CBD in marijuana may worsen glaucoma, raise eye pressure

Research in mice suggests over-the-counter substance could possess unknown side effects

December 17, 2018

Science Daily/Indiana University

A study has found that CBD -- a major chemical component in marijuana -- appears to increase pressure inside the eye of mice, suggesting the use of the substance in the treatment of glaucoma may actually worsen the condition.

One of the most commonly proposed uses of medical marijuana is to treat glaucoma.

But a study from researchers at Indiana University has found that a major chemical component in the substance appears to worsen the primary underpinning of the disease: a rise in pressure inside the eye.

The chemical that causes this rise in pressure is cannabidiol, or CBD, a non-psychoactive ingredient in cannabis that is increasingly marketed to consumers in products such as oil, gummies, creams and health food. It is also approved in many states as a treatment for conditions such as pediatric epilepsy.

The study was reported Dec. 14 in the journal Investigative Ophthalmology & Visual Science.

"This study raises important questions about the relationship between the primary ingredients in cannabis and their effect on the eye," said Alex Straiker, an associate scientist in the IU Bloomington College of Arts and Sciences' Department of Psychological and Brain Sciences, who led the study. "It also suggests the need to understand more about the potential undesirable side effects of CBD, especially due to its use in children."

The study, which was conducted in mice, specifically found that CBD caused an increase in pressure inside the eye of 18 percent for at least four hours after use.

Tetrahydrocannabinol, or THC, the primary psychoactive ingredient of marijuana, was found to effectively lower pressure in the eye, as has been previously reported. But the study found that the use of CBD in combination with THC blocked this effect.

Specifically, the study found that male mice experienced a drop in eye pressure of nearly 30 percent eight hours after exposure to THC alone. A lower pressure drop of 22 percent was also observed after four hours in male mice.

The effect was weaker in female mice. This group experienced a pressure drop of only 17 percent after four hours. No difference in eye pressure was measured after eight hours.

The results suggest that females may be less affected by THC, though it isn't clear whether this extends to the substance's psychoactive effects.

"This difference between males and females -- and the fact that CBD seems to worsen eye pressure, the primary risk factor for glaucoma -- are both important aspects of this study," Straiker said. "It's also notable that CBD appears to actively oppose the beneficial effects of THC."

By comparing the effect of these substances on mice without specific neuroreceptors affected by THC and CBD, the IU researchers were also able to identify the two specific neuroreceptors -- named CB1 and GPR18 -- by which the first substance lowered pressure inside the eye.

"There were studies over 45 years ago that found evidence that THC lowers pressure inside the eye, but no one's ever identified the specific neuroreceptors involved in the process until this study," Straiker said. "These results could have important implications for future research on the use of cannabis as a therapy for intraocular pressure."

https://www.sciencedaily.com/releases/2018/12/181217151537.htm

Cannabis-based drug in combination with other anti-spasticity

Drugs may help to relieve symptoms of motor neuron disease

December 13, 2018

Science Daily/The Lancet

Oral spray containing two compounds derived from the cannabis plant reduced spasticity compared with placebo in patients already taking anti-spasticity drugs.

Chemical compounds derived from the cannabis sativa plant given as an add-on treatment may help ease symptoms of spasticity (tight or stiff muscles), a major cause of disability and reduced quality of life in people with motor neuron disease, according to a phase 2 trial of 60 adults published in The Lancet Neurology journal.

The findings show for the first time that adults with motor neuron disease taking first-line anti-spasticity drugs who were then treated with an oral spray (nabiximols) containing equal parts delta-9 tetrahydrocannabinol THC and cannabidiol (THC-CBD) experienced less spasticity and pain at 6-week follow-up compared with those given placebo.

While there are several drugs to relieve spasticity, evidence for their effectiveness is scant and they do not sufficiently improve symptoms in all patients. Moreover, they can have undesirable side effects, such as increasing muscle weakness and fatigue. In the study, participants continued taking other medications throughout the trial.

"There is no cure for motor neuron disease, so improved symptom control and quality of life are important for patients," says Dr Nilo Riva from the San Raffaele Scientific Institute in Milan, Italy, who led the research. "Our proof-of-concept trial showed a beneficial effect of THC-CBD spray in people on treatment-resistant spasticity and pain. Despite these encouraging findings, we must first confirm that THC-CBD spray is effective and safe in larger, longer term phase 3 trials."

Spasticity is a common symptom in motor neuron disease, a rapidly progressive, fatal neurodegenerative disorder affecting the nerve cells that control muscle movement (motor neurons). It occurs to a variable degree in people with amyotrophic lateral sclerosis (ALS), the most common and severe form of motor neuron disease, and is a defining characteristic of primary lateral sclerosis (PLS), that is rarer and progresses more slowly.

Previous research has found possible therapeutic benefits of cannabinoids (components of the cannabis plant) to include muscle relaxation, appetite stimulation, and pain-relieving, anticonvulsant, and anti-inflammatory effects in patients with other neurological conditions. Cannabinoids have been licensed in several countries for symptomatic treatment of spasticity in multiple sclerosis, and are increasingly recognised as a valuable option for the management of pain.

To investigate whether cannabinoids might also reduce spasticity in motor neuron disease, Italian researchers recruited 60 adults (aged 18-80 years) with ALS or PLS from four tertiary motor neuron disease centres in Italy. To participate in the study, patients had to have experienced spasticity symptoms for at least 3 months and be taking a stable dose of any anti-spasticity medication for 30 days before enrolment and throughout the study.

Participants were randomised to receive THC-CBD mouth spray (29 participants) or placebo (30) for 6 weeks. The number of sprays was gradually increased for the first 2 weeks of treatment until the optimum dose was reached, and then that dose was maintained for 4 weeks.

Change in spasticity was assessed by a physician who rated the spasticity of each participant's joints on the Modified Ashworth Scale (MAS) -- an objective tool to evaluate intensity of muscle tone. Participants were also asked to keep a daily symptom diary on spasticity levels, pain, spasm frequency, and sleep disruption.

At the end of treatment (6 weeks), spasticity was significantly improved in the THC-CBD spray group compared with the placebo group (mean MAS-scores improved by an average 0.11 vs deteriorated by an average 0.16). Additionally, the number of participants treated with THC-CBD spray reporting an improvement was significantly higher compared with participants receiving placebo (55%; 16/29 participants vs 13%; 4/30). Finally, pain scores were significantly improved in the THC-CBD spray group compared with placebo on a 0-10 scale (-0.97 vs -0.06).

Overall, THC-CBD spray was well tolerated and adverse events were mild to moderate and typical of cannabinoids -- asthenia (loss of energy and fatigue), somnolence (sleepiness), vertigo, and nausea. Twenty-one (72%) participants in the THC-CBD spray group and four (13%) in the placebo group reported at least one potentially treatment-related adverse event. There were no serious adverse events and no participants permanently discontinued treatment. However, three patients temporarily discontinued treatment in the THC-CBD spray group, two because of adverse events (one had nausea and anxiety and the other influenza), and one because of disease progression.

The authors note that an important limitation of the study was that the Modified Ashworth Scale has lacked sensitivity in studies assessing cannabinoids efficacy in multiple-sclerosis-related spasticity.

Writing in a linked Comment, Dr Marinne de Visser from Amsterdam University Medical Centre, University of Amsterdam, the Netherlands, says: "Before asking for approval of cannabinoids for symptomatic treatment of spasticity in patients with amyotrophic lateral sclerosis, further studies are needed to establish the frequency of spasticity in the various presentations of motor neuron disease, and also whether reductions in spasticity improve quality of life. Natural history studies including all subtypes of motor neuron disease and better outcome measures aimed at assessment of spasticity are required. Riva and colleagues' data are encouraging, and larger multicentre randomised controlled trials should be done to identify which subgroups of patients derive clinically significant benefits from nabiximols."

https://www.sciencedaily.com/releases/2018/12/181213190606.htm

How catnip makes the chemical that causes cats to go crazy

December 11, 2018

Science Daily/John Innes Centre

Researchers at John Innes Centre have shed light on how catnip -- also known as catmint -- produces the chemical that sends cats into a state of wanton abandon.

The remarkable effect catnip has on cats is well known thanks to the scores on online videos showing pets enjoying its intoxicating highs.

The substance that triggers this state of feline ecstasy is called nepetalactone, a type of chemical called a terpene. This simple, small molecule is part of an unusual chain of events, not previously seen by chemists.

The researchers believe that understanding the production of these nepetalactones could help them recreate the way that plants synthesise other chemicals like vinblastine, which is used for chemotherapy. This could lead to the ability to create these useful medicines more efficiently and quickly than we are currently able to harvest them from nature.

Usually in plants, for example peppermint, terpenes are formed by a single enzyme. In their paper published online this week in Nature Chemical Biology, the researchers report that in catnip terpenes are formed in a two-step process; an enzyme activates a precursor compound which is then grabbed by a second enzyme to produce the substance of interest.

This two-step process has previously never been observed, and the researchers also expect something similar is occurring in the synthesis of anti-cancer drugs vincristine and vinblastine from Madagascan periwinkle, Catharanthus roseus, and elsewhere in olive and snapdragon.

In the publication, the team describe the process by which catmint produces nepetalactone in microscopic glands on the underside of its leaves. The study also identifies three new enzymes with unusual activity.

Dr Benjamin Lichman, who conducted the work while a post-doc at John Innes Centre and who is now a lecturer at the University of York, says: "We have made significant progress in understanding how catnip makes nepetalactones, the chemicals that sends cats crazy. Catnip is performing unusual and unique chemical processes, and we plan to use these to help us create useful compounds that can be used in treatment of diseases such as cancer. We are also working to understand the evolution of catnip to understand how it came to produce the cat-active chemicals."

Professor Sarah O'Connor, project leader at the John Innes Centre, says: "Nepetalactones have potential use in agriculture as they participate in certain plant-insect interactions. In future work we will explore the roles that these compounds have in plants."

https://www.sciencedaily.com/releases/2018/12/181211103125.htm

Vaping cannabis produces stronger effects than smoking cannabis for infrequent users

December 4, 2018

Science Daily/Johns Hopkins Medicine

In a small study of infrequent cannabis users, Johns Hopkins Medicine researchers have shown that, compared with smoking cannabis, vaping it increased the rate of short-term anxiety, paranoia, memory loss and distraction when doses were the same.

The findings of the new study, described in the Nov. 30 edition of JAMA Network Open, highlight the importance of dose considerations with the perception that vaping is a safer alternative to smoking cannabis, the researchers say. And they ask regulators of medical and recreational cannabis dispensaries to take note.

Vaping devices heat cannabis to a temperature in which the mind-altering compounds in the plant are released as a vapor that is inhaled. Vaping is thought to be safer for cannabis and tobacco use because it doesn't produce many of the harmful components of burning material such as tar and other cancer-causing agents.

But, the researchers say, their study suggests that at least for first-timers or others who don't use cannabis regularly, vaping delivers greater amounts of THC, the primary intoxicant in cannabis, which increases the likelihood of adverse reactions.

"In light of increased legalization of cannabis, we designed our study to be more representative of the general population's exposure to cannabis, namely someone who has never smoked it and wants to try it for medical or recreational purposes, or someone who does not use it regularly enough to understand or predict its effects," says Ryan Vandrey, Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "What our study suggests is that some people who use cannabis infrequently need to be careful about how much cannabis they use with a vaporizer, and they should not drive, even within several hours after use. It could be dangerous for themselves and others, and on top of that, they may experience negative effects such as anxiety, nausea, vomiting and even hallucinations," he adds.

For their study, the researchers chose 17 volunteer participants (nine men and eight women, average age 27 years), who hadn't used cannabis in the past 30 days, which was verified by a drug screen, and together on average hadn't used in over a year.

In a controlled setting at Johns Hopkins Bayview Medical Center's behavioral pharmacology research unit, each participant either smoked or vaped cannabis containing 0, 10 or 25 milligrams of ?9-tetrahydrocannabinol (THC), the active component in cannabis that gives people the high, in single visits once a week over six weeks. The researchers say that 25 milligrams of THC is a relatively low dose, and much less than is typically found in pre-rolled cannabis "joints" sold in dispensaries where cannabis is legal. The participants either smoked preloaded pipes or inhaled vapor from a vaporizer. Neither the participants nor the researchers knew the doses of THC that were delivered in a given experimental test session.

During each of the six sessions, the research team observed and assessed drug effects in the test subjects, including for adverse reactions. They also measured vital signs such as heart rate and blood pressure and collected blood samples just after smoking, every 30 minutes for two hours and then every hour for eight hours.

Each participant also completed the Drug Effect Questionnaire -- rating self-reported drug effects out of a score of 100 -- shortly after smoking and each hour for up to eight hours later. The survey assessed overall drug effect; feeling sick, anxious, hungry, sleepy and restless; and experiencing heart racing, dry mouth, dry eyes, memory impairment and coughing.

Results showed that a few minutes after smoking, those who vaped the 25-milligram THC dosage reported an average of 77.5 on the overall strength of the drug's effect, meaning how high they felt compared with the average score of 66.4 reported by those who smoked the same dose. Participants who vaped 25 milligrams of THC reported about a 7 percent higher score on average for anxiety and paranoia, compared with people who smoked the same amount of the compound. Those who vaped any dose of THC also reported higher levels of dry mouth and dry eyes than those who smoked it. For example, when vaping 25 milligrams of THC, the participants rated dry mouth at 67.1 on average compared with 42.6 for those smoking it.

Researchers say the participants also completed three computerized tasks designed to measure attention span, memory, physical reaction time and motor movement. One task required the participant to replicate the shape of patterns, another required them to add up strings of single-digit numbers and the third required them to follow a dot across the screen with the cursor while also tracking a dot that pops up in the periphery.

The tests are meant to represent skills needed for proper workplace performance, operating a car or other daily activities. Reaction times on average were slower by more than 120 milliseconds with both active test doses of THC, using either smoking or vaping, when compared with reaction time after smoking or vaping cannabis without any THC.

Next, the researchers compared the effects of vaping compared with smoking on participants taking the computerized Divided Attention Task, which required participants to track a square on the computer screen while also monitoring numbers in each corner of the screen. The amount of time participants accurately tracked the square on the computer in the Divided Attention Task dropped by an average of 170 percent after smoking 25 milligrams of THC compared with the cannabis without THC.

The amount of time they accurately tracked fell an average of 350 percent when vaping 10 milligrams of THC and fell 500 percent when vaping 25 milligrams of THC, compared with those smoking either dose.

"Our participants had substantially higher impairment on the tasks when vaping versus smoking the same dose, which in the real world translates to more functional impairment when driving or performing everyday tasks," says postdoctoral fellow Tory Spindle, Ph.D., a researcher in the behavioral pharmacology research unit at Johns Hopkins Bayview.

Other results showed that blood levels of THC were at their highest immediately after smoking or vaping cannabis. At 10 milligrams of THC, blood levels of THC reached an average of 7.5 nanograms per milliliter in vapers, compared with 3.8 nanograms per milliliter in smokers 10 minutes after they inhaled the drug. At 25 milligrams of THC, blood levels reached an average of 14.4 nanograms per milliliter when vaped compared with 10.2 nanograms per milliliter when smoked.

"There's a definite differences in the amount of drug making it into the blood when using a vaporizer versus smoking the drug, so considerations need to be made when dosing to ensure people are using cannabis safely," says Spindle.

The researchers note that they could only detect THC in the blood samples up to four hours after using, even though the participants reported the drug's effects lasted five or six hours. The researchers say this suggests that blood testing isn't an accurate way to tell if someone is high or perhaps driving under the influence.

Two participants vomited after vaping 25 milligrams of THC, and another experienced hallucinations. One person vomited after smoking 25 milligrams of THC.

Vandrey cautions that the study involved only a small number of younger adults and lasted only six weeks. "We still don't have a full look at the long-term effects of vaping, such as whether there is a risk for chronic bronchitis, and more work needs to be done on that front," he says. It is important to note that these effects were observed in individuals who don't use cannabis very often, and may not extend to people who use cannabis routinely; they may have developed tolerance to these effects and also may be better able to regulate their dose.

In recent years, Canada and several U.S. states including Washington, California, Colorado and Massachusetts have legalized cannabis for recreational use. Thirty-two states have made cannabis available with a doctor's prescription, including Maryland, where the research was performed.

Additional authors include Edward Cone, Nicolas Schlienz and George Bigelow of Johns Hopkins; John Mitchell of RTI International and Ronald Flegel and Eugene Hayes of the Substance Abuse and Mental Health Services Administration (SAMHSA).

This research was funded by SAMHSA.

https://www.sciencedaily.com/releases/2018/12/181204131115.htm

How ancient viruses got cannabis high

Ancient viruses contributed to the evolution of hemp and marijuana

November 26, 2018

Science Daily/University of Toronto

THC and CBD, bioactive substances produced by cannabis and sought by medical patients and recreational users, sprung to life thanks to ancient colonization of the plant's genome by viruses, researchers have found.

World's first cannabis chromosome map reveals the plant's evolutionary past and points to its future as potential medicine.

THC and CBD, bioactive substances produced by cannabis and sought by medical patients and recreational users, sprung to life thanks to ancient colonization of the plant's genome by viruses, U of T researchers have found.

The finding is only one of the insights revealed by the long-awaited cannabis genome map detailing gene arrangement on the chromosomes, published recently in the journal Genome Research. Among other revelations are discovery of a gene responsible for the production of cannabichromene, or CBC, a lesser known cannabinoid, as the active substances in cannabis are known, and new insights into how strain potency is determined.

"The chromosome map is an important foundational resource for further research which, despite cannabis' widespread use, has lagged behind other crops due to restrictive legislation," says Tim Hughes, a professor in the Donnelly Centre for Cellular and Biomolecular Research and co-leader of the study. Hughes is also a professor in the Department of Molecular Genetics and Senior Fellow at the Canadian Institute for Advancement of Research.

The researchers expect the map will speed up breeding efforts to create new strains with desired medical properties as well as varieties that can be grown more sustainably, or with increased resistance to diseases and pests.

The study was a three-part collaboration between Tim Hughes' team and those of Jonathan Page, of Aurora Cannabis and the University of British Columbia , and Harm van Bakel, of the Icahn School of Medicine at Mt Sinai in New York.

Hughes, Page and van Bakel first got together in 2011 when they released the first draft of cannabis genome which was too fragmented to reveal gene position on chromosomes.

The new map reveals how hemp and marijuana, which belong to the same species Cannabis sativa, evolved as separate strains with distinct chemical properties. Cannabis plants grown for drug use ("marijuana") are abundant in psychoactive tetrahydrocannabinol, or THC, whereas hemp produces cannabidiol, or CBD, popular of late for its medicinal potential. Some people use CBD to relieve pain and it is also being tested as a treatment for epilepsy, schizophrenia and Alzheimer's.

The enzymes making THC and CBD are encoded by THCA and CBDA synthase genes, respectively. Both are found on chromosome 6 of the ten chromosomes the cannabis genome is packaged into. There, the enzyme genes are surrounded by vast swathes of garbled DNA which came from viruses that colonized the genome millions of years ago. This viral DNA, or retroelements as it is known, made copies of itself that spread across the genome by jumping into other sites in the host cell's DNA.

"Plant genomes can contain millions of retroelement copies," says van Bakel, an assistant professor in the Icahn Institute for Data Science and Genomic Technology in New York and in the department of Genetics and Genome Sciences. "This means that linking genes on chromosomes is analogous to assembling a huge puzzle where three quarters of the pieces are nearly the same color. The combination of a genetic map and PacBio sequencing technology allowed us to increase the size of the puzzle pieces and find enough distinguishing features to facilitate the assembly process and pinpoint the synthase genes."

The researchers believe that gene duplication of the ancestral synthase gene and expanding retroelements drove ancient cannabis to split into chemically distinct types. Humans subsequently selected for plants containing desirable chemistry such as high THC.

The gene sequences for the THCA and CBDA synthases are nearly identical supporting the idea that they come from the same gene which was duplicated millions of years ago. Over time, one or both gene copies became scrambled by invading retroelements, and by evolving separately, they eventually came to produce two different enzymes -- CBDA synthase found in hemp (fibre-type), and THCA synthase in drug-type (marijuana).

Because the enzymes are so similar at the DNA level, until this study it was not even clear if they are encoded by separate genes or by two versions of the same gene. Adding to the confusion was the fact that most strains produce both CBD and THC despite breeders' efforts to grow hemp varieties free from the mind-altering THC for users looking to avoid it.

The chromosome map now clearly shows that two distinct genes are at play which should make it possible to separate them during breeding to grow plants without THC.

Some psychoactive effects in medical strains could be coming from CBC, a lesser known cannabinoid that has unusual pharmacology including anti-inflammatory properties. The discovery of the gene responsible for CBC synthesis will make it possible for breeders to tailor its content in future varieties.

"Mainstream science has still not done enough because of research restrictions," says Page, of UBC and Chief Scientific Officer at Aurora, one of Canada's largest producers of medical cannabis. "Legalization and looming ease of research regulation really provide for opportunities for more research to be done. And Canada is leading the way."

https://www.sciencedaily.com/releases/2018/11/181126105506.htm

Drug use, religion explain 'reverse gender gap' on marijuana

November 26, 2018

Science Daily/North Carolina State University

Women tend to be more conservative than men on political questions related to marijuana. A recent study finds that this gender gap appears to be driven by religion and the fact that men are more likely to have used marijuana.

"This subject got our attention because it is the rare political issue where women are more conservative than men," says Steven Greene, co-lead author of a paper on the study and professor of political science at North Carolina State University. "We wanted to better understand what was behind that 'reverse gender gap.'"

To explore the subject, Greene and co-lead author Laurel Elder -- a professor at Hartwick College -- evaluated a 2013 political survey by the Pew Research Center. The nationally representative survey had about 1,500 participants, evenly split between men and women. The survey also asked a range of questions about marijuana policy, as well as marijuana use.

The researchers evaluated responses to six survey questions about marijuana, such as "Should marijuana be legal?" and "Is marijuana a gateway drug?" They compiled these responses to create a "support for marijuana" scale, running from zero to 100. Men scored a 67 on the scale, while women scored a 61.

The researchers then delved into the survey data to identify what contributed to the gender gap.

"One hypothesis we saw in popular media was that women are less supportive of marijuana due to their role as mothers -- but the data didn't bear that out at all," Greene says. "In fact, mothers were no different from women without children in terms of either their support for marijuana policy or their reported use of marijuana."

Instead, Elder and Greene identified two other factors that accounted for the distinction: marijuana use and religiosity. Religiosity is measured by accounting for how often survey respondents said they attended church and whether they identified as born-again Christians.

"When we ran a statistical analysis that accounted for religiosity, the gender gap shrank, so it appears to play a role in attitudes toward marijuana," Greene says.

"But when we ran an analysis accounting for marijuana use, the gap disappeared altogether -- so that clearly plays a major role."

In the Pew survey, 57 percent of men reported having used marijuana, compared to 45 percent of women.

"One takeaway message from this work is that, as marijuana legalization and use become normalized, rather than being viewed as immoral or dangerous, the existing gender gap should shrink," Greene says.

The paper, "Gender and the Politics of Marijuana," is published in Social Science Quarterly.

https://www.sciencedaily.com/releases/2018/11/181126134251.htm

Ecstacy makes people cooperative, but not gullible

November 20, 2018

Science Daily/King's College London

New research from King's College London has found that MDMA, the main ingredient in ecstasy, causes people to cooperate better -- but only with trustworthy people. In the first study to look in detail at how MDMA impacts cooperative behaviour the researchers also identified changes to activity in brain regions linked to social processing.

Problems with social processing are recognised as a fundamental difficulty in a range of psychiatric conditions and are not treated effectively by current medications. The results of the study, published in The Journal of Neuroscience, may be relevant for psychiatric conditions such as post-traumatic stress disorder (PTSD).

MDMA is used by recreational users due to its profound social and emotional effects and is known to release neurotransmitters -- chemical messengers in the brain -- linked to behaviour and mood. However, scientists know little about how different neurotransmitter systems in the brain contribute to complex social behaviour.

Twenty healthy adult men were either given a typical recreational dose of MDMA or a placebo pill and completed several tasks while in an MRI scanner, including the Prisoner's Dilemma. In the Prisoner's Dilemma players choose to either compete or cooperate with another player. Both players get points if they cooperate, but if one player chooses to compete they receive all the points while the other player gets nothing.

The researchers found participants under the influence of MDMA became more cooperative, but only when interacting with trustworthy players.

Senior author, Professor Mitul Mehta from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), said: 'We asked people what they thought of their opponent and, surprisingly, MDMA did not alter how trustworthy they thought the other players were. Untrustworthy players were rated as low on the scale, whether on MDMA or placebo, and trustworthy players were given equally high ratings.'

'Importantly, MDMA did not cause participants to cooperate with untrustworthy players any more than normal. In other words, MDMA did not make participants naively trusting of others.'

When playing the Prisoner's Dilemma, participants believed that they were playing real people through a computer. In fact, the 'people' were pre-programmed computer responses which behaved in either a trustworthy or untrustworthy manner, differing by how much they cooperated over the course of the game.

First author, Dr Anthony Gabay who carried out the work at King's College London and is now at Oxford University, said: 'When trustworthy players betrayed the participants the breach in trust had an equally negative impact whether participants were under the influence of MDMA or not. However, MDMA led to a quicker recovery of cooperative behaviour and this tendency to rebuild a relationship led to higher overall levels of cooperation with trustworthy partners.'

'Using MRI scans, we were also able to see that MDMA had an impact on brain activity when processing the behaviour of others, rather than altering the decision-making process itself.'

MDMA increased activity in the superior temporal cortex and mid-cingulate cortex, areas known to be important in understanding the thoughts, beliefs and intentions of other people. When processing the behaviour of trustworthy players, MDMA increased activity in the right anterior insula but decreased it when processing behaviour of untrustworthy players, reflecting the different behaviour shown to different opponents. The right anterior insula is important for the integration of appraisals, risk and uncertainty.

Professor Mehta said: 'Understanding the brain activity underlying social behaviour could help identify what goes wrong in psychiatric conditions. Given the social nature of psychotherapy, understanding how MDMA affects social interaction sheds light on why the drug could become a valuable tool in treating patients.'

MDMA is currently undergoing phase 3 clinical trials for treating PTSD when used alongside with psychotherapy and has been given Breakthrough Therapy designation by the FDA.

https://www.sciencedaily.com/releases/2018/11/181120073632.htm

New insights into the neural risks and benefits of marijuana use

Compounds in cannabis can impair or improve memory depending on age, disease

November 6, 2018

Science Daily/Society for Neuroscience

Research released today underscores both the dangers and the therapeutic promise of marijuana, revealing different effects across the lifespan. Marijuana exposure in the womb or during adolescence may disrupt learning and memory, damage communication between brain regions, and disturb levels of key neurotransmitters and metabolites in the brain. In Alzheimer's disease, however, compounds found in marijuana, such as the psychoactive compound delta-9-tetrahydrocannabinol (THC), may improve memory and mitigate some of the disease's symptoms.

Research released today underscores both the dangers and the therapeutic promise of marijuana, revealing different effects across the lifespan. Marijuana exposure in the womb or during adolescence may disrupt learning and memory, damage communication between brain regions, and disturb levels of key neurotransmitters and metabolites in the brain. In Alzheimer's disease, however, compounds found in marijuana, such as the psychoactive compound delta-9-tetrahydrocannabinol (THC), may improve memory and mitigate some of the disease's symptoms. The findings were presented at Neuroscience 2018, the annual meeting of the Society for Neuroscience and the world's largest source of emerging news about brain science and health.

Marijuana is the most commonly used illicit drug in the United States and its popularity is expected to rise as it is legalized in more places. It is also the illegal drug most commonly used by pregnant women, despite the potential for long-term harm to the fetus. Many people start using marijuana as teenagers -- a particularly vulnerable time as the brain is still developing -- when there is evidence for increased risk. At the same time, a growing number of people are turning to marijuana for the relief of symptoms of chronic diseases such as epilepsy and multiple sclerosis. These use patterns highlight the need to better understand the long-term effects of marijuana, particularly in sensitive populations such as unborn children and adolescents.

Today's new findings show that:

·     Prenatal exposure to THC in rats has lasting effects on metabolites in the brain, making the animal more vulnerable to stress later in life (Robert Schwarcz, abstract 609.12).

·     Rats exposed to synthetic compounds that are similar to THC during fetal development show impaired formation of the neural circuits involved in learning and memory as adolescents (Priyanka Das Pinky, abstract 424.17).

·     Cannabinoid use by adolescent rats boosts activity in brain pathways responsible for habit formation (José Fuentealba Evans, abstract 602.07).

·     In adolescent rats, cannabinoids may disturb the development of a protein lattice important for balancing excitatory and inhibitory activity in a brain region involved in decision-making, planning, and self-control (Eliza Jacobs-Brichford, abstract 645.09).

·     Long-term cannabinoid use alters metabolism and connectivity of brain regions involved in learning and memory in adult mice (Ana M. Sebastião, abstract 778.08).

·     Treating Alzheimer's disease mice with the psychoactive compound found in marijuana improves memory and reduces neuronal loss, suggesting a possible therapy for the human disease (Yvonne Bouter, abstract 467.14).

"Today's findings lend new understanding of the complex effects that cannabis has on the brain," said press conference moderator Michael Taffe, PhD, of Scripps Research Institute and an expert in substance abuse research. "While it may have therapeutic potential in some situations, it is important to get a better understanding of the negative aspects as well, particularly for pregnant women, teens, and chronic users."

https://www.sciencedaily.com/releases/2018/11/181106150418.htm

Cognitive changes in offspring of heavy cannabis-using rats

Cannabis use is common among pregnant women, but effects are rarely tested

November 4, 2018

Science Daily/Washington State University

Washington State University researchers have seen cognitive changes in the offspring of rats exposed to heavy amounts of cannabis. Their work is one of the rare studies to look at the effects of cannabis during pregnancy. The drug is the most commonly used illicit substance among pregnant women.

Ryan McLaughlin, an assistant professor of Integrative Physiology and Neuroscience, exposed pregnant rats to various concentrations of cannabis vapor and documented how the offspring of those exposed to high amounts had trouble adjusting their strategy to get sugar rewards.

"Prenatal exposure to cannabis may cause meaningful changes in brain development that can negatively impact cognitive functioning into adulthood," McLaughlin and his colleagues wrote in a summary for a presentation Sunday at the Society for Neuroscience's annual meeting, Neuroscience 2018, in San Diego.

The researchers used a new model of exposure, vaporizing cannabis extracts to recreate the way humans most often use the drug. Pregnant rats, or dams, received various amounts of vapor. Controls received none, while others got cannabis-free vapor, or vapor with low or high amounts of cannabis. The smoke, administered in atmospherically controlled cages over two hour-long sessions per day from before pregnancy through gestation, raised the THC levels in the blood to that of a person who has had a few puffs.

About 60 offspring were submitted to a task similar to the Wisconsin Card Sorting Test, an 80-year-old method of testing a human's flexibility when the conditions of positive reinforcement change. Rats were first trained to press one of two levers, learning that they got sugar when they pressed the lever near a light. The next day, they got a sugar reward when they pressed the left or right lever, regardless of the light.

Rats exposed to cannabis in utero learned the first rule easily enough. But rats exposed to a high concentration of cannabis, "showed marked deficits in their ability to shift strategies when the new rule was implemented," the researchers wrote.

Rats from dams exposed to high levels of cannabis often appeared to learn the new reward strategy, hitting the correct lever several times in a row. But they would not keep to the strategy long enough to strike the right lever ten times, like the offspring of dams exposed to less or no cannabis.

"The general take-home message is that we see deficits, particularly in the domain of cognitive flexibility, in rats prenatally exposed to high doses of cannabis vapor," McLaughlin said. "The impairment is not a general learning deficit, as they can learn the initial rule just fine. The deficit only emerges when the learned strategy is no longer resulting in reward delivery. They cannot seem to adapt properly and tend to commit more regressive errors as a result, which suggests impairment in maintaining the new optimal strategy."

McLaughlin notes that the high-exposure rats may not necessarily be less intelligent, just less motivated. They could be less interested in the task, not want so much sugar, or want to explore other avenues.

"They don't have these opinions about how they need to perform because they don't want to be perceived as 'the stupid rat,'" he said. "Clearly that's not what's motivating their behavior. They're just going to try to get as many sugar pellets as they can. But at some point, do sugar pellets continue to motivate your behavior after you've eaten 100? Do you still care as much about them?"

The project, which is consistent with federal law, was supported by WSU's Alcohol and Drug Abuse Research Program. Funded by state cannabis taxes and liquor license fees, the program is aimed at pilot projects that focus on drug abuse.

https://www.sciencedaily.com/releases/2018/11/181104180029.htm

High on the highway -- stoned-driving on the increase

October 26, 2018

Science Daily/De Gruyter

Getting behind the wheel after cannabis use is on the rise in the US, and THC, not alcohol, is now the most commonly detected intoxicant in US drivers. Detecting levels of THC, however, is challenging and the methods used so far cannot accurately determine a person's level of impairment.

The article "Driving While Stoned: Issues and Policy Options" by Mark A.R. Kleiman, Tyler Jones, Celeste J. Miller, and Ross Halperin, published in De Gruyter's Journal of Drug Policy Analysis, looks at current issues associated with cannabis intoxication when driving and the options available in testing for THC levels.

The study suggests that, due to the recent legalization of the production and sale of cannabis in some US States, the number of people driving under the influence of cannabis is likely to rise, which is unsettling since there is a widespread belief among marijuana users that THC does not have an effect on driving. Americans now spend an estimated 15 billion hours under the influence of cannabis per year, with no sign of consumption slowing down soon.

Unlike breath alcohol detection tests, which are cheap, reliable and can be easily administered at the roadside, a breath test for cannabis remains to be developed.

Oral-fluid testing can demonstrate recent use but not the level of impairment and thus a blood test must be carried out by health professionals at a medical facility. A further challenge is that blood THC levels drop very sharply even after minutes. A blood test is also a poor indicator of how recently the drug was used or the extent of impairment, and other tests are also not completely accurate.

Research on the risk of driving under the influence of cannabis is still preliminary and subject to fierce debate. However, a few facts are certain: stoned-driving adds to accident risk, especially in combination with alcohol and other drugs. Also, while it is certain that the risk of driving under the influence of cannabis alone is much lower than under the influence of high levels of alcohol, it is difficult to determine levels of impairment after cannabis use.

Stoned driving, the article posits, should be discouraged by making it a traffic offense with the promotion of anti-stoned driving messages highlighting the dangers and risks.

"Even assuming that an acceptable test can be developed, stoned driving alone and not involving alcohol or other drugs, should be treated as traffic infraction rather than as a crime, unless aggravated by recklessness, aggressiveness, or high speed," said study author Professor Mark A.R Kleiman of New York University.

https://www.sciencedaily.com/releases/2018/10/181026105557.htm

Sex, drugs and estradiol: Why cannabis affects women differently

October 26, 2018

Science Daily/Frontiers

Sex differences in cannabis use are beginning to be explained with the aid of brain studies in animals and humans.

Cannabis use is riding high on a decade-long wave of decriminalization, legalization and unregulated synthetic substitutes. As society examines the impact, an interesting disparity has become apparent: the risks are different in females than in males.

A new review of animal studies says that sex differences in response to cannabis are not just socio-cultural, but biological too. Published in Frontiers in Behavioral Neuroscience, it examines the influence of sex hormones like testosterone, estradiol (estrogen) and progesterone on the endocannabinoid system: networks of brain cells which communicate using the same family of chemicals found in cannabis, called 'cannabinoids'.

Animal studies

"It has been pretty hard to get laboratory animals to self-administer cannabinoids like human cannabis users," says study co-author Dr Liana Fattore, Senior Researcher at the National Research Council of Italy and President of the Mediterranean Society of Neuroscience. "However, animal studies on the effects of sex hormones and anabolic steroids on cannabinoid self-administration behavior have contributed a lot to our current understanding of sex differences in response to cannabis."

So how does cannabis affect men and women differently? Besides genetic background and hormonal fluctuations, the paper highlights a number of important sex differences.

Men are up to four times more likely to try cannabis -- and use higher doses, more frequently.

"Male sex steroids increase risk-taking behavior and suppress the brain's reward system, which could explain why males are more likely to try drugs, including cannabis" explains Fattore. "This is true for both natural male sex steroids like testosterone and synthetic steroids like nandrolone."

But despite lower average cannabis use, women go from first hit to habit faster than men. In fact, men and women differ not only in the prevalence and frequency of cannabis use, pattern and reasons of use, but also in the vulnerability to develop cannabis use disorder.

"Females seem to be more vulnerable, at a neurochemical level, in developing addiction to cannabis," explains Fattore.

"Studies in rats show that the female hormone estradiol affects control of movement, social behavior and filtering of sensory input to the brain -- all targets of drug taking -- via modulation of the endocannabinoid system, whose feedback in turn influences estradiol production.

"Specifically, female rats have different levels of endocannabinoids and more sensitive receptors than males in key brain areas related to these functions, with significant changes along the menstrual cycle.

"As a result, the interactions between the endocannabinoid system and the brain level of dopamine -- the neurotransmitter of "pleasure" and "reward" -- are sex-dependent."

Human impact

The inconsistency of conditions in these studies greatly complicates interpretation of an already complex role of sex hormones in the endocannabinoid system and cannabinoid sensitivity.

"The effects varied according the specific cannabinoid studied, as well as the strain of animals tested and duration of hormone exposure," admits Fattore. However, the human data so far are consistent with the idea that estradiol regulates the female response to cannabinoids. As in animals, human males and females are diverse in their genetic and hormonally driven behaviour and they process information differently, perceive emotions in different ways and are differently vulnerable to develop drug addiction.

"Blood levels of enzymes which break down cannabinoids fluctuate across the human menstrual cycle, and imaging studies show that brain levels of cannabinoid receptors increase with aging in females -- mirroring in each case changes in estradiol levels."

Fattore believes that deepening our understanding of the interactions between cannabinoids and sex steroids is crucial in assessing the impact of increasing cannabis use, and tackling the fallout.

"Gender-tailored detoxification treatments and relapse prevention strategies for patients with cannabis addiction are increasingly requested. Optimizing personalized evidence-based prevention and treatment protocols demands further research on the source of sex disparities in cannabis response."

https://www.sciencedaily.com/releases/2018/10/181026102627.htm

Can tiny doses of magic mushrooms unlock creativity?

Preliminary study suggests that 'microdoses' of psychedelics may enhance a person's creative problem solving abilities

October 25, 2018

Science Daily/Springer

The use of minute doses of magic mushrooms and truffles containing psychedelic substances could induce a state of unconstrained thought that may produce more new, creative ideas. "Microdosing" in this way may allow people to experience the creative benefits of psychedelic drugs without the risk of the so-called "bad trips" that often come with high doses of such substances. This is according to a new study in the Springer-branded journal Psychopharmacology which is the official journal of the European Behavioural Pharmacology Society (EBPS). The research was led by Luisa Prochazkova of Leiden University in The Netherlands and is the first study of its kind to experimentally investigate the cognitive-enhancing effects of microdosing on a person's brain function within a natural setting.

Taking a tiny fraction of a normal dose of psychedelic substances is becoming a trend in some professional circles because this is thought to stimulate brain function and enhance mental flexibility and creativity. However, experimental research that moves away from anecdotal evidence is still rare.

In this study, Prochazkova and her colleagues investigated how a microdose of a psychedelic substance affected the cognitive brain function of 36 people who were present at an event organized by the Psychedelic Society of The Netherlands. During the experimental phase, participants were set three tasks before and after they consumed on average 0.37 grams of dried truffles. The tests assessed their convergent thinking (the identification of a single solution to a problem), their fluid intelligence (the capacity to reason and solve new problems) and their divergent thinking (the ability to recognize many possible solutions). Afterwards, the researchers analyzed the active substances present in the truffles consumed by participants.

After taking the microdose of truffles, the researchers found that participants' convergent thinking abilities were improved. Participants also had more ideas about how to solve a presented task, and were more fluent, flexible and original in the possibilities they came up with. Microdosing with psychedelic substances therefore improved both the divergent and convergent thinking of participants.

These findings are in line with earlier studies that found high doses of psychedelics can enhance creative performance. The fact that participants' intelligence scores and general analytical abilities did not change suggests that the effect of the truffles is rather selective, and more to the benefit of a person's creative domain.

"Taken together, our results suggest that consuming a microdose of truffles allowed participants to create more out-of-the-box alternative solutions for a problem, thus providing preliminary support for the assumption that microdosing improves divergent thinking," explains Prochazkova. "Moreover, we also observed an improvement in convergent thinking, that is, increased performance on a task that requires the convergence on one single correct or best solution."

Prochazkova hopes that these findings will stimulate further research into the beneficial effects of microdosing psychedelics. "Apart from its benefits as a potential cognitive enhancement technique, microdosing could be further investigated for its therapeutic efficacy to help individuals who suffer from rigid thought patterns or behavior such as individuals with depression or obsessive-compulsive disorder," she explains.

https://www.sciencedaily.com/releases/2018/10/181025103329.htm

Liverwort could prove to be more medically effective than cannabis

October 24, 2018

Science Daily/University of Bern

Researchers have for the first time investigated a substance found in liverwort that resembles THC. The psychoactive substance, which is consumed as a 'legal high,' also exerts analgesic and anti-inflammatory effects, which might be superior to that of THC.

Currently, the medicinal use of cannabinoids, extracted from cannabis, is a subject of debate around the world. In Switzerland, more and more people are advocating for increased research into cannabis. Today, tetrahydrocannabinol (THC) is used in the medical field to deal with certain types of pain, muscle cramps, dizziness and loss of appetite.

However, it is an illegal narcotic and, accordingly, can trigger side effects. THC in its pure form was first isolated from cannabis in 1964 by Raphael Mechoulam at the Weizmann Institute of Science in Israel. Until now, it was thought that cannabis was the only plant that produces THC. However, as early as 1994, Japanese phytochemist Yoshinori Asakawa had discovered a substance in the liverwort plant Radula perrottetii which was related to THC and had named this natural substance "perrottetinene." In this natural product, the individual atoms are linked together in a manner similar to that of THC, however they differ in their three-dimensional structure and further exhibit an additional benzyl group.

A few year ago, Jürg Gertsch from the Institute of Biochemistry and Molecular Medicine at the University of Bern discovered that liverworts were being advertised as so-called "legal highs" on the internet. At the time, nothing was known about the pharmacological effects of this substance. Together with chemists from Erick Carreira's team from the Department of Chemistry at the ETH Zürich, Gertsch's research team in Bern biochemically and pharmacologically compared THC and perrottetinene.

Using animal models, they were able to demonstrate that perrottetinene reaches the brain very easily and that, once there, it specifically activates cannabinoid receptors. It even demonstrates a stronger anti-inflammatory effect in the brain than THC, something which makes perrottetinene particularly interesting when you consider its potential medical application "It's astonishing that only two species of plants, separated by 300 million years of evolution, produce psychoactive cannabinoids," says Gertsch. The study was published in the journal Science Advances.

Perrottetinene is less psychoactive than THC

Low doses of THC have great therapeutic potential when it comes to treating various chronic illnesses. However, to date, THC is rarely used therapeutically. This is because, in higher doses, the substance has a strong psychoactive effect and is an illegal -- and thus controlled -- narcotic. Andrea Chicca, a member of scientific staff in Jürg Gertsch's group, sees a potential for development in the therapeutic use of perrottetinene or similar substances: "This natural substance has a weaker psychoactive effect and, at the same time, is capable of inhibiting inflammatory processes in the brain." In particular, in contrast to THC, perrottetinene inhibits the prostaglandins in the brain which are factors causing inflammation. In doing so, perrottetinene has an effect on cannabinoid receptors which is similar to that of the endocannabinoids produced by our own bodies. However, according to the researchers, more studies are necessary, for example in pre-clinical models of chronic and inflammatory pain.

Transdisciplinary cannabinoid research

Large amounts of this bioactive substance were required for the pharmacological investigations. The collaboration with the chemists in Erick Carreira's group from the ETH Zurich was fundamental for this research project, because it would have been impossible to isolate the natural substance from the liverwort, which only grows in Japan, New Zealand and Costa Rica. To this end, Erick Carreira's group developed a new synthesis method specifically for controlling the three-dimensional structure on a molecular level. "The present study is a prime example of how new synthetic concepts can make a contribution towards enriching our pharmacological knowledge of biologically-active natural substances," said Michael Schafroth in recognition of the ETH Zurich's work. As a PhD student under Professor Carreira, Schafroth focused on new synthesis methods for cannabinoids. "Both solid fundamental research in the field of biochemical and pharmacological mechanisms as well as controlled clinical studies are required to carry out cannabinoid research," says Gertsch. To achieve this, researchers from various disciplines are working together.

https://www.sciencedaily.com/releases/2018/10/181024142607.htm

Cannabis pain relief without the 'high'

Mechanism of cannabidiol for safe pain relief without side effects

October 24, 2018

Science Daily/McGill University Health Centre

In the wake of cannabis legalization, a team of scientists at the Research Institute of the McGill University Health Centre (MUHC) and McGill University have delivered encouraging news for chronic pain sufferers by pinpointing the effective dose of marijuana plant extract cannabidiol (CBD) for safe pain relief without the typical "high" or euphoria produced by the THC. The findings of their study have been published in the journal PAIN (The Journal of the International Association for the Study of Pain).

Cannabis indica and sativa are the two main cannabis strains that produce the pharmacological principles known as tetrahydrocannabinol (THC) and cannabidiol (CBD). Dr. Gabriella Gobbi's team demonstrated that CBD does not act on the CB1 cannabinoid receptors like THC but through the mechanism that binds specific receptors involved in anxiety (serotonin 5-HT1A) and pain (vanilloid TRPV1). Researchers were able to extrapolate the exact dosage of CBD displaying analgesic and antianxiety properties without the risk of addiction and euphoria classically produced by the THC.

"We found in animal models of chronic pain that low doses of CBD administered for seven days alleviate both pain and anxiety, two symptoms often associated in neuropathic or chronic pain," says first author of the study Danilo De Gregorio, a post-doctoral fellow at McGill University in Dr. Gobbi's laboratory.

Lead author Dr. Gobbi, a researcher in the Brain Repair and Integrative Neuroscience (BRaIN) Program of the RI-MUHC, sees this as advancement for the evidence-based application of cannabis in medicine with CBD offering a safe alternative to THC and opioids for chronic pain, such as back pain, sciatica, diabetic, cancer and post-trauma pain.

"Our findings elucidate the mechanism of action of CBD and show that it can be used as medicine without the dangerous side effects of the THC," says Dr. Gobbi, who is also Professor of Psychiatry at the Faculty of Medicine at McGill University and staff psychiatrist at the MUHC. "This research is a new advancement for an evidence-based application of cannabis in medicine."

Despite widespread public usage, little clinical studies exist on CBD, which became legal in Canada on October 17, 2018, following the passage of Canada's Cannabis Act.

"There is some data showing that CBD provides pain relief for humans but more robust clinical trials are needed ," says Dr. Gobbi, a recent grant recipient for her study of the pharmalogical effects of CBD.

https://www.sciencedaily.com/releases/2018/10/181024163625.htm

More than one in ten heavy cannabis users experience withdrawal after quitting cannabis

October 22, 2018

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

As the number of Americans who regularly use cannabis has climbed, so too has the number of those experiencing cannabis withdrawal symptoms. A new study by researchers at the Columbia University Mailman School of Public Health and Columbia University Irving Medical Center finds that 12 percent of frequent marijuana smokers experienced Cannabis Withdrawal Syndrome (CWS), which includes emotional, behavioral and physical symptoms. The study is published in the journal Drug and Alcohol Dependence.

CWS was first included in the Diagnostic and Statistical Manual of Mental Disorders in its most recent edition, DSM-5, published in 2013. The new study is the first large-scale report on the link between CWS and DSM-5 psychiatric disorders among frequent U.S. adult cannabis users.

"In a rapidly changing landscape of marijuana laws and attitudes, cannabis use continues to increase among American adults. As a result, more information on the prevalence and correlates of clinical withdrawal in the general population is of critical importance," said Deborah Hasin, PhD, professor of Epidemiology at Columbia Mailman School of Public Health.

Study participants were interviewed as part of the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III), the only nationally representative survey that measures clinically diagnosed cannabis withdrawal syndrome, which encompasses six psychological symptoms and one or more physical symptoms. Face-to-face interviews in respondents' homes were conducted with 36,309 participants. The final analysis was based on 1,527 participants who were frequent cannabis users, defined as using the drug three or more times a week during the year prior to the interview.

CWS symptoms were associated with numerous psychiatric disorders, significant mental disability, and a family history of depression. Psychiatric disorders included mood disorders; anxiety disorders, including social phobia, agoraphobia, and panic disorder; personality disorders; and post-traumatic stress disorder.

Among withdrawal symptoms, the most commonly reported were nervousness/anxiety (76 percent), hostility (72 percent), sleep difficulty (68 percent) and depressed mood (59 percent). While physical symptoms were reported less frequently than behavioral and emotional symptoms, headaches, shakiness/tremors, and sweating were also prevalent.

Frequent cannabis users were primarily male (66 percent), white (59 percent), aged 18-29 (50 percent), college educated (49 percent), never married (54 percent), and with low household income (45 percent). While frequency of use (within a week) was not significantly associated with withdrawal symptoms, the number of joints smoked per day was significantly associated with withdrawal symptoms.

Cannabis withdrawal syndrome was not significantly associated with family history of drug or alcohol problems, but significantly associated with family history of depression.

"Cannabis withdrawal syndrome is a highly disabling condition," noted Hasin, who is also a professor in the Department of Psychiatry. "The syndrome's shared symptoms with depressive and anxiety disorders call for clinician awareness of cannabis withdrawal symptoms and the factors associated with it to promote more effective treatment among frequent cannabis users."

In an earlier study by Hasin and colleagues (LINK TK), cannabis withdrawal symptoms were prevalent and associated with psychiatric disorders and intensity of cannabis use. However, at that time,NESARC did not cover the DSM-5 cannabis withdrawal symptoms. As a new diagnosis, much remains to be learned about DSM-5 CWS, according to Hasin and colleagues.

"Most users of the newer modes of administration -- vaping and edibles -- also smoke cannabis. Therefore, for users in modes other than smoking, the amount of consumption could be underestimated," said Hasin. "Given the increase in cannabis potency in recent decades, developing reliable measures to investigate the effect of cannabis concentration and mode of administration will be important in advancing our understanding of cannabis withdrawal syndrome."

Co-authors are Ofir Livne (lead author), Lev Hasharon Medical Center, Israel; Dvora Shmulewitz, Columbia University Medical Center; and Shaul Lev-Ran, Lev Hasharon Medical Center and Tel Aviv University.

The study of cannabis withdrawal was supported by the National Institute on Drug Abuse. The NESARC-III survey was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with supplemental support by the National Institute on Drug abuse, and by the Intramural Research Program of the NIAAA.

https://www.sciencedaily.com/releases/2018/10/181022122837.htm

THC amounts identical in most cannabis strains

But newly uncovered compounds could explain different pharmacological effects

October 10, 2018

Science Daily/University of British Columbia Okanagan campus

Newly published research has determined that many strains of cannabis have virtually identical levels of tetrahydrocannabinol (THC) and cannabidiol (CBD), despite their unique street names.

A rose by any other name is still a rose. The same, it turns out, can be said for cannabis.

Newly published research from UBC's Okanagan campus has determined that many strains of cannabis have virtually identical levels of tetrahydrocannabinol (THC) and cannabidiol (CBD), despite their unique street names.

"It is estimated that there are several hundred or perhaps thousands of strains of cannabis currently being cultivated," says Professor Susan Murch, who teaches chemistry at UBC Okanagan. "We wanted to know how different they truly are, given the variety of unique and exotic names."

Cannabis breeders have historically selected strains to produce THC, CBD or both, she explains. But the growers have had limited access to different types of plants and there are few records of the parentage of different strains.

"People have had informal breeding programs for a long time," Murch says. "In a structured program we would keep track of the lineage, such as where the parent plants came from and their characteristics. With unstructured breeding, which is the current norm, particular plants were picked for some characteristic and then given a new name."

Until now, the chemical breakdown of many strains has been unknown because of informal breeding.

Elizabeth Mudge, a doctoral student working with Murch and Paula Brown, Canada Research Chair in Phytoanalytics at the British Columbia Institute of Technology, examined the cannabinoid -- a class of chemical compounds that include THC and CBD -- profiles of 33 strains of cannabis from five licensed producers.

The research shows that most strains, regardless of their origin or name, had the same amount of THC and CBD. They further discovered that breeding highly potent strains of cannabis impacts the genetic diversity within the crop, but not THC or CBD levels.

However, Mudge says that they found differences in a number of previously unknown cannabinoids -- and these newly discovered compounds, present in low quantities, could be related to pharmacological effects and serve as a source of new medicines.

"A high abundance compound in a plant, such as THC or CBD, isn't necessarily responsible for the unique medicinal effects of certain strains," says Mudge. "Understanding the presence of the low abundance cannabinoids could provide valuable information to the medical cannabis community."

Currently licensed producers are only required to report THC and CBD values. But Murch says her new research highlights that the important distinguishing chemicals in cannabis strains are not necessarily being analysed and may not be fully identified.

Murch says while patients are using medical cannabis for a variety of reasons, they actually have very little information on how to base their product choice. This research is a first step towards establishing an alternative approach to classifying medical cannabis and providing consumers with better information.

Murch's research was recently published in Nature's Scientific Reports.

https://www.sciencedaily.com/releases/2018/10/181010164710.htm

Molecule flight speed is the new key for detecting drugs

October 1, 2018

Science Daily/University of Córdoba

Scientists are developing an analytical methodology able to quickly differentiate cannabinoids in plant material and in waste remaining after being manipulated.

The presence of cannabinoids in different textile and pharmacological goods and the need to distinguish them from those found in drugs and psychotropics has led to the development of different analytical techniques that allow for effectively differentiating them.

A University of Cordoba research group headed by Analytical Chemistry Professor Lourdes Arce participated in the development of a new methodology using Ion Mobility Spectrometry in collaboration with the University of Barcelona, the Bioengineering Institute of Catalonia and the firm Phytoplant Research, Ltd. The new method has been shown to be effective and uses a simple way to determine the difference between certain cannabinoids and others in a short period of time.

The secret of this new methodology, published in the journal Sensors and Actuators B: Chemical, is rooted in focusing attention on the molecule volatility of hemp, using a chemical sensor known as ion mobility spectrometry, capable of detecting the presence of volatile or semivolatile substances even in very small samples. On one side, the sample about to be analyzed is placed, which could be a plant extract (approximately 100 mgs) or a plate with a fingerprint from a hand that has handled plant waste. The sample is heated to 240 degrees Celsius, which allows for extraction of the volatile compounds, that are separated according to their shape, size and chemical composition. Later on, this is used to classify the kinds of molecules. These chemical compounds travel through a tube at different speeds, depending on the characteristics of their molecules. Once the time needed by the compounds present in the plants to travel the entire distance until arriving at the detector is determined, it is compared to the behavior of chemical patterns of different kinds of cannabinoids and to the concentrations characterized by their different uses.

This research group has designed a methodology to extract compounds from plants and carry out the mathematical treatment of the data that allows for classifying plants in terms of the content in psychoactive substances. According to Lourdes Arce, our final aim is that state law enforcement could use this portable detection system for cases when seizing drugs and for road checkpoints, to be able to quickly discern if the variety of cannabis has psychotropic substances or not.

https://www.sciencedaily.com/releases/2018/10/181001130328.htm

Reclassification recommendations for drug in 'magic mushrooms'

Reclassification recommendations for drug in 'magic mushrooms'

If phase III clinical trials are successful, researchers suggest categorizing the drug as schedule IV

September 26, 2018

Science Daily/Johns Hopkins Medicine

In an evaluation of the safety and abuse research on the drug in hallucinogenic mushrooms, Johns Hopkins researchers suggest that if it clears phase III clinical trials, psilocybin should be re-categorized from a schedule I drug -- one with no known medical potential -- to a schedule IV drug such as prescription sleep aids, but with tighter control.

 The researchers summarize their analysis in the October print issue of Neuropharmacology.

 "We want to initiate the conversation now as to how to classify psilocybin to facilitate its path to the clinic and minimize logistical hurdles in the future," says Matthew W. Johnson, Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. "We expect these final clearance trials to take place in the next five years or so."

Following the Controlled Substances Act of 1970, any drug with the potential for abuse is categorized based on criteria that take into account whether the drug has accepted medical use, and its safety and the potential for abuse. Although preliminary research studies suggest that psilocybin may be effective for smoking cessation and for disorders such as cancer-specific depression and anxiety, it must clear phase III clinical trials before the Food and Drug Administration can be petitioned to reclassify it.

Studies in animals and humans both show low potential for abuse, the researchers say. When rats push a lever to receive psilocybin, they don't keep pushing the lever like they do for drugs such as cocaine, alcohol or heroin. When it comes to human studies, people who have used psilocybin typically report using it a few times across their lifetime.

As for safety, studies show it frequently falls at the end of the scales with the least harm to users and society, say the researchers. Psilocybin also is lowest in the potential for lethal overdose as there is no known overdose level.

"We should be clear that psilocybin is not without risks of harm, which are greater in recreational than medical settings, but relatively speaking, looking at other drugs both legal and illegal, it comes off as being the least harmful in different surveys and across different countries," says Johnson.

That being said, although psilocybin is relatively less harmful than other drugs and not prone to compulsive abuse, the researchers don't recommend releasing psilocybin into patients' hands even with a prescription. "We believe that the conditions should be tightly controlled and that when taken for a clinical reason, it should be administered in a health care setting monitored by a person trained for that situation," says Johnson. The researchers foresee that the process for psilocybin use in the clinic would be similar to how an anesthesiologist prescribes and administers a drug, minimizing the potential for abuse or harm.

https://www.sciencedaily.com/releases/2018/09/180926082159.htm

Octopuses given mood drug 'ecstasy' reveal genetic link to evolution of social behaviors in humans

Octopuses given mood drug 'ecstasy' reveal genetic link to evolution of social behaviors in humans

September 20, 2018

Science Daily/Johns Hopkins Medicine

By studying the genome of a kind of octopus not known for its friendliness toward its peers, then testing its behavioral reaction to a popular mood-altering drug called MDMA or "ecstasy," scientists say they have found preliminary evidence of an evolutionary link between the social behaviors of the sea creature and humans, species separated by 500 million years on the evolutionary tree.

A summary of the experiments is published Sept. 20 in Current Biology, and if the findings are validated, the researchers say, they may open opportunities for accurately studying the impact of psychiatric drug therapies in many animals distantly related to people.

"The brains of octopuses are more similar to those of snails than humans, but our studies add to evidence that they can exhibit some of the same behaviors that we can," says Gül Dölen, M.D., Ph.D., assistant professor of neuroscience at the Johns Hopkins University School of Medicine and the lead investigator conducting the experiments. "What our studies suggest is that certain brain chemicals, or neurotransmitters, that send signals between neurons required for these social behaviors are evolutionarily conserved."

Octopuses, says Dölen, are well-known to be clever creatures. They can trick prey to come into their clutches, and Dölen says there is some evidence they also learn by observation and have episodic memory. The gelatinous invertebrates (animals without backbones) are further notorious for escaping from their tank, eating other animals' food, eluding caretakers and sneaking around.

But most octopuses are asocial animals and avoid others, including other octopuses. But because of some of their behaviors, Dölen still thought there may be a link between the genetics that guide social behavior in them and humans. One place to look was in the genomics that guide neurotransmitters, the signals that neurons pass between each other to communicate.

Dölen and Eric Edsinger, Ph.D., a research fellow at the Marine Biological Laboratory in Woods Hole, Massachusetts, took a closer look at the genomic sequence of Octopus bimaculoides, commonly referred to as the California two-spot octopus.

Specifically, in the gene regions that control how neurons hook neurotransmitters to their membrane, Dölen and Edsinger found that octopuses and humans had nearly identical genomic codes for the transporter that binds the neurotransmitter serotonin to the neuron's membrane. Serotonin is a well-known regulator of mood and closely linked to certain kinds of depression.

The serotonin-binding transporter is also known to be the place where the drug MDMA binds to brain cells and alters mood. So, the researchers set out to see if and/or how octopuses react to the drug, which also produces so-called pro-social behaviors in humans, mice and other vertebrates.

Dölen designed an experiment with three connected water chambers: one empty, one with a plastic action figure under a cage and one with a female or male laboratory-bred octopus under a cage.

Four male and female octopuses were exposed to MDMA by putting them into a beaker containing a liquefied version of the drug, which is absorbed by the octopuses through their gills. Then, they were placed in the experimental chambers for 30 minutes. All four tended to spend more time in the chamber where a male octopus was caged than the other two chambers.

"It's not just quantitatively more time, but qualitative. They tended to hug the cage and put their mouth parts on the cage," says Dölen. "This is very similar to how humans react to MDMA; they touch each other frequently."

Under normal conditions, without MDMA, five male and female octopuses avoided only male, caged octopuses.

Dölen says the experiments suggest that the brain circuits guiding social behavior in octopuses are present in normal conditions, but may be suppressed by natural or other circumstances. "Octopuses will suspend their antisocial behavior for mating, for example. Then, when they are done mating, they go into aggressive, asocial mode," says Dolen.

Dölen cautions the results are preliminary and need to be replicated and affirmed in further experiments before octopuses might be used as models for brain research.

https://www.sciencedaily.com/releases/2018/09/180920175206.htm

Children whose mothers use marijuana are more likely to try it at younger age

September 24, 2018

Science Daily/Elsevier

When mothers use marijuana during the first 12 years of their child's life, their cannabis-using children are more likely to start at an earlier age than children of non-using mothers, according to a new study from the Harvard T.H. Chan School of Public Health published in the American Journal of Preventive Medicine. This study is the first to establish a relationship between maternal cannabis use during a child's lifetime and earlier initiation in a nationally-representative, longitudinal cohort, and examine the role of race, gender, and other social environmental factors.

"Early initiation is one of the strongest predictors of the likelihood of experiencing health consequences from marijuana use. In a shifting regulatory environment in which we expect adult marijuana use to become more normative, developing a deeper and more nuanced understanding of social risk factors for early initiation is a critical step in intervention design and delivery. Incorporating maternal cannabis use into our understanding of the important risk factors for early initiation may help us better identify at-risk youth for more tailored or intensive prevention strategies," explained lead investigator Natasha A. Sokol, ScD, currently of the Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University School of Public Health, Providence, RI, USA.

The investigators analyzed two linked cohorts of The National Longitudinal Survey of Youth 1979 (1980-1998 waves) and Child and Young Adults (1988-2014 waves) to assess the timing and extent of maternal and child marijuana use and initiation. They evaluated the data for 4,440 children and 2,586 mothers for the effect of maternal marijuana use between a child's birth and age 12 on that child's subsequent marijuana initiation, controlling for potentially important factors related to the child's early life behavior and cognition and the family's socioeconomic position and social environment. Overall, 2,983 children (67.2 percent) and 1,053 mothers (35.3 percent) self-identified as cannabis users. The investigators found that the children whose mothers used marijuana were at increased risk for marijuana initiation prior to age 17 and began at a median age of 16, compared to age 18 among children of non-users, noting that this effect was slightly stronger among non-Hispanic non-black children.

Although marijuana is generally thought to be less harmful compared with other drugs of abuse, the likelihood of experiencing health consequences associated with marijuana use is strongly linked to age at initiation, such that those who initiate earlier are at much greater risk. Negative consequences may be particularly marked for children and adolescents during these developmentally critical ages. Child and adolescent cannabis use is associated with impairments in attention, concentration, decision-making and working memory, and increased impulsivity, which may persist for weeks after use, with evidence that some cognitive effects, including reductions in IQ, may linger into adulthood. Among cannabis users, earlier initiation is associated with increased risk of anxiety and depressive disorders.

The United States is currently experiencing a sea change surrounding marijuana. This cultural shift is expected to result in increases in the prevalence, frequency, visibility, and/or acceptability of adult marijuana use. Understanding the impact of parent use on early marijuana initiation is an important step in anticipating the ways in which social environmental changes may alter the disease burden associated with marijuana in the US.cognitive effects

The findings indicate that children of marijuana-using parents may be an important subgroup for identification and early, evidence-based intervention by pediatricians and adolescent healthcare providers. Although future research on the mechanisms underpinning this relationship is necessary before more specific recommendations can be made, marijuana prescribers and other physicians may consider educating marijuana-using parents about early marijuana initiation and equipping them with evidence-based preventive strategies to delay marijuana use in their children. Further research may seek to understand best practices for preventing early initiation, such as decreasing or pausing use, reducing the visibility of use until children are older, and providing training, tools, and resources to help address these issues.

"Cannabis has recognized therapeutic benefits for treating a number of different medical conditions. There is also evidence that the availability of legal medical and recreational cannabis may reduce population opioid overdose deaths. Cannabis arrests account for more than half of all drug arrests in the US, and cannabis possession is a major driver of racial disparities in arrest and incarceration. For these reasons, total cannabis prohibition may not be consistent with public health objectives. Instead, given the neurocognitive, health, and social consequences associated with early use, delaying initiation may be an important, but undervalued, public health goal," commented Dr. Sokol.

https://www.sciencedaily.com/releases/2018/09/180924084340.htm