Ketamine reverses neural changes underlying depression-related behaviors in mice

Study sheds light on the neural mechanisms underlying remission of depression

April 11, 2019

Science Daily/NIH/National Institute of Mental Health

Researchers have identified ketamine-induced brain-related changes that are responsible for maintaining the remission of behaviors related to depression in mice -- findings that may help researchers develop interventions that promote lasting remission of depression in humans. The study, funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health, appears in the journal Science.

Major depression is one of the most common mental disorders in the United States, with approximately 17.3 million adults experienced a major depressive episode in 2017. However, many of the neural changes underlying the transitions between active depression, remission, and depression re-occurrence remain unknown. Ketamine, a fast-acting antidepressant which relieves depressive symptoms in hours instead of weeks or longer, provides an opportunity for researchers to investigate the short- and long-term biological changes underlying these transitions.

"Ketamine is a potentially transformative treatment for depression, but one of the major challenges associated with this drug is sustaining recovery after the initial treatment," said study author Conor Liston, M.D., Ph.D., of Weill Cornell Medicine, New York City.

To understand mechanisms underlying the transition from active depression to remission in humans, the researchers examined behaviors related to depression in mice. Researchers took high-resolution images of dendritic spines in the prefrontal cortex of mice before and after they experienced a stressor. Dendritic spines are protrusions in the part of neurons that receive communication input from other neurons. The researchers found that mice displaying behaviors related to depression had increased elimination of, and decreased formation of, dendritic spines in their prefrontal cortex compared with mice not exposed to a stressor. This finding replicates prior studies linking the emergence of behaviors related to depression in mice with dendritic spine loss.

In addition to the effects on dendritic spines, stress reduced the functional connectivity and simultaneous activity of neurons in the prefrontal cortex of mice. This reduction in connectivity and activity was associated with behaviors related to depression in response to stressors. Liston's group then found that ketamine treatment rapidly restored functional connectivity and ensemble activity of neurons and eliminated behaviors related to depression. Twenty-four hours after receiving a single dose of ketamine, mice exposed to stress showed a reversal of behaviors related to depression and an increase in dendritic spine formation when compared to stressed mice that had not received ketamine. These new dendritic spines were functional, creating working connections with other neurons.

The researchers found that while behavioral changes and changes in neural activity in mice happened quickly (three hours after ketamine treatment), dendritic spine formation happened more slowly (12-24 after hours after ketamine treatment). While further research is needed, the authors suggest these findings might indicate that dendritic spine regrowth may be a consequence of ketamine-induced rescue of prefrontal cortex circuit activity.

Although dendritic spines were not found to underly the fast-acting effects of ketamine on behaviors related to depression in mice, they were found to play an important role in maintaining the remission of those behaviors. Using a new technology developed by Haruo Kasai, Ph.D., and Haruhiko Bito, Ph.D., collaborators at the University of Tokyo, the researchers found that selectively deleting these newly formed dendritic spines led to the re-emergence of behaviors related to depression.

"Our results suggest that interventions aimed at enhancing synapse formation and prolonging their survival could be useful for maintaining the antidepressant effects of ketamine in the days and weeks after treatment," said Dr. Liston.

"Ketamine is the first new anti-depressant medication with a novel mechanism of action since the 1980s. Its ability to rapidly decrease suicidal thoughts is already a fundamental breakthrough," said Janine Simmons, M.D., Ph.D., chief of the NIMH Social and Affective Neuroscience Program. "Additional insights into ketamine's longer-term effects on brain circuits could guide future advances in the management of mood disorders."

https://www.sciencedaily.com/releases/2019/04/190411145105.htm

Marijuana for morning sickness? It's not great for baby's brain

Study pinpoints how pot exposure during pregnancy can lead to problems with behavior and memory

April 9, 2019

Science Daily/Experimental Biology

With a growing number of states legalizing recreational or medical marijuana, more women are using the drug during pregnancy, in part due to its reported ability to relieve morning sickness. A new study, conducted in rats, sheds light on how cannabis exposure affects the brain of a developing fetus.

Previous research has shown children born to mothers who used marijuana during pregnancy are more likely to develop behavioral problems as well as learning and memory impairments. The new research offers further confirmation on those findings and pinpoints how the drug alters the intricate connections in nerves in the hippocampus, the brain's center for learning and memory. Understanding exactly how marijuana affects these brain connections could one day lead to interventions to reduce the damage, researchers say.

"The findings from this study will serve as an excellent premise for future interventions to restore memory in children exposed to cannabis during pregnancy, and for the first time, identify a specific mechanism by which learning and memory impairment occurs and how this impairment can be ameliorated," said Priyanka Das Pinky, a graduate student in the laboratory of Vishnu Suppiramaniam, PhD, acting associate dean for research and graduate programs at Auburn University.

Pinky will present the research at the American Society for Pharmacology and Experimental Therapeutics annual meeting during the 2019 Experimental Biology meeting, held April 6-9 in Orlando, Fla.

According to one previous analysis, the use of marijuana during pregnancy increased by 62 percent between 2002 and 2014, paralleling the rising popularity of marijuana in the adult U.S. population as a whole.

"Based on our research and the previous existing findings in the field, it can be said that using marijuana during pregnancy would not be a wise choice," said Pinky. "However, it is also notable that the observed effect in the offspring can vary according to their age and according to the trimester during which they were exposed to the drug as well as dose and route of administration of the drug."

The research team raised several groups of rats and exposed some of the females to a synthetic chemical that activates the same proteins as cannabis while they were pregnant. They used a dose equivalent to moderate-to-heavy marijuana use in humans. Examining the brains of the baby rats, they found the connections, or synapses, between the nerves in the hippocampus were reduced in those exposed to the synthetic cannabis.

Upon further examination, they found evidence that the root of the problem was a reduction in neural cell adhesion molecules (NCAM), a protein important for maintaining proper neural connection and synaptic strength. The finding suggests it may be possible to counteract marijuana's effects by increasing the NCAM, though more research is needed to understand the mechanisms involved and determine whether the findings, from studies in animals, would translate to human babies.

"It is still very early to come up with a conclusion about the possible safe use of marijuana during pregnancy," Pinky said. "More research is needed to evaluate the exact mechanism by which NCAM and/or its active form is modulating cellular effects while focusing on target specific drug development for amelioration of the observed cognitive deficits."

https://www.sciencedaily.com/releases/2019/04/190409135933.htm

Combining opioids and marijuana may be advantageous for pain sufferers

Study suggests using the two drugs together could reduce risk of dependency without causing cognitive problems

April 9, 2019

Science Daily/Experimental Biology

Researchers report combining cannabinoids with morphine did not significantly increase impulsivity or memory impairment in a study conducted in rhesus monkeys. The findings suggest using opioids and marijuana together could offer a safe way to cut opioid dosage among patients suffering from pain and thereby reduce their risk of becoming addicted to opioids.

"These data provide additional evidence supporting the notion that opioid-cannabinoid mixtures that are effective for treating pain do not have greater, and in some cases have less, adverse effects compared with larger doses of each drug alone," said Vanessa Minervini, PhD, a postdoctoral fellow at the University of Texas Health Science Center at San Antonio.

Minervini will present the research at the American Society for Pharmacology and Experimental Therapeutics annual meeting during the 2019 Experimental Biology meeting, held April 6-9 in Orlando, Fla.

Previous studies have suggested the cannabinoids in marijuana enhance some of the pain-relieving effects of opioid drugs but do not enhance effects related to addiction and overdose. However, both drugs individually are known to slightly impair cognition, leading to a concern that such side effects could be amplified if opioids and marijuana are used together. Researchers say the new study offers encouraging evidence this is not the case.

The research comes amid a national opioid abuse crisis in which many addictions start with opioids prescribed for pain. At the same time, marijuana use is on the rise as more states legalize the drug for medical or recreational use.

"The current opioid epidemic underscores the need for safe and effective pharmacotherapies for treating pain," said Minervini. "Combining opioid receptor agonists with drugs that relieve pain through actions at non-opioid mechanisms (for example, cannabinoid receptors) could be a useful strategy for reducing the dose of opioid needed to achieve pain relief."

The researchers gave several monkeys moderate doses of morphine and CP55940, a synthetic drug that mimics the activity of the tetrahydrocannabinol (THC) naturally found in marijuana. They assessed impulsivity and memory with tests involving touchscreens and treats. The results showed each drug impeded performance and that giving the monkeys both drugs together had a lower effect on performance than either drug alone.

While clinical trials would need to be conducted to confirm whether these results translate to humans, monkeys tend to process drugs similarly to humans and are considered a good model for cognition.

https://www.sciencedaily.com/releases/2019/04/190409135930.htm

Fresh guidance to fill 'information vacuum' on new cannabis products for medicinal use

April 7, 2019

Science Daily/University of Bath

A clinical review, published today (Saturday 6 April 2019) for the BMJ, provides new interim advice for doctors and clinicians in prescribing cannabis-based products and cannabinoids to treat certain conditions.

Since a policy change in November 2018, specialist doctors registered with the General Medical Council (GMC), have been permitted to prescribe new medicines which derive from cannabis. Yet, research into these products has, to date, been limited creating an 'information vacuum' about these medicines, their benefits or harms.

A new review authored by leading scientists and clinicians from the University of Bath and University College London (UCL) points to the array of different cannabis-based products and cannabinoids available, and a clear need to educate both patients and clinicians into what these different products do and how they might help.

In particular, it points to important differences between products containing THC (the main psychoactive and intoxicating constituent of cannabis) versus CBD (the non-intoxicating element). Although in certain medicines CBD and THC are combined for clinical benefit, in others these components can work independently, playing different roles in improving certain symptoms.

For example, several studies have found that a combination of THC and CBD can alleviate symptoms of chronic pain, while CBD alone may be effective for treatment-resistant epilepsy. By contrast THC alone may be effective for treating nausea and vomiting caused by chemotherapy. THC and CBD are both 'cannabinoids' that act in different ways on the body's endogenous cannabinoid system.

The cannabis plant produces over 144 different cannabinoids such as THC or CBD. Some medicinal products contain THC and/or CBD derived from the cannabis plant, while others contain synthetically produced cannabinoids. CBD is also available in non-medicinal products such as oils and tinctures.

Lead author, Dr Tom Freeman of the University of Bath's Addiction and Mental Health Group explains: "In this complex and rapidly evolving field, there are several different cannabis-based and cannabinoid medicinal products. These differ in their THC and CBD content, who can prescribe them, and the conditions they may be used to treat. Here we provide an update for clinicians in advance of forthcoming NICE guidelines.

"A key message is that CBD products widely sold online and in health food shops lack quality standards and should not be treated as medicinal products."

Research on cannabis was previously restricted because it was listed in Schedule 1, implying that it had no medical value. Cannabis was recently moved to Schedule 2 in the UK.

Dr Freeman adds: "Research on unlicensed cannabis products has been limited to date. The rescheduling of cannabis and allocation of dedicated UK research funding will improve the evidence we have to guide clinical decision-making."

Co-author, Dr Michael Bloomfield Head of Translational Psychiatry at University College London (UCL) added: "There have been leaps and bounds in our scientific knowledge in recent years, which combined with confusing claims about the medicinal uses of these drugs can be potentially perplexing for doctors and patients. We hope that our new guidance is helpful to doctors and patients worldwide. Much more research is needed into this new class of medicine."

Co-author Dr Chandni Hindocha of the Clinical Psychopharmacology Unit at UCL added: "Resources must be made available to update and educate clinicians about cannabis and cannabinoid based medicines. We would like to encourage doctors to maintain a compassionate and evidence-based approach when engaging with their patients in this rapidly developing field, in order to provide the best standard of care."

https://www.sciencedaily.com/releases/2019/04/190407144234.htm

Severe psychological distress and daily cannabis use: Implications for mental health?

April 4, 2019

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

Daily cannabis use increased significantly from 2008 to 2016 among those with and without past-month serious psychological distress (SPD) and use among those with SPD was persistently higher compared to those without SPD. Research at Columbia Mailman School and CUNY shows that in 2016, past-month daily cannabis use was about three times higher for SPD (8%) compared to those without SPD (2.7%). The findings are online in the journal Drug and Alcohol Dependence.

"Our research found that persons with SPD reported higher daily cannabis prevalence each study year," said senior author Renee Goodwin, PhD, Department of Epidemiology. "Therefore, it is important to consider potential consequences of this increased use for those with mental health vulnerabilities."

Data were drawn from adults age 18 and older in the 2008-2016 National Survey on Drug Use and Health, a sample of 356,413 and measured by the Kessler Psychological Distress Scale.

Non-Hispanic Black respondents were the only demographic group where daily cannabis use did not significantly differ among persons with and without SPD.

"With the rapid legalization of medicinal and recreational use of cannabis in the U.S. and liberalization of social norms, more research is needed to understand the impact of these changes on vulnerable groups," said Goodwin. "A better understanding of whether some subgroups need tailored clinical efforts to reduce (daily and/or heavy) cannabis use, especially among those with SPD, will also provide a clearer picture of what is needed next."

https://www.sciencedaily.com/releases/2019/04/190404132532.htm

Psychedelic drug MDMA may reawaken 'critical period' in brain to help treat PTSD

April 4, 2019

Science Daily/Johns Hopkins Medicine

Johns Hopkins neuroscientists have found that the psychedelic drug MDMA reopens a kind of window, called a "critical period," when the brain is sensitive to learning the reward value of social behaviors. The findings, reported April 3 in Nature, may explain why MDMA may be helpful in treating people with post-traumatic stress disorder (PTSD).

Critical periods were first described in the 1930s in snow geese. About 24 hours after a gosling hatches, if mother goose is nowhere to be found, the hatchling will bond with an object, including non-living ones. Yet, if mother goose disappears 48 hours after her gosling hatches, the critical period is over, and the hatchling won't bond to an object.

There is evidence for critical periods that smooth the way for development of language, touch and vision.

For the current study, neuroscientist Gül Dölen says, "We wanted to know if there was a critical period for learning social reward behaviors, and if so could we reopen it using MDMA, since this drug is well-known to have prosocial effects."

Dölen and her team studied groups of mice in enclosures with different bedding. They put several mice together in one enclosure with one type of bedding for 24 hours and, in the next 24 hours, put the same mice by themselves in another enclosure with a different type of bedding. The mice began to associate certain types of bedding with isolation or companionship. Then, they let the mice wander between enclosures with the two types of bedding and tracked how long the mice spent in each enclosure. The more time the mice spent in the bedding linked to their companions indicated more social reward learning.

"It's why people gather around the water cooler," says Dölen, assistant professor of neuroscience at the Johns Hopkins University School of Medicine. People are conditioned to know that the water cooler is an optimal place to chitchat with companions.

In their experiments, Dölen and her colleagues found that the critical period for social reward learning in mice is around puberty and wanes once they become mature adults. To determine if they could reopen the critical period, the scientists gave MDMA to mature mice, waited 48 hours for the drug to be washed out of their system, and observed how the mice explored their enclosure and behaved with other mice in the enclosure. Following the treatment with MDMA, most of the animals responded to social interactions the same way as juveniles, by forming a positive association between social interactions and the bedding. This effect lasted for at least two weeks after the MDMA treatment, and it was not observed in mice given saline injections.

"This suggests that we've reopened a critical period in mice, giving them the ability to learn social reward behaviors at a time when they are less inclined to engage in these behaviors," says Dölen.

Dölen and her postdoctoral student and first author of the current study, Romain Nardou, also observed that MDMA works to reopen the critical period only if the drug is given to mice when they are with other mice, not if it is given to mice while they are alone. This suggests that reopening the critical period using MDMA may depend on whether the animals are in a social setting, say the scientists.

The mice maintained their ability to learn the rewards of social behavior for up to two weeks from the time they were given MDMA. During this time, Dölen and her colleagues also found that the brains of the mice had corresponding responses to oxytocin, known as the "love hormone," which is made in the hypothalamus and acts in the brain as a signal between neurons that encode information about social rewards. They found these responses by looking more closely at synapses, the spaces between brain cells called neurons. Their experiments showed that, in mature mice given MDMA, oxytocin triggers signaling in the synapses that encodes learning and memory, which does not typically happen in mature mice.

Dölen says that opening the critical window for social reward behavior may also have implications for treating psychiatric conditions. A strong bond between a psychotherapist and patient is well-known to be important for successful treatment. If MDMA reopens the critical period for social reward learning in humans in the same way it does for mice, then it could explain why the drug has been successful in treating people with PTSD, perhaps by strengthening the psychotherapist-patient bond.

MDMA has been designated by the U.S. Food and Drug Administration as a "breakthrough therapy" for PTSD, meaning that the agency will fast-track the development and review of clinical trials to test it. However, the researchers caution that MDMA may not work for every psychiatric condition linked to social behaviors.

"As we develop new therapies or determine when to give these therapies, it's critical to know the biological mechanism on which they act," says Dölen.

Funding for the study was provided by the Kinship Foundation, Hartwell Foundation, Klingenstein-Simons Foundation, the National Institutes of Health (MH115177, 1R01NS075421), the New York Stem Cell Foundation-Robertson Award and the National Institutes of Health Director's Pioneer Award (1DP1NS087724).

In addition to Dölen and Nardou, other contributors to the study include Eastman M. Lewis and Rebecca Rothhaas from Johns Hopkins and Ran Xu, Aimei Yang and Edward Boyden from MIT.

https://www.sciencedaily.com/releases/2019/04/190404094832.htm

Cannabis during pregnancy bumps psychosis risk in offspring

With marijuana use rising among pregnant women, study raises new concerns

March 27, 2019

Science Daily/Washington University in St. Louis

Pregnant women who use cannabis may slightly increase the risk their unborn child will develop psychosis later in life, suggests new research from Washington University in St. Louis.

"Our research shows that prenatal marijuana exposure after maternal knowledge of pregnancy is associated with a small increase in psychosis proneness during middle childhood or about age 10," said Jeremy Fine, an undergraduate majoring in psychological & brain sciences in Arts & Sciences at Washington University and the study's lead author.

The findings come on the heels of several national studies documenting a dramatic increase in marijuana usage by pregnant women, including a 2018 study from Washington University School of Medicine in St. Louis that found past-month marijuana use among pregnant mothers in the United States increased by 75 percent between 2002 (2.85 percent) and 2016 (4.98 percent).

As more states legalize medicinal and recreational use of cannabis, other reports suggest that many marijuana dispensaries commonly suggest cannabis as a natural cure for pregnancy related nausea.

This latest study, published March 27 in the journal JAMA Psychiatry, suggests that pregnant women should be discouraged from using cannabis at any time in their pregnancy because so little is yet known about its health effects.

But its findings also raise new concerns that prenatal exposure to cannabis may pose a greater risk after the fetal brain begins to develop a receptor system for endocannabinoids, which are part of the naturally occurring neurotransmitter network through which cannabis affects the brain.

"One possible explanation for the finding of increased psychosis risk for marijuana use following, but not before, knowledge of pregnancy is that the endocannabinoid receptor system may not be in place during the early weeks of pregnancy," said Ryan Bogdan, associate professor of psychological & brain sciences and senior author of the paper. "Prenatal cannabis exposure may be associated with later psychosis proneness in offspring only when there is sufficient fetal endocannabinoid type 1 receptor expression, which may not occur until after many mothers learn they are pregnant."

Bogdan, who directs the Washington University BRAIN Lab where the research took place, said these latest findings build on other basic research suggesting that endocannabinoid signaling may contribute to processes, such as neurogenesis and neural migration, that play important roles in early development of brain structure and connections.

"This study raises the intriguing possibility there may be developmental windows during which cannabis exposure may be more likely to increase psychosis risk," he said.

Tetrahydrocannabinol (THC), which is the principal psychoactive component of marijuana, mimics our body's endocannabinoids and binds to endocannabinoid receptors to exert its effects. Various studies have confirmed that THC crosses the placental barrier to gain access to the developing fetus.

"Data from rodent studies suggest that the endocannabinoid type 1 receptor, through which the psychoactive effects of THC largely arise, is not expressed until the equivalent of 5-6 weeks of human gestation," Fine said. "Given that mothers in our study on average learned of their pregnancy at 7.7 weeks, it is plausible that any impact of THC on psychosis risk would not arise until sufficient endocannabinoid type 1 receptors are expressed."

The BRAIN Lab findings are based on data from the Adolescent Brain Cognitive Development (ABCD) study, an ongoing longitudinal study of child health and brain development with data collection sites throughout the nation. They used data from the initial ABCD baseline data release which included survey responses from 3,774 mothers about marijuana usage during 3,926 pregnancies. Risk of psychosis in the 4,361 children born from these pregnancies between 2005 and 2008 was measured using a questionnaire administered to the children between ages 8.9 and 11 years.

Among the 4,361 children sampled in this study, 201 (4.61 percent) were reported to have been exposed to marijuana before birth. Of these, 138 were exposed only before mothers knew they were pregnant; two were exposed only after the mother knew she was pregnant.

Bogdan and his co-authors acknowledge that the study has many limitations, including the small sample of prenatal cannabis-exposed offspring; potential maternal underreporting of use during pregnancy; imprecise data on timing, amount, frequency and potency of cannabis exposure; absence of data on whether childhood psychosis proneness is associated with conversion to psychosis; and lack of data on some potential confounders, such as maternal stress and genetic risk of psychosis among parents.

"Our research is correlational and as such cannot draw causal conclusions," said Allison Moreau, study co-author and a graduate student in psycholody at Washington University. "However, that the relationship between prenatal marijuana exposure following maternal knowledge of pregnancy was associated with offspring psychosis proneness after accounting for potentially confounding variables -- such as maternal education, prenatal vitamin usage, prenatal alcohol and nicotine use, child substance use, and so on -- increases the plausibility that prenatal cannabis exposure may contribute to a small risk of increased psychosis liability in children."

The study provides further evidence that expectant mothers should think twice before considering cannabis usage during pregnancy.

"Given increasing cannabis accessibility and potency, as well as growing public perceptions that it's safe to use, it is critical for additional research to understand the potential adverse consequences and benefits of cannabis throughout development and how these associations may arise." Bogdan said. "In the meantime, evidence that prenatal marijuana use is associated with a small increase in offspring psychosis proneness suggests that marijuana use during pregnancy should be discouraged until more is known."

Other Washington University co-authors include Nicole Karcher, post-doctoral research scholar; Arpana Agrawal, professor of psychiatry; and Cynthia Rogers, assistant professor of child psychiatry, all in the Department of Psychiatry in the School of Medicine; and Deanna Barch, chair of the Department of Psychological & Brain Sciences in Arts & Sciences and the Gregory B. Couch Professor of Psychiatry at the School of Medicine.

Funding for this study was provided by the Adolescent Brain Cognitive Development (ABCD) study, which was funded by awards from the National Institutes of Health and additional federal partners.

https://www.sciencedaily.com/releases/2019/03/190327112617.htm

Patients with or without cancer use different forms of marijuana

March 26, 2019

NYU Langone Health / NYU School of Medicine

People with and without cancer are more likely, over time, to use a more potent form of medical marijuana with increasingly higher amounts of tetrahydrocannabinol (THC), a new study shows.

In a report publishing in the Journal of Palliative Medicine on March 26, researchers say that cancer patients were more likely to favor forms of medical marijuana with higher amounts of THC, which relieves cancer symptoms and the side effects of cancer treatment, including chronic pain, weight loss, and nausea.

By contrast, marijuana formulations higher in cannabidiol (CBD), which has been shown to reduce seizures and inflammation in other studies, were more popular among non-cancer patients, including those with epilepsy and multiple sclerosis, say the study authors.

Cancer patients were also more likely to prefer taking oil droplets containing medical marijuana under the tongue than "vaping."

"Although there is growing patient interest in medical cannabis, there is a scarcity of solid evidence about the benefits, risks, and patterns of use of marijuana products in various disease settings," says study lead investigator Arum Kim, MD, an assistant professor of medicine and rehabilitation medicine at NYU School of Medicine and director of the supportive oncology program at its Perlmutter Cancer Center. "Such information is important for delivering the best care."

Since 1996, 31 states, including New York in 2014, have legalized medical marijuana.

For the study, researchers analyzed data from 11,590 men and women in New York, of whom 1,990 (17.2 percent of the total patient cohort) were cancer patients who purchased and used cannabis products from Columbia Care LLC., a dispensary licensed in New York State, between January 2016 and December 2017.

The researchers caution that their data did not include the type of cancer the purchasers had, how much of what they bought was used, or whether marijuana was used for symptoms unrelated to the cancer. Nevertheless, the patterns of use among cancer patients were distinctly different from those of non-cancer patients.

Specifically, the study found that cancer and non-cancer patients used different dosages of cannabis formulations with dramatically different THC:CBD ratios. The two most common formulations contained THC and CBD, but one had twenty times more THC than CBD, whereas the other had the opposite ratio.

Over the two years of the study, the research team found that all types of patients increased their THC dose by approximately 0.20 milligrams per week.

"Our study provides valuable new information about how cancer patients are using marijuana," says study senior investigator Benjamin Han, MD, MPH, an assistant professor of medicine and population health at NYU School of Medicine. "In the absence of strong clinical research data for medical marijuana, identifying patterns of use offers some sense of how to guide patients who come in with questions for using medical marijuana, and what may or may not help them."

Researchers say they next plan to get more detailed information about how medical marijuana affects patient response to therapy and functional status at different stages of their disease, as well as the risks and side effects of treatment. Furthermore, the profiles of other cannabinoids besides THC and CBD in medical marijuana products warrant further research, according to the study authors.

Along with Kim and Han, another co-author from NYU School of Medicine and Perlmutter Cancer Center, which funded the study, was Zujun Li, MD. Other study authors include Christopher Kaufmann, PhD, MHS, at University of California San Diego; and Roxanne Ko, BA, BS, at the University of Hawaii.

https://www.sciencedaily.com/releases/2019/03/190326081343.htm

Medical marijuana laws linked to health and labor supply benefits in older adults

Findings show that pain declines, assessments of health improve and Americans remain in the workforce

March 19, 2019

Science Daily/Johns Hopkins University Bloomberg School of Public Health

A study that examined older Americans' well-being before and after medical marijuana laws were passed in their state found reductions in reported pain and increased hours worked. The study suggests medical marijuana laws could be improving older Americans' health.

The paper analyzed more than 100,000 responses from survey participants age 51 and older from 1992 to 2012. Researchers found a 4.8 percent decrease in reported pain and a 6.6 percent increase in reported very good or excellent health among respondents with a health condition that would qualify for medical marijuana after their states passed medical marijuana laws relative to similar respondents whose states did not pass a law.

The study appears in the Spring 2019 issue of the Journal of Policy Analysis and Management.

"Our study is important because of the limited availability of clinical trial data on the effects of medical marijuana," says Lauren Hersch Nicholas, PhD, assistant professor in the Bloomberg School's Department of Health Policy and Management. "While several studies point to improved pain control with medical marijuana, research has largely ignored older adults even though they experience the highest rates of medical issues that could be treated with medical marijuana."

Medical marijuana remains controversial as national support for it surges. Opponents continue to argue that legalizing medical marijuana would promote illegal use of the drug and increase misuse of related substances. Supporters highlight the potential health benefits of medical marijuana for pain management and other conditions. By the end of 2018, 33 states and Washington, D.C. had passed laws legalizing medical use of marijuana.

For their study, researchers used data from the 1992-2012 Health and Retirement Study (HRS), the largest nationally representative survey to have track health and labor market outcomes among older Americans. The researchers examined survey responses about symptoms that have a plausible link to one's ability to work: frequency of pain, whether health limits work, overall health assessment and depressive symptoms. At the time of the analysis, 20 states had medical marijuana laws in place.

The analysis matched medical marijuana law effective dates to the HRS interview responses, based on month and year, to track the possible effects of these policy changes. The analysis used 100,921 participant responses that represented individuals with one or more of four health conditions that would qualify for medical marijuana treatment under most state laws (arthritis, cancer, glaucoma and pain). The paper found that 55 percent of the study sample were suffering from one or more of these diagnoses.

The study found that medical marijuana laws lead to increases in full-time work in both samples.

In the sample that would qualify for medical marijuana treatment, the researchers found a greater increase in full-time work after medical marijuana laws were passed. In the full sample, researchers found a 5 percent increase in full-time work versus a 7.3 percent in the sample that qualified for medical marijuana. These results suggest that any decline in productivity resulting from medical marijuana usage -- such as not being able to work at capacity while under treatment -- is outweighed by increased capacity to work.

The study found no evidence that medical marijuana laws were associated with changes in daily activities such as getting dressed, going to the bathroom or walking.

"These findings underscore the close relationship between health policy and labor supply within older adults," says Nicholas. "When we're doing policy evaluations, we have to think not only about whether the policy is changing health outcomes, but also whether it does it in a way that supports labor force participation."

The results can help inform policy decisions about medical marijuana policy and broaden clinical support for additional research on marijuana as an effective medical treatment. This is important, the authors say, because marijuana is still illegal and classified as a schedule 1 drug at the federal level, and there remains limited clinical evidence available to inform medical marijuana policies and treatment options for many patients, especially older adults.

The study was supported by the National Institute on Aging.

https://www.sciencedaily.com/releases/2019/03/190319121750.htm

Go for a run or eat chocolate: A choice dictated by the cannabinoid receptors

March 19, 2019

INSERM (Institut national de la santé et de la recherche médicale)

Physical inactivity is a common factor in lifestyle diseases -- and one that is often linked to the excessive consumption of fatty and/or sugary foods. The opposite scenario of excessive physical activity at the expense of caloric intake can also be harmful, as cases of anorexia nervosa illustrate. These data therefore point to the crucial need to research the neurobiological processes that control the respective motivations for exercise and food intake. A study by Inserm and CNRS researchers published on March 7, 2019 in JCI Insight reveals that the cannabinoid type 1 (CB1) receptors play an essential role in the choice between running and eating chocolatey food.

The authors of this paper had previously reported that the cannabinoid type-1 (CB1) receptors, present on several types of neurons, play a key role in performance during physical activity in mice. A conclusion based on the performances achieved by animals with free access to an exercise wheel -- a model in which it was not possible to distinguish the mechanism involved (motivation, pleasure...). Given that the motivation for a reward can only be estimated by measuring the efforts that the individual -- whether human or animal -- is prepared to make to get that reward, the researchers devised a model in which each access to the wheel was conditional on a prior effort. This involved the animal repeatedly introducing its snout into a recipient, an essential prerequisite for unlocking the wheel. After a training period during which the level of effort required to unlock the wheel remained the same, the mice were confronted with a test in which the effort required was gradually increased. When exposed to this test, the mice lacking CB1 receptors showed an 80 % deficit in the maximum effort they were prepared to make to unlock the wheel, and without a decrease in performance during their access to it. This finding indicates that the CB1 receptors play a major role in controlling motivation for exercise. The use of other genetically-modified mice also enabled the researchers to demonstrate that these CB1 receptors controlling motivation for exercise are located on GABAergic neurons.

The researchers then examined whether the CB1 receptors in the GABAergic neurons control the motivation for another reward: chocolatey food (like humans, mice love it even when they are otherwise well-fed). While the CB1 receptors also play a role in motivation for food -- albeit to a lesser extent than in motivation for exercise -- the CB1 receptors located on the GABAergic neurons are not implicated in the motivation for eating chocolatey food.

In our daily life, we are faced with an ongoing choice between various rewards. A fact which has encouraged the researchers to develop a model in which following a learning period the mice had the choice -- in return for the efforts described above -- between exercise and chocolatey food. The motivation for exercise was greater than that for chocolatey food, with the exception of the mice lacking CB1 -- whether generally or just on GABAergic neurons -- whose preference was for the food.

In addition to these findings indicating that the cannabinoid receptor is essential for the motivation for exercise, this study opens up avenues for researching the neurobiological mechanisms behind pathological increases in this motivation. One illustration is provided by anorexia nervosa which often combines the decreased motivation to eat with an increased motivation to exercise.

https://www.sciencedaily.com/releases/2019/03/190319121721.htm

Most teens report using marijuana less often after legalization

March 18, 2019

Washington State University

Only one group of teenagers used marijuana more often after retail sales were legalized in Washington than they did before -- high school seniors who work 11 or more hours per week, according to new research led by a WSU College of Nursing professor.

Marijuana use went down significantly among 8th and 10th graders after legalization, and among 12th graders who didn't work. It stayed nearly even for high school seniors who work less than 11 hours per week.

The research on marijuana use and employment, led by WSU College of Nursing Assistant Professor Janessa Graves, appears in the Journal of Adolescent Health.

Washington was one of the first states to approve legalization of marijuana for retail sale, with recreational cannabis stores opening in mid?2014.

The authors were interested in knowing whether legalization in Washington made a difference in marijuana use among 8th, 10th, and 12th graders who work in jobs that don't include household chores, yard work or babysitting. They used data from the state's biennial Healthy Youth Survey from 2010 and 2016 in their study.

No matter what grade the students were in, those who worked 11 or more hours per week reported using marijuana more often than their non?working peers.

Post-legalization, 4.8 percent of non?working 8th graders reported using pot within the last 30 days, while 20.8 percent of their working peers did. Among 10th graders, 13.9 percent reported using marijuana within the last 30 days in 2016, versus 33.2 percent of 10th graders who worked 11 or more hours per week. The difference for 12th graders was 20.5 percent non?working, versus 36.7 percent working.

"Kids who work more often use substances, that's not a shock," Graves said, noting other studies have shown the same result. Teenagers who work usually come into contact with adults who aren't their coaches, teachers and parents, and they are often exposed to adult substance use. In addition, working teens have more disposable income than their non?working peers, the study notes.

So what's a parent of an older teen to do?

"Kids learn a lot by working, in terms of responsibility," Graves said. "But there are also pretty good data showing that kids who work engage in adult?like behaviors earlier. I would say this for any parent of working kids: It's important to know the quality of management and supervision at your child's job. Be thoughtful about the quality of a particular workplace."

The study also suggests that employers could take action by advertising and enforcing zero-tolerance policies of adult employees providing substances or endorsing substance use to their adolescent co-workers.

https://www.sciencedaily.com/releases/2019/03/190318102423.htm

Fast-acting psychedelic associated with improvements in depression/anxiety

March 18, 2019

Science Daily/Johns Hopkins Medicine

Johns Hopkins researchers have discovered that use of the synthetic psychedelic 5-methocy-N,-N-dimethyltryptamine (5-MeO-DMT) appears to be associated with unintended improvements in self-reported depression and anxiety when given in a ceremonial group setting. 5-MeO-DMT is a psychedelic that is found in the venom of Bufo Alvarius toads, in a variety of plants species, and can be produced synthetically.

In a survey of 362 adults, approximately 80 percent of respondents reported improvements in anxiety and depression after use. These improvements were related to more intense acute mystical effects during the 5-MeO-DMT experience, as well as increases in rating of the personal meaning and spiritual significance of the experience. Improvements were also related to stronger beliefs that the experience contributed to enduring well-being and life satisfaction. These results were published in The American Journal of Drug and Alcohol Abuse.

One of the unique properties of 5-MeO-DMT is the fast action and short duration of the psychedelic effects when compared to other psychedelics. "Research has shown that psychedelics given alongside psychotherapy help people with depression and anxiety. However, psychedelic sessions usually require 7 -- 8 hours per session because psychedelics typically have a long duration of action," says Alan K. Davis, Ph.D., a postdoctoral research fellow in the Behavioral Research Unit, at the Johns Hopkins University School of Medicine. "Because 5-MeO-DMT is short-acting and lasts approximately 30-90 minutes, it could be much easier to use as an adjunct to therapy because current therapies usually involve a 60 -- 90 minute session."

Last year, Davis published a study in Frontiers in Psychology that found that 5-MeO-DMT administered in a psychospiritual retreat setting produced comparable ratings of mystical experience as a high-dose psilocybin session in the laboratory setting. Another study by Davis that came out last year in The Journal of Psychopharmacology showed that 5-MeO-DMT had a safe profile of use and low risk for health and legal consequences.

"It is important to examine the short- and long-term effects of 5-MeO-DMT, which may enhance mood in general or may be particularly mood enhancing for those individuals experiencing clinically significant negative mood," says Davis. "Regardless, this research is in its infancy and further investigation is warranted in healthy volunteers."

The authors on this paper were Alan K. Davis, Sara So and Roland R. Griffiths of Johns Hopkins, Rafael Lancelotta of University of Wyoming and Joseph P. Barsuglia of New School Research.

The study was funded by grants from the National Institute on Alcohol Abuse (AA 007747) and the National Institute on Drug Abuse (T32 DA007209, R01 DA003889).

https://www.sciencedaily.com/releases/2019/03/190318132628.htm

Psychedelic microdosing in rats shows beneficial effects

March 4, 2019

Science Daily/University of California - Davis

Microdosing -- taking tiny amounts of psychedelic drugs to boost mood and mental acuity -- is based on anecdotal reports of its benefits. Now, a study in rats suggests microdosing can provide relief for symptoms of depression and anxiety, but also has potential negative effects.

The growing popularity of microdosing -- taking tiny amounts of psychedelic drugs to boost mood and mental acuity -- is based on anecdotal reports of its benefits. Now, a study in rats by researchers at the University of California, Davis suggests microdosing can provide relief for symptoms of depression and anxiety, but also found potential negative effects. The work is published March 4 in the journal ACS Chemical Neuroscience.

"Prior to our study, essentially nothing was known about the effects of psychedelic microdosing on animal behaviors," said David Olson, assistant professor in the UC Davis departments of Chemistry and of Biochemistry and Molecular Medicine, who leads the research team. "This is the first time anyone has demonstrated in animals that psychedelic microdosing might actually have some beneficial effects, particularly for depression or anxiety. It's exciting, but the potentially adverse changes in neuronal structure and metabolism that we observe emphasize the need for additional studies."

Testing microdosing claims

Olson's group microdosed male and female rats with DMT, short for N,N-dimethyltryptamine. A psychedelic compound found in ayahuasca tea, DMT's molecular structure is embedded within the structures of popular microdosing drugs such as LSD and psilocybin. The researchers administered one-tenth of the estimated hallucinogenic dose in rats (1 milligram per kilogram of body weight) every third day for two months. Although there is no well-established definition of what constitutes a microdose, people who microdose tend to follow a similar schedule, taking one-tenth of a "trip" dose every three days. The rats were treated for two weeks before beginning behavioral tests relevant to mood, anxiety and cognitive function, and tests were completed during the two-day period between doses.

Olson's group found DMT microdosing helped rats to overcome a "fear response" in a test considered to be a model of anxiety and post-traumatic stress disorder (PTSD) in humans. The researchers also documented reduced immobility in an experiment that measures the effectiveness of antidepressant compounds. Less immobility is associated with antidepressant effects. In tests of cognitive function and sociability, the UC Davis researchers did not find any obvious impairments or improvements, which contrasts with human anecdotal reports.

Microdosing: potential risks

The team documented some potential risks: the dosing regimen significantly increased bodyweight in male rats, for example. It also caused neuronal atrophy in female rats. The latter change was unexpected, as previously Olson's group reported that rats treated with a single high dose of DMT showed increased neuronal growth. The results suggest an acute hallucinogenic dose and chronic, intermittent low doses of DMT produce very different biochemical and structural phenotypes, Olson said.

Despite the potential adverse effects of microdosing, the findings mean that it's possible to decouple the hallucinogenic effects from the therapeutic properties of these compounds.

"Our study demonstrates that psychedelics can produce beneficial behavioral effects without drastically altering perception, which is a critical step towards producing viable medicines inspired by these compounds," Olson said.

https://www.sciencedaily.com/releases/2019/03/190304100015.htm

Could medical marijuana help older people with their ailments?

New study shows it may be safe and effective for symptoms of chronic disease

February 28, 2019

Science Daily/American Academy of Neurology

Medical marijuana may bring relief to older people who have symptoms like pain, sleep disorders or anxiety due to chronic conditions including amyotrophic lateral sclerosis, Parkinson's disease, neuropathy, spinal cord damage and multiple sclerosis, according to a preliminary study released today that will be presented at the American Academy of Neurology's 71st Annual Meeting in Philadelphia, May 4 to 10, 2019. The study not only found medical marijuana may be safe and effective, it also found that one-third of participants reduced their use of opioids. However, the study was retrospective and relied on participants reporting whether they experienced symptom relief, so it is possible that the placebo effect may have played a role. Additional randomized, placebo-controlled studies are needed.

According to the Centers for Disease Control and Prevention, approximately 80 percent of older adults have at least one chronic health condition.

"With legalization in many states, medical marijuana has become a popular treatment option among people with chronic diseases and disorders, yet there is limited research, especially in older people," said study author Laszlo Mechtler, MD, of Dent Neurologic Institute in Buffalo, N.Y., and a Fellow of the American Academy of Neurology. "Our findings are promising and can help fuel further research into medical marijuana as an additional option for this group of people who often have chronic conditions."

The study involved 204 people with an average age of 81 who were enrolled in New York State's Medical Marijuana Program. Participants took various ratios of tetrahydrocannabinol (THC) to cannabidiol (CBD), the main active chemicals in medical marijuana, for an average of four months and had regular checkups. The medical marijuana was taken by mouth as a liquid extract tincture, capsule or in an electronic vaporizer.

Initially, 34 percent of participants had side effects from the medical marijuana. After an adjustment in dosage, only 21 percent reported side effects. The most common side effects were sleepiness in 13 percent of patients, balance problems in 7 percent and gastrointestinal disturbances in 7 percent. Three percent of the participants stopped taking the medical marijuana due to the side effects. Researchers said a ratio of one-to-one THC to CBD was the most common ratio among people who reported no side effects.

Researchers found that 69 percent of participants experienced some symptom relief. Of those, the most common conditions that improved were pain with 49 percent experiencing relief, sleep symptoms with 18 percent experiencing relief, neuropathy improving in 15 percent and anxiety improving in 10 percent.

Opioid pain medication was reduced in 32 percent of participants.

"Our findings show that medical marijuana is well-tolerated in people age 75 and older and may improve symptoms like chronic pain and anxiety," said Mechtler. "Future research should focus on symptoms like sleepiness and balance problems, as well as efficacy and optimal dosing."

The study was supported by the Dent Family Foundation.

https://www.sciencedaily.com/releases/2019/02/190228164023.htm

Junk food purchases increase after recreational marijuana legalization

February 28, 2019

Science Daily/University of Connecticut

It's an infamous pop culture portrayal. After smoking marijuana, the main characters in the movie go on an epic junk-food binge, consuming mass quantities of chips, cookies, and whatever other high-calorie, salt-or-sugar-laden snacks they can get. While some neuroscientists have hypotheses, there remains no formal causal evidence to support this notorious effect of marijuana on the human brain.

A study released this month from a UConn economist, however, did find a link between state recreational marijuana legalization and increased consumption of certain high-calorie foods, suggesting there may be something more substantial to the urban myth of "the munchies."

Assistant professor of economics Michele Baggio conducted the study in collaboration with Alberto Chong, a professor at Georgia State University's Andrew Young School of Policy Studies. Published by the Social Science Research Network, the study looked at data on monthly purchases of cookies, chips, and ice cream from grocery, convenience, drug, and mass distribution stores in more than 2,000 counties in the United States over a 10-year period. The data, largely taken from the Nielsen Retail Scanner database, covers 52 designated market areas in the 48 contiguous states.

The researchers compared purchasing trends to the implementation dates for recreational marijuana laws in states including Colorado, Oregon, and Washington. Their analysis showed that legalizing recreational marijuana led to a 3.1 percent increase in ice cream purchases, a 4.1 percent increase in cookie purchases, and a 5.3 percent increase in chip purchases immediately after recreational marijuana sales began. While increases in ice cream and chip purchases reduced slightly in the months following legalization, the increase for cookie purchases remains high.

"These might seem like small numbers," says Baggio. "But they're statistically significant and economically significant as well."

The trend was consistent across the three legalizing states included in the study. Additional states that have also legalized recreational marijuana were not included in the study because 18 months of purchasing data was not yet available for those states.

While Baggio initially set out to see whether ties existed between marijuana legalization and increased obesity rates, this study did not delve into an analysis of obesity rates, instead focusing strictly on trends in sales data. Further analysis of health trends may come at a later date, but he says that both the growing marijuana industry and policymakers may find the developing research around varying aspects of marijuana legalization of interest when considering future policies.

"I'm not an advocate for legalization or not," Baggio says. "I'm just interested in whether there are unintended consequences to the policy."

https://www.sciencedaily.com/releases/2019/02/190228134227.htm

Yeast produce low-cost, high-quality cannabinoids

February 27, 2019

Science Daily/University of California - Berkeley

Synthetic biologists have created an enzymatic network in yeast that turns sugar into cannabinoids, including tetrahydrocannabinol and cannabidiol, but also novel cannabinoids not found in the marijuana plant itself. The yeast factories would be more environmentally friendly and less energy intensive than growing the plant and separating out the psychoactive and non-psychoactive ingredients. They may also yield cannabinoid derivatives with unexpected medical uses.

University of California, Berkeley, synthetic biologists have engineered brewer's yeast to produce marijuana's main ingredients -- mind-altering THC and non-psychoactive CBD -- as well as novel cannabinoids not found in the plant itself.

Feeding only on sugar, the yeast are an easy and cheap way to produce pure cannabinoids that today are costly to extract from the buds of the marijuana plant, Cannabis sativa.

"For the consumer, the benefits are high-quality, low-cost CBD and THC: you get exactly what you want from yeast," said Jay Keasling, a UC Berkeley professor of chemical and biomolecular engineering and of bioengineering and a faculty scientist at Lawrence Berkeley National Laboratory. "It is a safer, more environmentally friendly way to produce cannabinoids."

Cannabis and its extracts, including the high-inducing THC, or tetrahydrocannabinol, are now legal in 10 states and the District of Columbia, and recreational marijuana -- smoked, vaped or consumed as edibles -- is a multibillion-dollar business nationwide. Medications containing THC have been approved by the Food and Drug Administration to reduce nausea after chemotherapy and to improve appetite in AIDS patients.

CBD, or cannabidiol, is used increasingly in cosmetics -- so-called cosmeceuticals -- and has been approved as a treatment for childhood epileptic seizures. It is being investigated as a therapy for numerous conditions, including anxiety, Parkinson's disease and chronic pain.

But medical research on the more than 100 other chemicals in marijuana has been difficult, because the chemicals occur in tiny quantities, making them hard to extract from the plant. Inexpensive, purer sources -- like yeast -- could make such studies easier.

Plus, he added, there is "the possibility of new therapies based on novel cannabinoids: the rare ones that are nearly impossible to get from the plant, or the unnatural ones, which are impossible to get from the plant."

Keasling, the Philomathia Foundation Chair in Alternative Energy at Berkeley, and his colleagues will report their results online Feb. 27 in advance of publication in the journal Nature.

Plugging chemical pathways into yeast

Cannabinoids join many other chemicals and drugs now being produced in yeast, including human growth hormone, insulin, blood clotting factors and recently, but not yet on the market, morphine and other opiates.

One of the pioneers of synthetic biology, Keasling has long sought to exploit yeast and bacteria as "green" drug factories, eliminating the expensive synthetic or extractive processes common in the chemical industry and the often toxic or environmentally- damaging chemical byproducts.

Cannabis cultivation is a prime example of an energy-intensive and environmentally-destructive industry. Farms in northwest California have polluted streams with pesticide and fertilizer runoff and helped drain watersheds because marijuana plants are water-hungry. Illegal grows have resulted in clear-cutting and erosion.

Indoor cultivation under grow lights with ventilation fans uses a lot of energy, accounting for a growing percentage of annual power consumption. One study estimated that California's cannabis industry accounted for 3 percent of the state's electricity usage. Indoor grows have caused blackouts in some cities, and energy consumption can add more than $1,000 to the price of a pound of weed.

Hence Keasling's interest in finding a "green" way to produce the active chemicals in marijuana.

"It was an interesting scientific challenge," he admitted, that was akin to other challenges he and his team have successfully overcome in yeast: producing an antimalarial drug, artemisinin; turning plant waste into biofuels; synthesizing flavors and scents for the food and cosmetics industries and chemical intermediates for making new materials. "But when you read about cases of patients who have seizures and are helped by CBD, especially children, you realize there is some value in these molecules, and that producing cannabinoids in yeast could really be great."

With approval and oversight by the U.S. Drug Enforcement Agency -- cannabis is still illegal under federal law -- Berkeley postdoc Xiaozhou Luo and visiting graduate student Michael Reiter, who led the project, started assembling in yeast a series of chemical steps to produce, initially, the mother of all cannabinoids, CBGA (cannabigerolic acid). In both marijuana and yeast, the chemical reactions involve the acid form of the compounds: CBGA and its derivatives, THCA and CBDA. They readily convert to CBG, THC and CBD when exposed to light and heat.

Turning yeast into chemical factories involves co-opting their metabolism so that, instead of turning sugar into alcohol, for example, yeast convert sugar into other chemicals that are then modified by added enzymes to produce a new product, such as THC, that the yeast secrete into the liquid surrounding them. The researchers ended up inserting more than a dozen genes into yeast, many of them copies of genes used by the marijuana plant to synthesize cannabinoids.

One step, however, proved to be a roadblock for Keasling's group and competing groups: an enzyme that performs a key chemical step in making CBGA in the marijuana plant didn't work in yeast.

Rather than engineer a different synthetic pathway, Berkeley postdoc Leo d'Espaux and graduate student Jeff Wong went back to the plant itself and isolated a second enzyme, prenyl transferase, that does the same thing, and stuck it in the yeast.

"It worked like gangbusters," Keasling said.

Once they had yeast-producing CBGA, they added another enzyme to convert CBGA to THCA and a different enzyme to create a pathway to CBDA. Though the products the yeast produce are predominantly THC or CBD, Keasling said, each must still be separated from other chemicals present in tiny quantities.

They also added enzymes that made the yeast produce two other natural cannabinoids, CBDV (cannabidivarin) and THCV (tetrahydrocannabivarin), whose effects are not well understood.

Surprisingly, Xiaozhou and Michael discovered that the enzymatic steps involved in making CBGA in yeast are flexible enough to accept a variety of starter chemicals -- different fatty acids in place of the one used by the marijuana plant, hexanoic acid -- that generate cannabinoids that do not exist in the plant itself. They also got the yeast to incorporate chemicals into cannabinoids that could later be chemically altered in the lab, creating another avenue for producing never-before-seen, but potentially medically useful, cannabinoids.

Keasling subsequently founded an Emeryville, California, company, Demetrix Inc., which d'Espaux and Wong later joined, that licensed the technology from Berkeley to use yeast fermentation to make cannabinoids.

"The economics look really good," Keasling said. "The cost is competitive or better than that for the plant-derived cannabinoids. And manufacturers don't have to worry about contamination -- for example, THC in CBD -- that would make you high."

https://www.sciencedaily.com/releases/2019/02/190227131838.htm

THC found more important for therapeutic effects in cannabis than originally thought

Researchers measure product characteristics and associated effects with mobile app

February 26, 2019

Science Daily/University of New Mexico

Researchers recently solved a major gap in scientific literature by using mobile software technology to measure the real-time effects of actual cannabis-based products used by millions of people every day.

Contrary to popular media-reports and scientific dogma, the psychoactive chemical, tetrahydrocannabinol or "THC," showed the strongest correlation with therapeutic relief and far less evidence for the benefits of relying on the more socially acceptable chemical, cannabidiol or "CBD."

In a new study titled, "The Association between Cannabis Product Characteristics and Symptom Relief," published in the journal Scientific Reports, UNM researchers Sarah See Stith, assistant professor in the Department of Economics, and Jacob Miguel Vigil, associate professor in the Department of Psychology, found that THC and CBD contents were the most important factor for optimizing symptom relief for a wide variety of health conditions.

The findings were based on the largest database of real-time measurements of the effects of cannabis in the United States, collected with the ReleafApp, developed by co-authors Franco Brockelman, Keenan Keeling and Branden Hall.

Since its release in 2016, the commercially developed ReleafApp has been the only publicly available, incentive-free app for educating patients on how their type of product (e.g., flower or concentrate), combustion method, cannabis subspecies (indica, sativa, and hybrid), and major cannabinoid contents (THC and CBD) affect their symptom severity levels, essentially providing invaluable user feedback on their health status, medication choices, and the clinical outcomes of those choices as measured by symptom relief and side effects.

The study aimed to address the practical questions of knowing how fundamental characteristics of currently available and frequently used cannabis products, characteristics that often influence consumer choices, affect health symptom intensity levels. The average patient, across the roughly 20,000 measured user sessions and 27 measured symptom categories ranging from depression to seizure activity, showed an immediate symptom improvement of 3.5 points on a 0-10 scale. Dried flower was the most commonly used product and generally associated with greater symptom improvement than other types of products.

Cannabis is rapidly gaining popularity as a mid-level analgesic and promising substitute for prescription opioids and other classes of medications, which often carry undesirable side effects, dangerous drug interactions and risk of death. Presently, federal barriers restrict researchers from conducting cannabis administration studies in the U.S.

"We were able to fill the most significant absence in the previous medical literature, understanding the 'efficacy, dose, routes of administration, or side effects of commonly used and commercially available cannabis products in the United States,'" said Vigil, quoting from the recently released report from the National Academies of Sciences, Engineering, and Medicine, Committee on the Health Effects of Marijuana.

By studying products containing both THC and CBD, the authors were able to analyze the relative importance of these cannabinoids for symptom relief and side effect prevalence, advancing previous research examining either chemical in the absence of the other. One of the most striking patterns in the current results was that THC was generally associated with a more intense user experience, as measured by symptom relief and the prevalence of both positive and negative side effects.

"Despite the conventional wisdom, both in the popular press and much of the scientific community that only CBD has medical benefits while THC merely makes one high, our results suggest that THC may be more important than CBD in generating therapeutic benefits. In our study, CBD appears to have little effect at all, while THC generates measurable improvements in symptom relief. These findings justify the immediate de-scheduling of all types of cannabis, in addition to hemp, so that cannabis with THC can be more widely accessible for pharmaceutical use by the general public," said Vigil.

"More broadly understanding the relationship between product characteristics and patient outcomes is particularly important given the lack of medical guidance received by medical cannabis patients," said Stith. "Most receive only a referral for cannabis treatment from their healthcare provider with all other treatment advice coming from prior recreational experience, the internet, social interactions, and/or often minimally trained personnel working in dispensaries.

"This is very different from how patients receive treatment using conventional pharmaceuticals that come with clear dosing instructions and a standardized, uniform product," she added.

The authors caution that cannabis use does carry the risks of addiction and short-term impairments in cognitive and behavioral functioning, and may not be effective for everyone.

"However, I have seen many people use it as a primary medication for a full spectrum of health conditions as part of their broader desire to gain more control over their healthcare treatment," says Vigil, a perspective that seems to gaining momentum as cannabis appears to be re-emerging as one of the most widely used medications in the U.S.

This investigation was supported in part by public donations to the University of New Mexico Medical Cannabis Research.

https://www.sciencedaily.com/releases/2019/02/190226112353.htm

A 'joint' problem: Investigating marijuana and tobacco co-use

February 22, 2019

Science Daily/Medical University of South Carolina

A survey of marijuana and tobacco co-users investigators found that co-users with high degree of interrelatedness between their use of the two substances had greater tobacco dependence and smoked more cigarettes per day. However, the finding of a strong link between the two substances was not universal. These finding suggest that highly personalized treatments are needed for co-users who want to quit smoking.

Tobacco isn't the only thing being smoked in the Deep South, and for many, it's only half of their habit.

Marijuana, long thought to be a gateway drug to harder substances, turns out to be popular among cigarette smokers, with rates of co-use of the two substances increasing among adults from 2003-2012. Researchers don't yet know how much of a problem that could pose for people trying to quit tobacco.

As more states move to legalize medicinal marijuana and some to decriminalize recreational use, a better understanding is needed of how co-use of marijuana affects quit attempts by smokers.

To learn more, a team of addiction investigators at the Medical University of South Carolina (MUSC) led by Erin A. McClure, Ph.D., assistant professor in the Department of Psychiatry and Behavioral Sciences, conducted an online survey of those who had used both marijuana and tobacco within a 30-day period about their smoking habits. Their results were published online on November 27, 2018 in Addictive Behaviors.

"We focused on marijuana and tobacco because of the high prevalence of their co-use," says Saima Akbar, first author on the article. "We don't fully understand how these substances interact and what the implications are for treatment."

The MUSC team found that more participants used marijuana and tobacco sequentially than simultaneously. For example, more participants used a tobacco cigarette as a "chaser" to marijuana than smoked joints mixing both marijuana and tobacco, known as spiffs.

The study also found that the degree to which marijuana and tobacco use were interrelated differed greatly by user. However, 26 percent of users reported they had smoked most of their cigarettes around the time they were using marijuana or were high. They were more likely to have a greater tobacco dependence and to smoke more cigarettes per day.

"So, if somebody's trying to quit smoking cigarettes, but they always use marijuana and tobacco together, it's probably going to be much, much harder for them if they are still using marijuana than for somebody who uses both, but their use is not related in any way," says McClure.

The finding also raises the question of whether smoking tobacco after marijuana use enhances its subjective effects. More than 50 percent of those surveyed reported using tobacco cigarettes as a chaser. However, another 35 percent reported not doing so. It is possible that co-users of marijuana and tobacco who feel a more intense high because of the tobacco use would be more likely to use them closer together. They could have a harder time quitting smoking than those who did not feel such an enhanced high. This possibility requires further study.

What is clear from the researchers' findings is that everyone's habit is a little different, and cessation programs will need to be personalized if they are to be effective.

McClure hopes to focus on tobacco cessation as she continues her research but also identify the people who will likely struggle with quitting due to their marijuana use. She then plans to further tailor treatment to these individuals to improve the likelihood that their smoking cessation efforts will be successful.

"We need to tailor a treatment strategy for each individual rather than doing this one-size-fits-all approach that doesn't always work very well," says McClure.

For instance, in an age of medical marijuana and increasing legalization, not all users wanting to quit tobacco will want to discontinue marijuana as well. For some, with a lesser degree of interrelatedness between their use of the two substances, this may be possible. But for those with a higher degree of interrelatedness, dual cessation strategies could be needed.

McClure is pursuing funds for a prospective clinical trial that would further explore how marijuana co-use affects tobacco cessation and compare quit attempts and cessation rates in co-users and tobacco-only users.

"That trial would help us identify the people who are going to have more difficulty with quitting smoking cigarettes because of their marijuana use, and how we can tailor treatment for them," says McClure. "It would also help clarify how we can tailor treatment for those not interested in quitting marijuana so that they still have the best chances of stopping cigarette smoking."

https://www.sciencedaily.com/releases/2019/02/190222101426.htm

American drug overdose death rates the highest among wealthy nations

February 21, 2019

Science Daily/University of Southern California

A new study found that the United States has the highest drug overdose death rates among a set of high-income countries. The study found that drug overdose death rates in the United States are 3.5 times higher on average when compared to 17 other high-income counties. The study is the first to demonstrate that the drug overdose epidemic is contributing to the widening gap in life expectancy between the United States and other high-income countries.

In the most comprehensive international comparison of its kind, a USC study found that the United States has the highest drug overdose death rates among a set of high-income countries.

Drug overdose mortality has reached unprecedented levels in the United States, more than tripling over the past two decades. But is this a uniquely American epidemic, or are other high-income counties facing a similar crisis?

"The United States is experiencing a drug overdose epidemic of unprecedented magnitude, not only judging by its own history but also compared to the experiences of other high-income countries," said study author Jessica Ho, assistant professor at USC Leonard Davis School of Gerontology. "For over a decade now, the United States has had the highest drug overdose mortality among its peer countries."

The study, published February 21 in Population and Development Review, found that drug overdose death rates in the United States are 3.5 times higher on average when compared to 17 other high-income counties. The study is the first to demonstrate that the drug overdose epidemic is contributing to the widening gap in life expectancy between the United States and other high-income countries.

Drug overdose deaths cut into American life expectancy

The study found that prior to the early 2000s, Finland and Sweden had the highest levels of drug overdose mortality. Drug overdose mortality in the United States is now more than 27 times higher than in Italy and Japan, which have the lowest drug overdose death rates, and double that of Finland and Sweden, the countries with the next highest death rates.

By 2013, drug overdose accounted for 12 percent and 8 percent of the average life expectancy gap for men and women, respectively, between the United States and other high-income countries. Without drug overdose deaths, the increase in this gap between 2003 and 2013 would have been smaller: one-fifth smaller for men and one-third smaller for women.

"The American epidemic has important consequences for international comparisons of life expectancy. While the United States is not alone in experiencing increases in drug overdose mortality, the magnitude of the differences in levels of drug overdose mortality is staggering," said Ho.

In 2003, life expectancy at birth would have been 0.28 years higher for American men and 0.17 years higher for American women in the absence of drug overdose deaths. Ten years later, these figures had increased to 0.45 years for American men and 0.30 years for women. In both 2003 and 2013, the United States lost the most years of life from drug overdose among high-income countries, with the difference increasing dramatically over that time period.

"On average, Americans are living 2.6 fewer years than people in other high-income countries. This puts the United States more than a decade behind the life expectancy levels achieved by other high-income countries. American drug overdose deaths are widening this already significant gap and causing us to fall even further behind our peer countries," Ho said.

A uniquely American phenomena -- but will it stay that way?

Over 70,000 people died from drug overdoses in the United States in 2017, and the National Safety Council announced in January that Americans are now more likely to die of an accidental opioid overdose than in a car crash.

Potential drivers of the country's strikingly elevated drug overdose mortality levels include health care provision, financing and institutional structures, such as fee-for-service reimbursement systems and tying physician reimbursement to patient satisfaction. Additional factors include a well-documented marketing blitz by the manufacturers of Oxycontin, American cultural attitudes towards pain and the medical establishment, and the scarcity of substance abuse treatment in the United States, where only an estimated 10 percent of those with a substance abuse disorder receive treatment.

Despite its rapid ascent to the top of this tragic list, the United States may soon have competition for its dubious distinction. Ho points to the potential for drug overdose mortality to increase in other countries in the near future, noting similar and troubling patterns in Australia, Canada and the United Kingdom.

While opioids became a cornerstone of pain treatment in the late 1990s and early 2000s in the United States, other countries either didn't use strong opioids for pain relief or placed greater restrictions on their use. Exceptions include Australia, which experienced a switch from weak to strong opioids that is reflected in its 14-fold increase in oxycodone consumption between 1997 and 2008, and Ontario, Canada, which saw an 850 percent increase in oxycodone prescriptions between 1991 and 2007. Both countries also experienced large increases in drug overdose mortality.

Although the current American epidemic started with prescription opioids, it is now rapidly transitioning to heroin and fentanyl. European countries may be on the opposite trajectory, which could nonetheless result in more drug overdose deaths over time. "The use of prescription opioids and synthetic drugs like fentanyl are becoming increasingly common in many high-income countries and constitute a common challenge to be confronted by these countries," Ho said.

The USC study utilized data on cause of death from the Human Mortality Database and the World Health Organization Mortality Database for the set of 18 countries, along with additional data from vital statistics agencies in Canada and the United States to produce country-, year-, sex-, and age-specific drug overdose death rates between 1994 and 2015. Deaths from both legal and illegal drugs (not limited to opioids) and deaths of all intents were included.

https://www.sciencedaily.com/releases/2019/02/190221083419.htm

Potent marijuana edibles can pose a major unrecognized risk to patients with cardiovascular disease

February 11, 2019

Science Daily/Elsevier

With widespread legalization and increasing use, more care, education a research needed about how each marijuana formulation may affect and sometimes compromise the cardiovascular system of our aging population, according to a new article and editorial.

As marijuana legalization sweeps North America, use of the substance has been on the rise, and the public's attitude is shifting. An increasing number of people believe that "weed" is the safest recreational drug, one that carries health benefits that outweigh its risks. Those assumptions are challenged in an article and editorial published in the Canadian Journal of Cardiology that examine the story of a patient who developed crushing chest pain and myocardial ischemia after consuming most of a marijuana lollipop.

"Marijuana can be a useful tool for many patients, especially for pain and nausea relief. At the same time, like all other medications, it does carry risk and side effects. In a recent case, inappropriate dosing and oral consumption of marijuana by an older patient with stable cardiovascular disease resulted in distress that caused a cardiac event and subsequent reduced cardiac function," said Alexandra Saunders, MD, Dalhousie University, Internal Medicine Program and Horizon Health Network's Department of Cardiology, Saint John, NB, Canada.

The case report describes a 70-year-old man with stable coronary artery disease, taking the appropriate cardiac medications, who ate most of a lollipop that was infused with 90 mg of THC (delta-9-tetrahydrocannabinol) to relieve pain and aid sleep, which caused him to have a potentially-serious heart attack. He consumed a much larger dose than the 7 mg that is typically ingested by smoking a single joint or taking the 2.5 mg starting dose of dronabinol (Marinol), a synthetic THC marketed for nausea and appetite stimulation in AIDS and cancer patients. While the patient had smoked marijuana in his youth, he had not done so since the THC content of the substance had increased significantly from three percent to 12 percent. He was also not familiar with the time-delayed and extended effect of oral THC dosing.

The patient's cardiac event was likely triggered by unexpected strain on his body from anxiety and fearful hallucinations caused by the unusually large amount of THC he ingested. His sympathetic nervous system was stimulated, causing increased cardiac output with tachycardia, hypertension, and catecholamine (stress hormone) release. After the psychotropic effects of the drug wore off, and his hallucinations ended, his chest pain stopped.

A number of prior case reports, as well as epidemiological studies, have described the association between cannabis use and acute cardiovascular (CV) adverse events, including myocardial infarction, stroke, arrhythmias, and sudden death.

"Most previous research on marijuana-induced myocardial ischemia focused mostly on younger patients and did not focus on its different formulations and potencies. As a result of widespread marijuana legalization, healthcare providers need to understand and manage cannabis use and its complications in older patients, particularly in those with cardiovascular disease," said Robert S. Stevenson, MD, Horizon Health Network, Department of Cardiology, Saint John, NB, Canada.

CV toxicity of marijuana is described in an accompanying editorial. It can be viewed as a consequence of one or more the following: 1) inhalation of combustion products of marijuana; 2) direct CV effects of THC; and 3) indirect effects of THC related to acute anxiety, hallucination, and/or psychosis. Individuals who are THC-naïve and are not used to taking mind-altering drugs can become highly distressed by impaired cognition and feelings of loss of control produced by THC. Extreme emotional responses in the context of THC psychiatric toxicity are associated with surges of catecholamines, which can have adverse acute CV effects. Important considerations with respect to cannabis toxicity are the pattern of use, dose, route of administration, and degree of tolerance.

"The legalization of cannabis has considerable public support but also raises public health concerns," commented the editorial's author, Neal L. Benowitz, MD, Chief, Division of Clinical Pharmacology and Experimental Therapeutics, Medical Service, Departments of Medicine, and Biopharmaceutical Sciences; Center for Tobacco Control Research and Education, University of California, San Francisco, CA, USA. "Some users may benefit from the social and medical effects, but others will be at risk for adverse health outcomes. Little information has been disseminated to patients or healthcare providers about cannabis use in older patients, and in particular those with cardiovascular disease. For better or worse, providing advice and care to such patients who are using cannabis is now necessary for the provision of optimal medical care to these patients."

https://www.sciencedaily.com/releases/2019/02/190211083204.htm