising results reveal two distinct populations of cortical neurons, one engaged in normal awake brain function, the other linked to the ketamine-induced brain state," said the co-lead and co-senior author Joseph Cichon, MD, PhD, an assistant professor of Anesthesiology and Critical Care and Neuroscience in the Perelman School of Medicine at the University of Pennsylvania. "It's possible that this new network induced by ketamine enables dreams, hypnosis, or some type of unconscious state. And if that is determined to be true, this could also signal that it is the place where ketamine's therapeutic effects take place."

Anesthesiologists routinely deliver anesthetic drugs before surgeries to reversibly alter activity in the brain so that it enters its unconscious state. Since its synthesis in the 1960s, ketamine has been a mainstay in anesthesia practice because of its reliable physiological effects and safety profile. One of ketamine's signature characteristics is that it maintains some activity states across the surface of the brain (the cortex). This contrasts with most anesthetics, which work by totally suppressing brain activity. It is these preserved neuronal activities that are thought to be important for ketamine's antidepressant effects in key brain areas related to depression. But, to date, how ketamine exerts these clinical effects remains mysterious.

In their new study, the researchers analyzed mouse behaviors before and after they were administered ketamine, comparing them to control mice who received placebo saline. One key observation was that those given ketamine, within minutes of injection, exhibited behavioral changes consistent with what is seen in humans on the drug, including reduced mobility, impaired responses to sensory stimuli, which are collectively termed "dissociation."

"We were hoping to pinpoint exactly what parts of the brain circuit ketamine affects when it's administered so that we might open the door to better study of it and, down the road, more beneficial therapeutic use of it," said co-lead and co-senior author Alex Proekt, MD, PhD, an associate professor of Anesthesiology and Critical Care at Penn.

Two-photon microscopy was used to image cortical brain tissue before and after ketamine treatment. By following individual neurons and their activity, they found that ketamine turned on silent cells and turned off previously active neurons.

The neuronal activity observed was traced to ketamine's ability to block the activity of synaptic receptors -- the junction between neurons -- called NMDA receptors and ion channels called HCN channels. The researchers found that they could recreate ketamine's effects without the medications by simply inhibiting these specific receptors and channels in the cortex. The scientists showed that ketamine weakens several sets of inhibitory cortical neurons that normally suppress other neurons. This allowed the normally quiet neurons, the ones usually being suppressed when ketamine wasn't present, to become active.

The study showed that this dropout in inhibition was necessary for the activity switch in excitatory neurons -- the neurons forming communication highways, and the main target of commonly prescribed antidepressant medications. More work will need to be undertaken to determine whether the ketamine-driven effects in excitatory and inhibitory neurons are the ones behind ketamine's rapid antidepressant effects.

"While our study directly pertains to basic neuroscience, it does point at the greater potential of ketamine as a quick-acting antidepressant, among other applications," said co-author Max Kelz, MD, PhD,a distinguished professor of Anesthesiology and vice chair of research in Anesthesiology and Critical Care. "Further research is needed to fully explore this, but the neuronal switch we found also underlies dissociated, hallucinatory states caused by some psychiatric illnesses."

Support for the study was provided by the Foundation for Anesthesia Education and Research, and the National Institutes of Health (T32NS091006, R01GM124023-01A1, R01GM088156-08, R01 EY020765).

https://www.sciencedaily.com/releases/2022/12/221201141927.htm

Pregnant women's cannabis usage in legalized U.S. states raises calls for screening

November 29, 2022

Science Daily/Taylor & Francis Group

Pregnant women living in US states where cannabis is legal must be screened for the drug, for the health of both mother and baby, claim scientists who in a new national study have found that they are far more likely to use the substance.

Published in The American Journal of Drug and Alcohol Abuse, the peer-reviewed research shows pregnant women were around 4.6 times more likely to report using cannabis, where it is legal for medical and recreation, compared to where CBD is only allowed.

A large proportion of women reported using the drug for medical purposes, which is in keeping with "a growing body of evidence" that suggests in order to alleviate pregnancy symptoms cannabis is being used as a substitute for medical drugs in legalized areas.

"Therefore it is increasingly important to evaluate the risk-benefit profile of cannabis as compared to other medical treatments to understand any potential therapeutic indications for cannabis use in pregnancy," says Lead Author Kathak Vachhani, who was a student in the Keenan Research Summer Student Program at St. Michael's Hospital, a site of Unity Health Toronto, when the research was conducted.

The team is calling for prenatal and primary care providers to screen and counsel patients regarding cannabis use in pregnancy, particularly in states where it is legal, for the potential effects on fetal development.

They also state public messaging "around the risks" of cannabis in pregnancy is "particularly relevant now," as many states have recently implemented cannabis laws and established cannabis markets.

The legalization of cannabis products has increased exponentially in the last decade in the United States. The legalization has been piecemeal -- states variously allow the use of cannabidiol (CBD) products, the use of medically prescribed cannabis, the use of cannabis for recreational purposes, or some combination thereof. Use of these products has risen among all demographics.

Among the least studied are pregnant women. Because cannabis has been known to be used to treat some symptoms associated with pregnancy -- notably nausea and vomiting.

Here, the team used data from the Behavioral Risk Factor Surveillance System compiled by the Centers for Disease Control and Prevention (CDC) between 2017 to 2020 to analyze the consumption of cannabis by 1,992 pregnant women.

While previous studies have examined the use of cannabis by pregnant women in restricted geographic areas and under particular legislative parameters, this study involved a broader dataset to compare use across legalization frameworks in 27 states.

The authors found self-reported use was "significantly higher" in pregnant women residing in states that allow medical and adult use, compared to those residing in states with restricted use.

"The unweighted dataset consisted of 426 CBD-only, 1,114 medical, and 394 reactional group respondents," they claim. Weights were applied to each datapoint to obtain the population they represented. Of this weighted data, 2.4% from CBD-only regions reported cannabis use, while 7.1% from medical regions and 6.9% from adult-use regions reported the same. Respondents from the medical and recreational areas were 4.5 and 4.7 times more likely to use cannabis than those in CBD-only areas.

Most respondents who reported cannabis use smoked it partially or mostly for recreational purposes. "Mode of intake and reason for consumption did not differ between state groups," the authors observe.

But what impact is this having on the mother or the fetus?

Previous studies have shown that medical cannabis usage during pregnancy can be effective for nausea and vomiting. Medical cannabis may be suitable to treat pregnancy-specific conditions which, if untreated, could be more harmful to the fetus than cannabis.

However, safe usage depends on having a comprehensive understanding of the benefits and risks of cannabis when weighed against the risks of untreated or refractory conditions such as hyperemesis gravidarum.

Therefore, more research is needed, states Vachhani, who is also from the University of Toronto Temerty Faculty of Medicine.

"Cannabis is a complex substance and its use is further complicated by factors such as the form of intake and frequency of use.

"From the mother's health standpoint, our current understanding is rudimentary regarding the complex

interplay between use (whether CBD or THC-based) and long-term health outcomes for the mother.

"There is currently no accepted therapeutic indication or safe amount of cannabis that may be consumed during pregnancy.

"Although further studies may lead to an accepted therapeutic indication, based on the current consensus the positive association between cannabis use and legalization found in our study warrants further inquiry."

The analysis carried out here was limited by a relatively small sample size, a lack of information regarding timing of use in pregnancy, lack of information about the chemical composition of cannabis consumed, and the potential for self-reporting biases.

https://www.sciencedaily.com/releases/2022/11/221129112845.htm

Legalization of recreational cannabis linked with increased alcohol drinking

November 28, 2022

Science Daily/University of Pittsburgh

States that legalized recreational cannabis saw a slight population-level uptick in alcohol consumption that was largely driven by young adults and men, according to new research by University of Pittsburgh School of Public Health policy scientists.

The increase in alcohol use, recently reported in JAMA Health Forum, suggests that states that legalize recreational cannabis should also consider targeted public health messaging around alcohol and other policy interventions aimed at mitigating problem drinking.

"Recreational cannabis laws have made cannabis legally accessible to nearly half of U.S. adults, but it has been unclear how this affects the use of other substances, such as alcohol," said senior author Coleman Drake, Ph.D., assistant professor in the Department of Health Policy and Management at Pitt Public Health. "It appears that cannabis use increases the probability that people drink, at least in the three years after legalization."

Drake and his team obtained data on alcohol use by more than 4.2 million adults through the Centers for Disease Control and Prevention's annual Behavioral Risk Factor Surveillance System surveys administered from 2010 through 2019 -- at which point 11 states had legalized recreational cannabis.

The survey inquired about any alcohol use, binge drinking and heavy drinking within the last month, and the researchers looked at differences in responses before and after recreational cannabis legalization.

Any drinking -- measured as having "at least one drink of any alcoholic beverage" in the past month -- increased by 1.2 percentage points in the first year after recreational cannabis was legalized, but diminished in the following two years. There was no change in binge or heavy drinking in the overall population.

When the team dove into the data, they found that the increase was driven by adults ages 18 to 24 who had a 3.7 percentage point increase in any drinking. None of the other age groups had a statistically significant increase in any drinking after cannabis legalization.

Demographically, the increase was also associated with men, non-Hispanic whites and people without some college education.

While recreational cannabis legalization was linked to a small increase in alcohol consumption, the team did not find any evidence of sustained effects on binge or heavy drinking. However, Drake noted that cannabis use has nearly doubled over the past decade, and a prior study estimated that, between 2011 and 2015, excessive alcohol use resulted in the death of over 93,000 Americans per year.

"So, it will be important to monitor whether recreational cannabis laws cause increases in drinking over longer periods of time, particularly among younger adults and men," he said.

By zeroing in on the groups of people who may be most likely to increase risky behaviors, such as drinking more while using cannabis, states can proactively engage those communities and look for ways to mitigate risk -- such as through public health campaigns or alcohol tax strategies -- before recreational cannabis laws go into effect, Drake explained.

"In prior work, I found that recreational cannabis laws temporarily reduced opioid-related emergency department visits," Drake said. "So, I would resist characterizations of cannabis legalization as categorically good or bad. We need to learn more about how cannabis legalization affects all substance use, health, and non-health outcomes, such as drug-related arrest rates, work-related injuries and labor market outcomes. Policymakers should try to think through all these costs and benefits as they consider passing recreational cannabis laws."

https://www.sciencedaily.com/releases/2022/11/221128101208.htm

Cannabis legalization boosts use by double digits

A first-of-its kind study of twins finds those who live in states where marijuana is legal use it 24% more

August 27, 2022

Science Daily/University of Colorado at Boulder

Residents of states where cannabis has been legalized use marijuana 24% more frequently than those living in states where it remains illegal, according to new research published today in the journal Addiction.

The study of more than 3,400 adult twins, by researchers at University of Minnesota and University of Colorado, constitutes some of the strongest evidence yet that legalization causes increased use.

It comes at a time when cannabis use is rising nationwide, including during adulthood -- a phase of life when individuals have historically tended to cut back.

"Across America, there is a trend toward using more marijuana but we found that the change is bigger in states where it is legal," said lead author Stephanie Zellers, a recent University of Minnesota graduate who began the research while a PhD student at CU Boulder's Institute for Behavioral Genetics (IBG).

For the study, Zellers and co-authors at CU Boulder, CU Anschutz Medical Campus and University of Minnesota analyzed data from two large longitudinal twin studies, which have tracked twins since childhood in both states: one housed at IBG and another at the Minnesota Center for Twin Family Research.

Participants were asked how frequently they used cannabis before and after 2014 when Colorado became one of the first states to commence legal sales of recreational marijuana. Recreational cannabis remains illegal in Minnesota. Before 2014, there was little difference in use between states, the study found. After 2014, across all participants, residents of states where recreational use of marijuana was legalized used cannabis 24% more frequently than those in illegal states.

When specifically comparing identical twins in which one now lives in a state where marijuana is legal and the other lives in a state where it is illegal, those living in the state with legal marijuana used cannabis 20% more frequently, the researchers found.

Because twins share their genes and tend to share socioeconomic status, parental influences and community norms, they provide well-matched controls for each other, enabling researchers to minimize alternative explanations for results and get at what causes what.

"This is the first study to confirm that the association between legal cannabis and increased use holds within families in genetically identical individuals," said co-author John Hewitt, a professor in the Department of Psychology and Neuroscience and faculty fellow at IBG. "This makes it much more likely that legalization does, in itself, result in increased use."

More than 141 million Americans now live in a state with recreationally legal cannabis and, according to the National Institute on Drug Abuse, use among young adults age 19 to 30 is at an all-time high, with 43% reporting use in the past year and 29% in the last month.

"Typically, what we would expect to see is that people tend to increase use as adolescents and then reduce it as they transition into adult roles, family life and stable jobs," said Zellers. "Interestingly, we saw escalation, not reduction, in adults."

The authors note that it is unlikely that legalization would cause those who abstained from marijuana before to pick up the habit.

And preliminary results from their broader ongoing research project suggest increased use may not necessarily be a bad thing.

"In other analyses, we are finding that this increased use is not accompanied by increased problems, may be associated with less alcohol-related problems, and otherwise does not, in general, seem to have adverse consequences," said Hewitt.

https://www.sciencedaily.com/releases/2022/08/220827092455.htm

Psychedelics may lessen fear of death and dying, similar to feelings reported by those who've had near death experiences

August 24, 2022

Science Daily/Johns Hopkins Medicine

In a survey study of more than 3,000 adults, Johns Hopkins Medicine researchers compared psychedelic experiences with near-death experiences that were not drug related and found notable similarities in people's attitudes toward death. Survey participants in both groups reported having less fear of death and dying after the experience. They also reported that the experience had a lasting positive effect, providing personal meaning, spiritual significance and psychological insight.

The study was published Aug. 24, 2022 in the journal PLOS ONE.

The results are consistent with several recent clinical trials showing that a single treatment with the psychedelic psilocybin produced sustained decreases in anxiety and depression among patients with a life-threatening cancer diagnosis. The largest of these trials (Griffiths et al., 2016) was conducted at Johns Hopkins Medicine by the authors of this survey. That study, a randomized trial of 51 patients with cancer who had clinically significant anxiety or depressive symptoms, demonstrated that receiving a controlled, high dose of psilocybin given with supportive psychotherapy resulted in significant increases in ratings of death acceptance, as well as decreases in anxiety about death.

For the present study, the researchers analyzed data gathered from 3,192 people who answered an online survey between December 2015 and April 2018. Participants were divided into groups: 933 individuals had non-drug-related near-death experiences, and the rest of the participants had psychedelic experiences, which were prompted by either lysergic acid diethylamide (LSD) (904), psilocybin (766), ayahuasca (282) or N,N-dimethyltryptamine (DMT) (307). Participants were predominantly white (85%) and mostly from the United States. Compared with the non-drug group, there were more men in the psychedelic group (78% versus 32%), and they tended to be younger (32 versus 55 years of age) at the time of the experience.

Similarities between the groups include:

• About 90% of participants in both groups reported a decrease in fear of death when considering changes in their views from before to after the experience.

• Most participants in both groups (non-drug group, 85%; psychedelics group, 75%) rated the experience to be among the top five most personally meaningful and spiritually significant of their life.

• Participants in both groups reported moderate to strong persisting positive changes in personal well-being and life purpose and meaning.

Differences between the groups include:

• The non-drug group was more likely to report that their life was in danger (47% versus the psychedelics group, 3%), being medically unconscious (36% versus the psychedelics group, 10%), or being clinically dead (21% versus the psychedelics group, less than 1%).

• The non-drug group was more likely to report that their experience was very brief, lasting five minutes or less (40% versus the psychedelics group, 7%).

The researchers say that future studies are needed to better understand the potential clinical use of psychedelics in ameliorating suffering related to fear of death.

https://www.sciencedaily.com/releases/2022/08/220824152209.htm

Psychedelic drug therapy may help treat alcohol addiction

August 24, 2022

Science Daily/NYU Langone Health / NYU Grossman School of Medicine

wo doses of psilocybin, a compound found in psychedelic mushrooms, reduces heavy drinking by 83% on average among heavy drinkers when combined with psychotherapy, a new study shows.

Led by researchers at NYU Grossman School of Medicine, the investigation involved 93 men and women with alcohol dependence. They were randomly assigned to receive either two doses of psilocybin or an antihistamine placebo. Neither the researchers nor the study participants knew which medication they received. Within an eight-month period from the start of their treatment, those who were given psilocybin reduced heavy drinking by 83% relative to their drinking before the study began. Meanwhile, those who had received antihistamine reduced their drinking by 51%.

Among the other key findings, the study showed that eight months after their first dose, almost half (48%) of those who received psilocybin stopped drinking altogether compared with 24% of the placebo group.

"Our findings strongly suggest that psilocybin therapy is a promising means of treating alcohol use disorder, a complex disease that has proven notoriously difficult to manage," says study senior author and psychiatrist Michael Bogenschutz, MD, director of the NYU Langone Center for Psychedelic Medicine.

The U.S. Centers for Disease Control and Prevention reports that excessive alcohol use kills roughly 95,000 Americans every year, often due to binge drinking or liver disease. It is also linked to enormous economic and workplace losses, injury accidents, and impaired learning, memory, and mental health, says Bogenschutz, also a professor in the Department of Psychiatry at NYU Langone Health. Current methods to prevent excessive alcohol use and dependency include psychological counseling, supervised detoxification programs, and certain drug regimens that dampen cravings.

According to study investigators, previous research had already identified psilocybin treatment as an effective means of alleviating anxiety and depression in people with the most severe forms of cancer. And earlier research by Bogenschutz and others suggested that psilocybin could serve as a potential therapy for alcohol use disorder and other addictions.

The new study, publishing Aug. 24 in the journal JAMA Psychiatry, is the first placebo-controlled trial to explore psilocybin as a treatment for excessive alcohol consumption, according to the study authors.

For the investigation, the research team recruited men and women who were diagnosed with alcohol dependence based on standard definitions and consumed on average seven drinks on days when they drank. Forty-eight patients received at least one dose and up to three doses of psilocybin, and 45 patients received the antihistamine placebo.

All received up to 12 psychotherapy sessions. These took place both before and after the drug treatments. Afterwards, the participants were asked to report the percentage of heavy drinking days they experienced during weeks 5 to 36 of the study. They also provided hair and fingernail samples to confirm that they had not been drinking. All participants were then offered a third session of psilocybin to ensure that those who previously received a placebo had the chance to be treated with the psychedelic drug.

"As research into psychedelic treatment grows, we find more possible applications for mental health conditions," says Bogenschutz. "Beyond alcohol use disorder, this approach may prove useful in treating other addictions such as cigarette smoking and abuse of cocaine and opioids."

Bogenschutz says the research team next plans to conduct a larger, multicenter trial under an FDA IND sponsored by B.More Inc.

He cautions that more work needs to be done to document psilocybin's effects and to clarify appropriate dosing before the drug is ready for widespread clinical use. He notes that researchers have started such trials.

Psilocybin is a naturally occurring compound derived from fungi with mind-altering qualities similar to those of LSD and mescaline. Most study participants experience profound alterations in perception, emotions, and sense of self, often including experiences which are felt to be of great personal and spiritual significance. Because the drug raises blood pressure and heart rate and can cause incapacitating and sometimes overwhelming psychological effects, researchers caution that it should only be used in carefully controlled settings and in conjunction with psychological evaluation and preparation.

https://www.sciencedaily.com/releases/2022/08/220824120823.htm

People who use therapeutic cannabis are more likely to use nicotine, too

Study is among the first to examine the association between therapeutic cannabis use and nicotine use

August 23, 2022

Science Daily/Rutgers University

People who use therapeutic cannabis are more likely to also use nicotine products than the general population, according to a Rutgers study.

The study, published in the American Journal on Addictions, is among the first to examine nicotine use among patients of a medical marijuana dispensary.

"Simultaneous use of cannabis and nicotine is a growing concern, but while the relationship between recreational cannabis and nicotine use is well-established, little is known about nicotine use among users of medical cannabis," said Mary Bridgeman, a clinical professor at Rutgers Ernest Mario School of Pharmacy.

The researchers surveyed 697 patients between ages 18 and 89 at a medical marijuana dispensary on their nicotine and cannabis use, how they self-administered the cannabis (smoked, vaped) and the medical conditions that qualified them for using therapeutic cannabis.

They found that close to 40 percent of medical marijuana users also use nicotine -- sharply higher than the 14 percent of U.S. adults who smoke.

Therapeutic cannabis users who also used electronic cigarettes or didn't use nicotine at all were about four times more likely to vape, rather than smoke, cannabis than those who exclusively smoked cigarettes.

The study also found 75 percent of the respondents smoked cannabis rather than vaped and about 80 percent of the cigarette smokers reported planning to quit in the next six months.

These findings reveal that while medical cannabis dispensaries may recommend vaping rather than smoking cannabis due to the health concerns associated with combustible products, this recommendation alone may not influence patients who also smoke cigarettes," said co-author Marc Steinberg, author of the study and a professor in the department of psychiatry at Rutgers Robert Wood Johnson Medical School.

"Between the higher rates of nicotine use in those using medical cannabis, the fact that cigarette smokers opt to smoke cannabis as well and that those people also are seeking to quit using nicotine presents a strong argument that dispensaries provide tobacco control messaging at the point-of-sale to encourage cigarette smokers to quit," Steinberg added. "The strategy also could increase the chances that a medical cannabis user would vape the product, which is a less harmful route than smoking."

https://www.sciencedaily.com/releases/2022/08/220823135701.htm

Marijuana and hallucinogen use among young adults reached all time-high in 2021

Study also found past-month vaping levels rebound after early pandemic drop

August 22, 2022

Science Daily/NIH/National Institute on Drug Abuse

Marijuana and hallucinogen use in the past year reported by young adults 19 to 30 years old increased significantly in 2021 compared to five and 10 years ago, reaching historic highs in this age group since 1988, according to the Monitoring the Future (MTF) panel study. Rates of past-month nicotine vaping, which have been gradually increasing in young adults for the past four years, also continued their general upward trend in 2021, despite leveling off in 2020. Past-month marijuana vaping, which had significantly decreased in 2020, rebounded to pre-pandemic levels in 2021.

Alcohol remains the most used substance among adults in the study, though past-year, past-month, and daily drinking have been decreasing over the past decade. Binge drinking (five or more drinks in a row in the past two weeks) rebounded in 2021 from a historic low in 2020, during the early stages of COVID-19 pandemic. On the other hand, high-intensity drinking (having 10 or more drinks in a row in the past two weeks) has been steadily increasing over the past decade and in 2021 reached its highest level ever recorded since first measured in 2005.

"As the drug landscape shifts over time, this data provides a window into the substances and patterns of use favored by young adults. We need to know more about how young adults are using drugs like marijuana and hallucinogens, and the health effects that result from consuming different potencies and forms of these substances," said National Institute on Drug Abuse Director Nora Volkow, M.D. "Young adults are in a critical life stage and honing their ability to make informed choices. Understanding how substance use can impact the formative choices in young adulthood is critical to help position the new generations for success."

Since 1975, the Monitoring the Future study (https://nida.nih.gov/research-topics/trends-statistics/monitoring-future) has annually surveyed substance use behaviors and attitudes among a nationally representative sample of teens. A longitudinal panel study component of MTF conducts follow-up surveys on a subset of these participants to track their drug use through adulthood. Participants self-report their drug use behaviors across three primary time periods -- lifetime, past year (12 months), and past month (30 days). The MTF study is conducted by scientists at the University of Michigan's Institute for Social Research, Ann Arbor, and is funded by NIDA, part of the National Institutes of Health.

Data for the 2021 survey were collected online from April 2021 through October 2021. Key findings in the young adult group include:

Marijuana Use: Past-year, past-month, and daily marijuana use (use on 20 or more occasions in the past 30 days) reached the highest levels ever recorded since these trends were first monitored in 1988. The proportion of young adults who reported past-year marijuana use reached 43% in 2021, a significant increase from 34% five years ago (2016) and 29% 10 years ago (2011). Marijuana use in the past month was reported by 29% of young adults in 2021, compared to 21% in 2016 and 17% in 2011. Daily marijuana use also significantly increased during these time periods, reported by 11% of young adults in 2021, compared to 8% in 2016 and 6% in 2011.

Hallucinogen Use: Past-year hallucinogen use had been relatively stable over the past few decades until 2020, when reports of use started to increase dramatically. In 2021, 8% of young adults reported past-year hallucinogen use, representing an all-time high since the category was first surveyed in 1988. By comparison, in 2016, 5% of young adults reported past-year hallucinogen use, and in 2011, only 3% reported use. Types of hallucinogens reported by participants included LSD, MDMA, mescaline, peyote, "shrooms" or psilocybin, and PCP. The only hallucinogen measured that significantly decreased in use was MDMA (also called ecstasy or Molly), showing statistically significant decreases within one year as well as the past five years -- from 5% in both 2016 and 2020 to 3% in 2021.

Vaping: Nicotine vaping in the past month increased significantly among young adults in 2021 despite leveling off in 2020 during the earlier part of the pandemic. The continued increase in 2021 reflects a general long-term upward trend: in 2021, nicotine vaping prevalence nearly tripled to 16% compared to 6% in 2017, when the behavior was first recorded.

Prevalence of marijuana vaping in the past month among young adults had significantly dipped in 2020 but returned to near pre-pandemic levels in 2021. Since 2017, when marijuana vaping was included in this study, past-month prevalence has doubled -- from 6% in 2017 to 12% in 2021.

Alcohol Use: Reports of binge drinking by young adults -- defined as having five or more drinks in a row in the past two weeks -- returned to pre-pandemic levels in 2021 after significantly decreasing in 2020 (32% reported in 2021, versus 28% in 2020 and 32% in 2019). High-intensity drinking, defined as having 10 or more drinks in a row in the past two weeks, was at its highest level since it was first measured in 2005, reported by 13% of young adults in 2021, compared with 11% in 2005. However, past-month and past-year alcohol use, and daily drinking have been on a downward trend in young adults for the past 10 years. For example, in 2021, 66% of young adults reported alcohol use in the past 30 days, a significant decline from 70% recorded in 2016 and 69% in 2011.

The study also showed significant decreases in past-month cigarette smoking by young adults and non-medical use of opioid medications in the past year (surveyed as "narcotics other than heroin") compared to 10 years ago. Both substances have been declining steadily in use for the past decade. Additional data from the 2021 MTF panel study include drug use reported by adults 35 to 50 years old, college/non-college young adults, and among various demographic subgroups.

"One of the best ways we can learn more about drug use and its impact on people is to observe which drugs are appearing, in which populations, for how long, and under which contexts," said Megan Patrick, Ph.D., a research professor at the University of Michigan and principal investigator of the MTF panel study. "Monitoring the Future and similar large-scale surveys on a consistent sample population allow us to assess the effects of 'natural experiments' like the pandemic. We can examine how and why drugs are used and highlight critical areas to guide where the research should go next and to inform public health interventions."

View more information on the methods behind MTF panel study data collection (http://monitoringthefuture.org/pubs/monographs/mtfpanelreport2022) and how the survey adjusts for the effects of potential exclusions in the report (http://monitoringthefuture.org/pubs/monographs/mtfpanelchap1_2022).

Results from the related 2021 MTF study of substance use behaviors and related attitudes among teens in the United States was released in December 2021, and 2022 results are upcoming in December 2022.

https://www.sciencedaily.com/releases/2022/08/220822130344.htm

New study estimates over 5.5 million U.S. adults use hallucinogens

Past 12-month LSD use rate increased from 0.9 percent in 2002 to 4 percent in 2019

August 18, 2022

Science Daily/Columbia University's Mailman School of Public Health

Hallucinogen use has increased since 2015, overall and particularly among adults 26 and older, while use decreased in adolescents aged 12-17 years according to a new study by Columbia University Mailman School of Public Health and Columbia University Irving Medical Center. Estimates of over 5.5 million people in the U.S. used hallucinogens in the past year in 2019, which represents an increase from 1.7 percent of the population ages 12 years and over in 2002 to 2.2 percent in 2019.

LSD use between 2002 and 2019 increased overall and in all age groups with the past 12-month rate increasing from 0.9 percent in 2002 to 4 percent in 2019 for those 18-25 years of age. Conversely, PCP use between 2002 and 2019 decreased, as did the drug Ecstasy since 2015. The study is the first to provide formal statistical analyses of trends in prevalence of hallucinogen use overall and by age groups during the last two decades.

The findings are published online in the peer-reviewed journal Addiction.

To assess trends in hallucinogen use in the U.S. general population, the researchers analyzed data from the National Survey on Drug Use and Health (NSDUH) from 2002 to 2019 for participants 12 years of age and older.

The use of hallucinogens -- a broad category of psychoactive substances, including "classic" psychedelics such as LSD -- are mostly designated as Schedule I drugs in the U. S., and may entail risk for adverse consequences including anxious reactions, confusion, acute delusional states and a prolonged sense of fear and dread. LSD and Ecstasy and several other hallucinogens are associated with an increased risk of autonomic, endocrine, cardiovascular and neurological adverse effects including elevated blood pressure, heart rate and loss of appetite, tremors and seizures. PCP is considered to be one of the most dangerous hallucinogens, and known to cause adverse effects similar to LSD and ecstasy, but unlike those drugs, PCP can lead to hostile and violent behaviors that may result in severe trauma.

"While new findings suggesting benefits from use of certain hallucinogens among a range of cognitive areas are being published at a rapid rate, there are still gaps in knowledge concerning safe hallucinogen use, and evidence for potential adverse effects even with professionally supervised use that warrant attention." said Ofir Livne, MD, MPH, postdoctoral fellow in the Department of Epidemiology at Columbia Mailman School, and first author.

From 2002 to 2019, the prevalence of 12-month LSD use increased significantly overall and among respondents aged 12-17 years. However, the prevalence of great risk for regular LSD use decreased significantly overall for the years 2002-14, and among all age groups.

"Our finding of an upward trend in 12-month LSD use, overall and by age, matches our finding of a downward trend in perception of LSD as risky," said Deborah Hasin, PhD, professor of epidemiology (in psychiatry) at the Columbia University Irving Medical Center, and senior author. "Factors such as changes in risk perception, in the specific types of drugs available and in expectations of beneficial effects of 'microdosing' may all have led to increased use of certain hallucinogens in recent years."

According to author Livne, "Given the recent media coverage showing that an increasing number of adults may be reporting positive effects of 'microdosing' and expecting therapeutic benefits of hallucinogens without negative effects, our findings merit a comprehensive examination of time trends and motives for hallucinogen frequency and quantity of use."

"In light of popular media reports of a forthcoming 'psychedelic revolution' with commercialization and marketing that may further reduce public perception of any risk, researchers, clinicians and policymakers should increase their attention to the rising rates of unsupervised hallucinogen use among the general public," observes Hasin. "Our results highlight such use as a growing public health concern and suggest that the increasing risk of potentially unsupervised hallucinogen use warrants preventive strategies."

https://www.sciencedaily.com/releases/2022/08/220818122413.htm

Low addiction risk with medical use of ketamine

August 4, 2022

Science Daily/Université de Genève

Commonly used in medicine as an anaesthetic, ketamine is also increasingly prescribed to relieve depressive symptoms. This very fast-acting psychotropic drug is particularly indicated for the treatment of patients resistant to conventional antidepressants. However, its prescription has been the subject of debate: some believe that it presents a strong addictive risk. A team from the University of Geneva (UNIGE) has investigated this by administering the drug to mice. While it triggers an increase in dopamine in their brains -- like all drugs -- it also inhibits a specific receptor that precludes the progression to addiction. These results can be found in the journal Nature.

Discovered in 1962 by the American chemist Calvin Lee Stevens, ketamine is a synthetic drug derived from phencyclidine with powerful anaesthetic properties. It is commonly used in human and veterinary medicine, particularly for pain relief and brief sedation. It is also used illicitly for recreational purposes, its dissociative effect inducing an altered perception of reality.

For the past ten years or so, ketamine has also been prescribed to treat the depressive symptoms of people who are resistant to conventional treatments. Its action has the advantage of being very rapid: its effect is felt a few hours after the first dose, whereas traditional antidepressants take several weeks to act. Although its prescription is increasing for this type of treatment, this substance is still widely debated within the scientific community.

''Some people believe that ketamine presents a strong addictive risk if taken for a long time, others do not. The whole point of our research was to try to provide some answers,'' explains Christian Lüscher, a Full Professor in the Department of Basic Neurosciences at the UNIGE Faculty of Medicine and a specialist in the mechanisms underlying addiction.

Addiction vs. Dependence

Addiction is defined as the compulsive use of a substance despite its negative consequences (behavioural disorder). Dependence, on the other hand, is characterised by the appearance of one or more withdrawal symptoms on abrupt cessation of use (physiological disorder). Dependence -- the physical manifestations of which vary greatly depending on the drug -- affects everyone. Addiction, on the other hand, affects only a minority of people and is not caused by all drugs.

In the case of cocaine, for example, only 20% of users become addicted, even after prolonged exposure. For opiates, the rate is 30%. In its recent work, Christian Lüscher's team sought to assess the risk of addiction to ketamine.

Short stimulation of the reward system

The UNIGE researchers used a device that allowed mice to self-administer doses of ketamine. ''The drugs intensely stimulate the reward system in the brain, which leads to an increase in dopamine levels. The first step was to observe whether this mechanism was also at work when taking ketamine,'' explains Yue Li, a Postdoctoral Scholar in the Department of Basic Neuroscience at the UNIGE Faculty of Medicine.

The scientists found that the level of dopamine -- also known as the ''pleasure molecule'' -- increased with each dose and induced a positive reinforcement in the mice, which motivated them to repeat the self-administration. ''However, unlike cocaine, for example, we found that the dopamine level fell very quickly after taking the drug,'' says Yue Li.

A drug that does not leave its "mark"

The research team wanted to understand this phenomenon. They discovered that ketamine triggered an increase in dopamine by inhibiting a molecule called NMDA receptor in the reward center of the rodent brain. Dopamine then binds to another receptor (called the D2 receptor), which acts as a rapid brake on the increase in dopamine. The researchers also confirmed that the action of the NMDA receptor is necessary to modify the communication between the nerve cells that underlie the behavioural change leading to addiction. Ketamine's inhibition of the NMDA receptor makes this modification impossible.

''The consequence of this dual action of ketamine is that it does not induce the synaptic plasticity that addictive drugs do and that persists in the brain after the substance has worn off. It is this memorization of the product in the reward system -- absent in the case of ketamine -- that drives the repetition of consumption, explains Christian Lüscher. Therefore, the addictive risk of ketamine appears to be zero in rodents. Is this also the case in humans? Could this risk vary according to the individual? Our study provides a solid framework for debating access to its therapeutic use,'' concludes Christian Lüscher.

https://www.sciencedaily.com/releases/2022/08/220804102555.htm

Researchers ID the high-efficiency hacks cannabis cells use to make cannabinoids

August 2, 2022

Science Daily/University of British Columbia

Plant biologists have defined the high-efficiency 'hacks' that cannabis cells use to make cannabinoids (THC/CBD). Although many biotechnology companies are currently trying to engineer THC/CBD outside the plant in yeast or cell cultures, it is largely unknown how the plant does it naturally.

For the first time, plant biologists have defined the high-efficiency "hacks" that cannabis cells use to make cannabinoids (THC/CBD). Although many biotechnology companies are currently trying to engineer THC/CBD outside the plant in yeast or cell cultures, it is largely unknown how the plant does it naturally.

"This really helps us understand how the cells in cannabis trichomes can pump out massive quantities of tetrahydrocannabinol (THC) and terpenes -- compounds that are toxic to the plant cells at high quantities -- without poisoning itself," says Dr. Sam Livingston, a botanist at the University of British Columbia who led the research.

"This new model can inform synthetic biology approaches for cannabinoid production in yeast, which is used routinely in biotechnology. Without these 'tricks' they'll never get efficient production."

For centuries, humans have cultivated cannabis for the pharmacological properties that result from consuming its specialized metabolites, primarily CBD and terpenoids. Today, production within the $20 billion global cannabis market largely relies on the biological activity of tiny cell clusters, called glandular trichomes, found mainly on the plant's flowers.

The study, published today in Current Biology, reveals the microenvironments in which THC is produced and transported in cannabis trichomes, and sheds light on several critical points in the pathway of making THC or CBD within the cell.

Dr. Livingston and co-author Dr. Lacey Samuels used rapid freezing of cannabis glandular trichomes to immobilize the plant's cellular structures and the metabolites in situ. This enabled them to investigate cannabis glandular trichomes using electron microscopes that revealed cell structure at the nano level, showing that the metabolically active cells in cannabis form a "supercell" that acts as a tiny metabolic biofactory.

Until now, synthetic biology approaches have focused on optimizing the enzymes responsible for making THC/CBD -- like building a factory with the most efficient machinery to make as much product as possible. However, these approaches haven't developed an efficient way to move intermediate substances from one enzyme to another, or from inside the cell to the outside of the cell where final products can be collected. This research helps to define the subcellular "shipping routes" that cannabis uses to create an efficient pipeline from raw materials to end products without accumulating toxins or waste products.

"For more than 40 years, everything that we thought about cannabis cells was inaccurate because it was based on dated electron microscopy," says Dr. Samuels, a plant cell biologist at UBC. "This work defines how cannabis cells make their product. It's a paradigm shift after many years, producing a new view of cannabinoid production. This work has been challenging, partly the result of legal prohibition and also due to the fact that no protocol for the genetic transformation of cannabis has been published."

https://www.sciencedaily.com/releases/2022/08/220802121714.htm

Study identifies new links between REM sleep disturbances and drug relapse

Hypothalamic MCH neurons may be a treatment target, report researchers

July 26, 2022

Science Daily/Elsevier

Relapse presents a major barrier to recovery from substance use disorders -- when people begin taking drugs such as cocaine again after a period of abstinence. Sleep disruptions have long been associated with drug withdrawal and relapse. Now, a new study provides a more detailed picture of recovery-related sleep that could lead to insights for better recovery treatments.

The study, led by Yanhua Huang, PhD, at the University of Pittsburgh, appears in Biological Psychiatry, published by Elsevier.

"Rapid eye movement (REM) sleep is important for regulating emotion. For years, we have seen REM sleep changes associated with cocaine-seeking behaviors in our rat models. This is our first comprehensive study to examine what specific features of REM sleep may be related and why," said Dr. Huang.

In 2006, Peter Morgan, Robert Malison, and their collaborators first reported the existence of an unappreciated form of insomnia in individuals recovering from cocaine use disorder defined by brain waves measured during sleep. The pattern emerged over the initial weeks of cocaine abstinence, at a time when people were reporting subjectively "improved" sleep, and which was related to their risk for relapse. In a continuation of that work, said Biological Psychiatry Editor John Krystal, MD, "this interesting new study in rodents by Guo et al. identifies a disturbance in REM sleep during the recovery from chronic cocaine administration that also predicts the propensity for subsequent relapse to cocaine self-administration."

Dr. Huang said, "Previously there was a notion that poor sleep may worsen drug craving and relapse -- and we now offer a more granular view on the specific sleep features to be considered for potential biomarkers for predicting relapse."

For the study, the researchers trained male rats to self-administer cocaine and then removed access to the drug, so that the rats were in long-term withdrawal. The rats were subsequently re-exposed to cocaine-associated cues, and demonstrated "craving incubation," in which the drive to take the drug increases over time. The rats also displayed REM sleep disturbances.

To further investigate potential casual relationships, the investigators increased the temperature of the rats' bedding, which increased time spent in REM sleep and improved REM sleep continuity. That led to an attenuation of the incubation of drug-seeking behavior.

The phenomenon of incubation depends on physiological changes at neuronal synapses in a brain area called the nucleus accumbens (NAc), according to previous studies. A particular type of protein, called calcium-permeable AMPA receptors, accumulates in synapses, increasing the neuronal activity there and driving drug-seeking behavior. In the current study, rats with improved REM sleep showed responses at NAc synapses that resembled those of drug-naïve rats, suggesting the ion channel normalization could underlie the improvement in relapse behavior.

Next, lead author Rong Guo and colleagues examined melanin-concentrating hormone-producing (MCH) neurons in the lateral hypothalamus, which are central to REM sleep regulation. Their activity -- and REM sleep -- increased with bedding warming. Activation of MCH neurons with optogenetic or chemogenetic technology also promoted REM sleep, decreased craving incubation, and normalized NAc synaptic activity to different extents, but only when they were activated during the light phase, when rats are normally asleep more. Together, the results indicate that MCH neuron activities in sleep recapitulate the REM sleep effects on reducing drug-seeking behavior.

Dr. Krystal said of the findings, "Guo and colleagues identify hypothalamic MCH release and its normalization of calcium-permeable AMPA receptor availability in the NAc in the resilience of rodents to relapse to cocaine self-administration."

"The results have important implications," said Dr. Huang. "For example, when treating relapse, it is important to pay attention to REM sleep improvement, complementary to current practice focusing on non-REM sleep interventions. Additionally, we have identified the important roles of MCH neurons in this regulation. This will provide the rationale for testing potential drugs in the future. Finally, we found that stimulating MCH neurons is most effective during the rat's inactive phase, thus underscoring the importance of considering the time of day and sleep/wake state for future drug development and applications."

Dr. Krystal added, "Their work draws further attention to the importance of disturbances in the integrity of sleep to relapse, and it points us toward strategies that enhance MCH signaling in sleep as a potential medication target that may be protective against cocaine relapse."

https://www.sciencedaily.com/releases/2022/07/220726132617.htm