Cannabinoid drugs make pain feel 'less unpleasant, more tolerable'

September 19, 2018

Science Daily/Syracuse University

Researchers in the College of Arts and Sciences have determined that cannabinoid drugs do not appear to reduce the intensity of experimental pain, but, instead, may make pain feel less unpleasant and more tolerable.

Martin De Vita G'17, a doctoral candidate in the clinical psychology program, is the lead author of a highly anticipated paper on the subject in JAMA Psychiatry (American Medical Association, 2018).

The paper, whose publication coincides with "Pain Awareness Month," represents the first systematic review of experimental research into the effects of cannabis on pain.

"Cannabinoid drugs are widely used as analgesics [painkillers], but experimental pain studies have produced mixed findings," says De Vita, who studies interactions between substance use and co-occurring health conditions. "Pain is a complex phenomenon with multiple dimensions that can be affected separately."

Cannabinoids are chemical compounds that give the Cannabis plant its medical and recreational properties. Marijuana -- a mixture of dried, crumbled parts from the plant -- contains hundreds of these compounds, of which Tetrahydrocannabinol, or THC, is the best known.

"THC is the primary psychoactive compound in marijuana and, along with CBD [also known as cannabidiol, a naturally occurring constituent of cannabis] has been the focus of most medicinal use and research," says Associate Professor Emily Ansell, the study's senior author and director of the University's Research Lab on Personality, Addiction and Trauma (REPEAT).

When ingested, THC binds to receptors in the brain that control pleasure, time perception and pain. This activity boasts the production of dopamine -- what Ansell calls the "feel-good chemical," resulting in euphoria or relaxation.

Although the use of cannabis for medical purposes is legal in more than 30 states, the U.S. Drug Enforcement Administration still considers it a Schedule I drug, with no accepted medical use and a high potential for abuse. This classification, De Vita says, poses a significant challenge to researchers interested in cannabis' therapeutic effects.

Thus, high-quality evidence supporting the effectiveness of cannabis in treating chronic pain has yet to be established.

"Patients reliably endorse the belief that cannabis is helpful in alleviating pain; however, its analgesic properties are poorly understood," says De Vita, also a student therapist in the Syracuse VA Medical Center's PTSD clinic and a graduate researcher in the University's REPEAT Lab and Alcohol Research Lab. "Experimental pain studies of cannabinoid analgesia in healthy adults have produced mixed results."

De Vita and his co-authors in the Department of Psychology -- doctoral candidate Dezarie Moskal, Professor Stephen Maisto and Ansell -- initially identified more than 1,830 experimental studies on cannabis that had been conducted in North America and Europe over a 40-year period. They whittled the group down to 18 studies, and extracted data from more than 440 adult participants.

The team found that cannabinoid drugs were associated with modest increases in experimental pain threshold and tolerance, no reduction in the intensity of ongoing experimental pain, reduced perceived unpleasantness of painful stimuli and no reduction of mechanical hyperalgesia.

"What this means is that cannabinoid analgesia may be driven by an affective, rather than a sensory component. These findings have implications for understanding the analgesic properties of cannabinoids," De Vita says.

Adds Ansell: "The studies predominantly focused on THC varieties, so it is unclear whether or not other cannabinoids may have resulted in different experimental effects on pain."

The first meta-analytic review of its kind, Syracuse's study closely followed published guidelines for conducting and reporting systematic reviews, as well as a pre-registered protocol to enhance transparency. Two independent reviewers also examined the data separately.

"The mean quality and validity score across the studies was high, and analyses did not suggest publication bias," De Vita says.

Whereas the study was limited to experimental (i.e., laboratory induced) pain, the group hopes to expand their line of research into clinical and neuropathic pain.

Clinical pain usually is associated with a progressive, non-malignant disease; neuropathic pain is synonymous with disease or damage to the nervous system, resulting in tissue injury.

The researchers also are interested in studying dynamic pain processes, different types and doses of cannabinoids, and the role of recreational cannabis use.

"The cumulative research synthesized in our review has helped characterize how cannabis and cannabinoids affect different dimensions of pain reactivity," De Vita adds. "It may underlie the widely held belief that cannabis relieves pain. For now, we still have much to learn."

https://www.sciencedaily.com/releases/2018/09/180919111454.htm

The effectiveness of online cannabis responsible vendor training program

September 17, 2018

Science Daily/Pacific Institute for Research and Evaluation

A new study on the quality of online responsible marijuana vendor for cannabis (RMV) training has just been released. The study used an online RMV training that was developed in consultation with state regulators, store personnel, and local law enforcement in Colorado and Washington state. The training focused on knowledge of state statutes and regulations, ID checking, the health effects of marijuana, customer service practices (including recognizing intoxicated patrons), and rules of the trade.

To date, 6 U.S. states have implemented retail sales of recreational marijuana: Alaska, California, Colorado, Nevada, Oregon, and Washington state. One important issue for these states has been how to implement training in responsible retail sales practices. Examples of how to accomplish this task successfully come from the Responsible Beverage Service trainings for selling and serving alcohol.

A new study on the quality of online responsible marijuana vendor (RMV) training has just been released. The study used an online RMV training that was developed in consultation with state regulators, store personnel, and local law enforcement in Colorado and Washington state. The training focused on knowledge of state statutes and regulations, ID checking, the health effects of marijuana, customer service practices (including recognizing intoxicated patrons), and rules of the trade.

The curriculum was developed for a randomized controlled trial to test its efficacy for staff recruited from a random sample of 225 stores in Colorado, Oregon and Washington state. A total of 420 diverse store employees completed the online training. Then each trainee was given a survey about their experiences to gauge usability and trainee attitudes about the training.

The results showed that:

1.     more than 75 percent of trainees found the training user-friendly;

2.     almost 70 percent were satisfied with the training; and

3.     slightly more than 90 percent would recommend the training to another employee.

4.     Critically, the training significantly improved trainees' ability to check IDs, and to spot intoxicated customers as well as their confidence to use their state's inventory tracking system.

Says one of the co-authors, Dr. Robert Saltz of the Pacific Institute for Research and Evaluation, Prevention Research Center: "The online curriculum was seen very favorably by the employees, which is a good sign. We're looking forward to seeing the results of the next phase of the research -- a randomized trial to see if the training results in more responsible selling and serving behavior."

The study concluded that online RMV training was acceptable to retail recreational marijuana staff and that using it may improve responsible sales practices. Thus, the authors suggest that RMV should be considered for the recreational marijuana market.

https://www.sciencedaily.com/releases/2018/09/180917101309.htm

Prenatal exposure to cannabis impacts sociability of male offspring only

September 11, 2018

Science Daily/eLife

Taking cannabinoids during pregnancy can cause behavioural and neuronal deficits in adult male offspring, while females remain unaffected, says new research published in eLife.

The study in rats, from the Inserm and Aix-Marseille University Mediterranean Institute of Neurobiology, France, and Roma Tre University, Italy, in collaboration with Indiana University, US, suggests that prenatal cannabinoid use can lead to less sociability and increased neuronal excitability in males only. The findings also point towards a potential pharmacological strategy to help reverse these effects in humans.

Senior author Olivier Manzoni, Inserm Research Director at the Mediterranean Institute of Neurobiology, and Director of the CannaLab at the institute, says: "As cannabinoids can cross the placenta, they may interfere with fetal endocannabinoid signaling during neurodevelopment, which is involved in regulating a variety of processes such as pregnancy, appetite, pain sensation, and mediating the pharmacological effects of cannabis. This could in turn lead to some serious long-term deficits. But despite increasing reports of cannabis consumption during pregnancy, the long-term consequences of prenatal cannabinoid exposure remain incompletely understood."

To fill this knowledge gap, the international collaborators examined how prenatal cannabinoid exposure influences the synaptic and behavioral functions of the medial prefrontal cortex -- a brain region often implicated in neuropsychiatric disorders -- in adult male and female rats.

Their results revealed that males exposed to cannabinoids while in the uterus were less sociable than normal animals, and spent less time interacting with others. Their sniffing and playing behaviors were impaired, while the number of attacks among males remained unchanged. Additionally, the researchers saw that the exposed males had a heightened excitability of pyramidal neurons in the prefrontal cortex. None of these effects were seen in females.

"The deleterious effects of prenatal exposure to cannabinoids on social behavior were specific to male offspring only," explains co-first author Anissa Bara, who was a PhD candidate in Manzoni's lab at the time the study was carried out. "But while social interaction was specifically impaired in males, locomotion, anxiety and cognition remained unaffected in both sexes, suggesting discrete and sex-specific behavioral consequences of cannabinoid exposure during adulthood."

The results also revealed that the mGlu5 gene -- an effector of endocannabinoid signaling in the prefrontal cortex -- was reduced in the exposed males' prefrontal cortex. The team discovered that amplifying mGlu5 signaling could normalise the synaptic and behavioral deficits induced by prenatal exposure to cannabinoids partly by activating the cannabinoid type 1 receptor (CB1R). Similarly, later tests also revealed that enhancing levels of anandamide (a type of endocannabinoid) in exposed males helped to restore their social deficits via CB1R.

"Altogether, these results provide compelling evidence for sex-specific effects of prenatal cannabinoid exposure," concludes co-first author Antonia Manduca, Inserm Postdoctoral Researcher at the Mediterranean Institute of Neurobiology. "The fact that increasing mGlu5 signaling and enhancing anandamide levels helped to reverse the negative effects of early exposure in rats also hints at a new pharmacological strategy that could one day be trialled in humans."

https://www.sciencedaily.com/releases/2018/09/180911132101.htm

Medical cannabis effective in treating a wide range of health conditions

September 10, 2018

Science Daily/University of New Mexico

Utilizing new mobile application technology, researchers at The University of New Mexico found that medical cannabis provides immediate symptom relief across dozens of health symptoms with relatively minimal negative side effects.

In two recent studies titled, "Patient-Reported Symptom Relief Following Medical Cannabis Consumption," and "Effectiveness of Raw, Natural Medical Cannabis Flower for Treating Insomnia under Naturalistic Conditions" published in the journals, Frontiers in Pharmacology and Medicines, respectively, UNM Department of Psychology Associate Professor Jacob Miguel Vigil and UNM Department of Economics Assistant Professor Sarah See Stith, document that patients experienced statistically and clinically significant therapeutic benefits when they used cannabis for symptoms ranging from chronic pain to insomnia.

These studies analyzed data collected with the Releaf App, developed by co-authors Franco Brockelman, Keenan Keeling and Branden Hall and currently, the largest repository of user-entered information on the consumption and effects of cannabis use in the United States with nearly 100,000 recorded user sessions.

Since its release in 2016, the commercially developed Releaf App has been the only publicly available, incentive-free patient educational software program designed for recording how individual cannabis usage sessions correspond to immediate changes in symptom intensity levels and experienced side effects.

"If the results found in our studies can be extrapolated to the general population, cannabis could systematically replace multi-billion dollar medication industries around the world. It is likely already beginning to do so." -- Jacob Vigil

This electronic assessment tool enables patients to monitor and manage their cannabis consumption decisions under naturalistic conditions while avoiding the limitations of retrospective survey collection methods (e.g., memory bias, social desirability effects) making it an ideal research tool for measuring real-world cannabis use.

In the first study, across 27 different health conditions with symptoms that ranged from seizure disorders to depression, users reported an average symptom reduction of nearly 4 points on a 1-10 scale following the consumption of cannabis in its various product forms, from concentrates to topicals.

The second study focused specifically on the use of raw natural cannabis flower, or 'buds' for treating insomnia, with similar degrees of effectiveness that varied according to characteristics of the flower and combustion methods. Both investigations were supported in part by the University of New Mexico Medical Cannabis Research Fund, which was designed to facilitate the types of biomedical cannabis-based research that historically have been difficult to fund through conventional governmental entities, such as the National Institutes of Health.

Most prescription medications carry a long list of unavoidable negative side effects and risks of serious health concerns and even death, allowing alternative forms of medication to compete for patient preferences and healthcare industry demands. Medical cannabis is rapidly gaining popularity with the largest expansions in use among older people and patients with significant health conditions.

"Observational studies are more appropriate than experimental research designs for measuring how patients choose to consume cannabis and the effects of those choices," said Vigil. "By collecting massive amounts of patient-entered information on actual cannabis used under real-life circumstances we are able to measure why patients consume cannabis, the types of products that patients use, and the immediate and longer-term effects of such use. In other words, many of the important and practical research questions that randomized controlled trials fail to address."

Cannabis has been investigated as a potential treatment for a wide range of medical conditions from post-traumatic stress disorder to cancer, with the most consistent support for the treatment of chronic pain, epilepsy and spasticity. These studies hint at just how wide cannabis' therapeutic potential may be and are among the first to measure how characteristics of cannabis consumed by millions of people in the U.S. every day are likely to affect different types of health disturbances, both in symptom severity levels and experienced positive and negative side effects.

One of the most striking patterns in the current results was the breadth of symptoms that appeared to improve following cannabis consumption. More than 94 percent of cannabis users reported symptom intensity reductions following self-administered cannabis use across the various health conditions measured with the Releaf App. This may reflect the ability of the plant's phytocannabinoids to influence the human endocannabinoid system, which regulates both mental and physical health and behavioral systems.

According to the endocannabinoid deficiency theory, many mental and physical health disturbances result from the dysregulation of the body's innate endocannabinoid system (ECS), often described as a master network of chemical signals that promote physical and psychological homeostasis, or biological state-efficiency. The ECS consists of natural ligands (e.g., anandamide and 2-AG) and receptors (CB1 and CB2) that appear to play a major role in efficient regulation of a basic bodily systems including sleep, feeding (e.g., gut permeability and adipogenesis), libido and fertility, pain perception, motivation, happiness, anxiety, learning and memory, social functioning, autoimmune responses, cellular redox, and cancer pathophysiology.

"In other words and unlike conventional pharmaceutical approaches, which largely target specific neurotransmitter sites, cannabis may act to improve a broad spectrum of symptoms by regulating homeostatic functioning, perhaps best described as a system-modulating rather than symptom-modulating form of therapy," said Vigil. "The medicinal potential of this concept and practical application for treating so many and seemingly diverse health conditions is unlike that of any other single medication currently known to exist."

In addition to therapeutic benefits, these studies also showed that cannabis use is associated with frequent and numerous, yet generally non-serious side effects. Positive and context-specific side effects were far more commonly reported than negative side effects by the Releaf App users, with the most frequent reported side effects being positive (relaxed, peaceful, comfy) and the least frequent side effects being negative (paranoid, confused, headache).

Ultimately, cannabis could find a permanent place among our modern repertoire of medication options if it can treat users' health conditions more effectively and more safely than conventional pharmaceutical remedies. As in the case of insomnia, prescription sleep aids such as antidepressants (e.g., trazodone, amitriptyline, and doxepin), benzodiazepines (e.g., diazepam and lorazepam), gamma-aminobutyric acid (GABA) medications (zolpidem and eszopiclone), and anti-psychotics (aripiprazole, olanzapine, quetiapine and risperidone) are associated with significant clinical drawbacks and heightened risk of morbidity.

The widespread apparent use of cannabis as a sleep aid and for treating myriad other health symptoms underscores the importance of further medical research regarding its risk-benefit profile and the effectiveness of cannabis as a substitute for other substances, including alcohol, over-the-counter and prescription sleep aids, and scheduled medications (e.g., opioids and sedatives).

According to Stith, "The economic impact of cannabis treatment should also be considered given the current burden of opioid and other high-risk prescriptions on healthcare systems, which have been forced to implement costly modifications to general patient care practices, including prescription monitoring programs, drug screening, and more frequent doctor-patient interactions.

"In addition, if the short-term risk-benefit profile of cannabis found in our studies reflects its longer-term therapeutic potential, substitution of cannabis for traditional pharmaceuticals could reduce the risk of dangerous drug interactions and the costs associated with taking multiple medications by allowing patients to treat a constellation of comorbidities with a single treatment modality. "

"If the results found in our studies can be extrapolated to the general population, cannabis could systematically replace multi-billion dollar medication industries around the world. It is likely already beginning to do so," Vigil added.

https://www.sciencedaily.com/releases/2018/09/180910173731.htm

Marijuana use continues to grow among baby boomers

Middle-aged and older adults more likely to use if used marijuana as teens

September 6, 2018

Science Daily/New York University

Marijuana use is becoming more prevalent among middle-aged and older adults, with 9 percent of adults aged 50-64 and nearly 3 percent of adults 65 and older reporting marijuana use in the past year, according to a study by researchers at NYU School of Medicine and the Center for Drug Use and HIV/HCV Research (CDUHR) at NYU Rory Meyers College of Nursing.

These new figures, which use data from 2015-2016, demonstrate a substantial increase in marijuana use over the past near-decade -- double the percentage of adults aged 50-64 (4.5 percent) and more than seven times the percentage of adults 65 and older (0.4 percent) reporting use in 2006-2007.

The new findings, published online in the journal Drug and Alcohol Dependence, build on an earlier Addiction study by the same researchers to illustrate this growing trend among baby boomers.

Attitudes towards marijuana use are changing in the U.S., with a growing number of states legalizing medical and recreational marijuana. Although marijuana users are more likely to be young adults, the baby boomer generation is unique, having more experience with recreational use of drugs than previous generations.

"The baby boomer generation grew up during a period of significant cultural change, including a surge in popularity of marijuana in the 1960s and 1970s. We're now in a new era of changing attitudes around marijuana, and as stigma declines and access improves, it appears that baby boomers -- many of whom have prior experience smoking marijuana -- are increasingly using it," said lead author Benjamin Han, MD, MPH, an assistant professor in the Department of Medicine's Division of Geriatric Medicine and Palliative Care and Department of Population Health at NYU Langone Health.

In this study, the researchers analyzed responses from 17,608 adults aged 50 and older from the 2015-2016 National Survey on Drug Use and Health. Participants were asked about marijuana use, including when they first used it and whether they used it in the past year. The researchers also looked at respondents' demographics and several health factors, including other substance use and chronic disease.

In the past year, 9 percent of adults aged 50-64 and 2.9 percent of adults 65 and older reported using marijuana. In addition, more than half (54.5 percent) of adults 50-64 have used marijuana at some point in their lives, and over a fifth (22.4 percent) of adults 65 and older have ever used it.

When people first started using marijuana varied by age group. Nearly all adults aged 50-64 (92.9 percent), but only roughly half of adults 65 and older (54.7 percent), first used marijuana when they were 21 years of age or younger.

"Most baby boomers who recently used marijuana first used as teens during the 1960s and 1970s. This doesn't mean these individuals have been smoking marijuana for all these years, but most current users are by no means new initiates," said CDUHR researcher Joseph Palamar, PhD, MPH, the study's senior author and an associate professor in the Department of Population Health at NYU Langone Health.

In addition, some adults who used marijuana in the past year (15 percent of users aged 50-64 and 22.9 percent of those 65 and older) reported that a doctor had recommended it to them, reflecting the substantial use of marijuana for medical purposes.

A concerning finding from the study was the correlation between marijuana use and other unhealthy substance use. Adults who used marijuana were more likely to also report alcohol use disorder, nicotine dependence, cocaine use, and misuse of prescription medications (including opioids and sedatives) than non-users.

"Marijuana has been shown to have benefits in treating certain conditions that affect older adults, including neuropathic pain and nausea. However, certain older adults may be at heightened risk for adverse effects associated with marijuana use, particularly if they have certain underlying chronic diseases or are also engaged in unhealthy substance use," said Han, who is also a CDUHR researcher.

Because using multiple drugs may have additive adverse effects -- for instance, simultaneously using marijuana and alcohol can be detrimental for cognitive and motor functioning -- the researchers suggest that clinicians screen older patients who use marijuana for other substance use to ensure they are educated on the potential risks of using multiple drugs, especially concurrently.

https://www.sciencedaily.com/releases/2018/09/180906100458.htm

Increased cortical activation in cannabis users' brains in resting state

September 5, 2018

Science Daily/Center for BrainHealth

Recent research from the Center for BrainHealth® at The University of Texas at Dallas shows that cannabis users experience increased cortical activation during the brain's resting state when compared with nonusers.

The resulting "noisy brain" might impair brain activity and disrupt cognitive processes, said Dr. Shikha Prashad, the study's lead author and a research scientist at the Center for BrainHealth.

"This study is the first to characterize global cortical activation and both inter- and intrahemispheric functional connectivity during resting state in cannabis users," said Prashad, who works in the lab of Dr. Francesca M. Filbey, the Bert Moore Chair in BrainHealth at UT Dallas.

The results of the study were published in the journal NeuroImage.

The researchers collected electroencephalogram (EEG) data from 38 participants in two groups: 17 cannabis users and 21 nonusers. The EEG test measures electrical activity in the brain -- also known as brain waves. Scientists measured the synchronization of brain waves to evaluate the strength of the brain signals in different cortical regions. Such coherence of the EEG signal is a measure of the communication between different regions of the brain.

The results demonstrated that cannabis users exhibited increased synchronization -- or activation -- of most of the different types of brain waves, compared to nonusers. Similar results have been found in other studies of heroin-, alcohol- and cocaine-dependent users.

In addition, greater cortical communication among the frontal regions of the brain was observed in cannabis users. Prashad said this could signify that participants had difficulty inhibiting neural activity that has been observed in Dr. Filbey's previous studies, which would cause them to exert more effort as they attempted to stop doing certain tasks. Changes in communication between the brain's cortical areas could also be related to cognitive impairments correlated with cannabis use.

The findings of this research suggest that further studies are needed during task-related activity for comparison, Prashad said. These results could contribute to understanding cognitive impairments and the development of electrophysiological patterns to help map and evaluate the success of interventions.

This study was funded by the National Institutes of Health (grant number R01 DA030344).

https://www.sciencedaily.com/releases/2018/09/180905131826.htm

Nerve pain in the legs? Medical marijuana may alter brain connections, bring relief

September 5, 2018

Science Daily/American Academy of Neurology

When medical marijuana is taken for chronic nerve pain, it may provide pain relief by reducing connections between the areas of the brain that process emotions and sensory signals, according to a study published in the September 5, 2018, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study looked specifically at radicular pain, a type of nerve pain that radiates from the spine into the legs. Sciatica is a common form of radicular pain.

The component of marijuana examined in this study was tetrahydrocannabinol (THC), one of many cannabinoids found in marijuana and the one most commonly associated with producing a high.

"Pain is a complex experience that involves both the senses and emotions," said study author Haggai Sharon, MD, of the Sagol Brain Institute, Tel Aviv Medical Center in Israel. "Our study results link pain relief from THC with a reduction in the connections between areas of the brain otherwise heavily connected, suggesting that THC may alleviate pain by disrupting signals between these pain processing pathways."

The study involved 15 men with chronic radicular nerve pain with an average age of 33. Women were excluded since hormone fluctuations during menstruation may affect pain sensitivity. All participants had medium to high radicular pain for over six months.

Before treatment, participants rated their pain levels and had brain scans with functional magnetic resonance imaging (fMRI) to look at the connections between various areas of the brain. Participants were then given treatment with THC.

For the first visit, nine participants were given an average of 15 milligrams of THC oil placed under the tongue and six were given placebo oil. One hour after treatment, participants were questioned again, and had another brain scan approximately two hours after treatment.

At least one week later, participants returned for a second visit and those who had the placebo now received the treatment, and vice versa.

Researchers found that THC reduces a person's pain when compared to placebo. On a scale of zero to 100, before taking medication, on average participants rated their pain levels at 53. After taking THC oil, they rated their pain levels at an average of 35 compared to an average of 43 for those who were given the placebo.

In addition, the more pain relief a person experienced, the greater the reduction of connections between the areas of the brain involved in processing pain.

"Interestingly, our results also show that the more connected the areas of the brain that process emotion and sensory prior to treatment, the greater the pain relief experienced when taking THC," said Sharon. "Larger studies are needed to confirm our findings."

Limitations of the study are that women were excluded and the number of participants was small. Also, this study looked only at THC. Future studies are needed to examine how other components of the marijuana plant, like cannabidiol, may be useful in relieving pain in combination with THC.

The study was funded by the Yahel Foundation and the Israeli Ministry of Science, Technology and Space.

https://www.sciencedaily.com/releases/2018/09/180905161942.htm

Cannabis extract helps reset brain function in psychosis

August 29, 2018

Science Daily/King's College London

Research from King's College London has found that a single dose of the cannabis extract cannabidiol can help reduce brain function abnormalities seen in people with psychosis. Results from a new MRC-funded trial, published in JAMA Psychiatry, provide the first evidence of how cannabidiol acts in the brain to reduce psychotic symptoms.

Cannabidiol, also referred to as CBD, is a non-intoxicating compound found in cannabis. A purified form of cannabidiol has recently been licensed in the USA as a treatment for rare childhood epilepsies, and a 2017 King's College London trial has demonstrated cannabidiol has anti-psychotic properties.

However, exactly how cannabidiol may work in the brain to alleviate psychosis has remained a mystery.

"The mainstay of current treatment for people with psychosis are drugs that were first discovered in the 1950s and unfortunately do not work for everyone," says Dr Sagnik Bhattacharyya, from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN). "Our results have started unravelling the brain mechanisms of a new drug that works in a completely different way to traditional anti-psychotics."

The researchers studied a group of 33 young people who had not yet been diagnosed with psychosis but who were experiencing distressing psychotic symptoms, along with 19 healthy controls. A single dose of cannabidiol was given to 16 participants while the other 17 received a placebo.

All participants were studied in an MRI scanner while performing a memory task which engages three regions of the brain known to be involved in psychosis.

As expected, the brain activity in the participants at risk of psychosis was abnormal compared to the healthy participants. However, among those who had cannabidiol, the abnormal brain activity was less severe than for those who received a placebo, suggesting cannabidiol can help re-adjust brain activity to normal levels.

The influence of cannabidiol on these three brain regions could underlie its therapeutic effects on psychotic symptoms.

Intriguingly, previous research from King's College London shows cannabidiol appears to work in opposition to tetrahydrocannabinol (THC); the ingredient in cannabis responsible for getting users high which has been strongly linked to the development of psychosis. THC can be thought of as mimicking some of the effects of psychosis, while cannabidiol has broadly opposite neurological and behavioural effects.

Dr Bhattacharyya and colleagues at IoPPN are now launching the first large scale, multi-centre trial to investigate whether cannabidiol can be used to treat young people at high risk of developing psychosis. The trial is supported by a £1.85 million grant from an NIHR and MRC partnership.

Some estimates suggest that in England alone, over 15,000 people present with early symptoms of psychosis every year. Despite symptoms that can be extremely severe, there are currently no treatments that can be offered to patients at high risk of psychosis because current anti-psychotic drugs can have serious side-effects.

"There is an urgent need for a safe treatment for young people at risk of psychosis," says Dr Bhattacharyya. "One of the main advantages of cannabidiol is that it is safe and seems to be very well tolerated, making it in some ways an ideal treatment. If successful, this trial will provide definitive proof of cannabidiol's role as an antipsychotic treatment and pave the way for use in the clinic."

https://www.sciencedaily.com/releases/2018/08/180829115228.htm

In test with rats, cannabidiol showed sustained effects against depression for seven days

August 30, 2018

Science Daily/Fundação de Amparo à Pesquisa do Estado de São Paulo

First results appeared 24h after one single dose of the marijuana component; scientists concluded that CBD activate mechanisms which repair neuronal circuitry in patients' prefrontal cortex and hippocampus.

Commercial antidepressants typically take two to four weeks to have a significant effect on a depressed patient. They are also inneffective in approximately 40% of the cases. Finding new drugs for depression that are fast-acting and have more lasting effects is the goal of research conducted by Brazilian scientists in São Paulo State in collaboration with Danish colleagues.

Their study found that a single dose of cannabidiol in rats with symptoms of depression was highly effective, eliminating the symptoms on the same day and maintaining the beneficial effects for a week.

The findings reinforce those of prior research showing that cannabidiol, a component of Cannabis sativa, the plant most commonly used to make marijuana, has promising therapeutic potential in the treatment of broad-spectrum depression in preclinical and human models.

The results have been published in an article in the journal Molecular Neurobiology by researchers of the group led by Sâmia Regiane Lourenço Joca, a professor in the University of São Paulo's Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP) in Brazil.

The first author is Amanda Juliana Sales, who has a PhD scholarship from the São Paulo Research Foundation -- FAPESP. The research itself was supported by FAPESP via a Thematic Project, by Brazil's National Council for Scientific and Technological Development (CNPq), and by Denmark's Aarhus University Research Foundation.

FAPESP Thematic Project coordinator Francisco Silveira Guimarães, who is also a professor at the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP), stresses that cannabidiol produces neither dependence nor psychotropic effects, despite being extracted from marijuana plant. "The main psychoactive component of marijuana is tetrahydrocannabinol, known as THC. Cannabidiol, on the contrary, blocks some of the effects of THC," he said.

Methodology

The researchers performed tests using rat and mouse lines selected by cross-breeding to develop symptoms of depression. The tests and behavioral analysis involved a total of 367 animals.

Five tests were performed altogether. "We submitted the animals to situations of stress such as the forced swimming test," said Joca, who is also a visiting professor at Aarhus University.

Before the test, some of the animals were given an injection of cannabidiol with doses of 7, 10 and 30 mg/kg in saline solution, and the rest, which were the control group, received only saline.

After 30 minutes, the animals were placed for five minutes in cylinders with a height of 25 cm and a diameter of 17 cm, containing 10 cm of water for mice and 30 cm of water for rats.

"The water depth is calculated to force them to swim by preventing them from touching the bottom with their feet or tails. They learn to float after swimming for a short time. They remain practically immobile while floating, merely keeping their heads above water to avoid drowning. This floating behavior, when they stop swimming, is classified as immobility," said the FAPESP-supported researcher.

"The forced swim test is used to measure the effect of antidepressant drugs because all known antidepressants shorten the duration of immobility and hence lengthen swim time. A reduction in immobility time in this test is interpreted as 'antidepressant-like' behavior."

The researchers found that cannabidiol induced acute and sustained antidepressant-like effects in mice submitted to the forced swim test.

"However, to make sure this result isn't due to the increase in movement caused by a psychostimulant effect leading the animals to swim more vigorously, for example, we performed a separate test to control for locomotor activity," Joca explained.

"To do this we used the open-field test, which consists of putting the animal in a novel arena and letting it explore the new environment freely while its locomotor and exploratory activity is recorded. A drug is said to have potential antidepressant effects if it reduces immobility time and increases swim time in the forced swim test without increasing locomotor activity in the open-field test, showing that the effects observed in the forced swim test aren't secondary to nonspecific alterations in locomotor activity."

Restoration of neuronal circuitry

The conclusion was that the effects of treatment with cannabidiol were fast-acting and sustained, persisting for up to seven days after a single dose was administered to animals belonging to different models of depression (including a stress model and a genetic susceptibility model).

Seven days after treatment, the researchers observed a rise in the number of synaptic proteins in the prefrontal cortex, which is closely linked to depression in humans. "In light of this finding, we believe cannabidiol rapidly triggers neuroplastic mechanisms that help repair the neuronal circuitry that gets damaged in depression," Joca said.

"When we studied the mechanisms involved in these effects, we found that treatment with cannabidiol induces a rapid rise in levels of brain-derived neurotrophic factor, or BDNF, a neurotrophin that plays a key role in neuronal survival and neurogenesis, the formation of new neurons in the brain," Joca said. "We also observed an increase in synaptogenesis in the prefrontal cortex of these animals." Synaptogenesis is the formation of synapses between neurons in the central nervous system.

The beneficial action of cannabidiol is not limited to the prefrontal cortex, however. "In a separate study, we showed that the effects of cannabidiol also involve neuroplastic mechanisms in the hippocampus, another structure involved in the neurobiology of depression," noted the FAPESP-funded researcher.

According to Joca, if studies in humans also find cannabidiol to be beneficial in treating depression, given that cannabidiol is already used in humans to treat other diseases or disorders, "they could result in an important advance in the treatment of depression, potentially helping patients who suffer for weeks, often with a risk of suicide, until the treatment starts working."

Studies in humans

The researchers are currently investigating other mechanisms involved in the effects of cannabidiol, as well as its efficacy in animal models of resistance to conventional treatment.

"For example, we're studying whether cannabidiol would also be effective in patients who don't respond to conventional therapy and whether combining it with antidepressants would improve their symptoms. Indeed, we've just published another paper in the journal Progress in Neuro-Psychopharmacology and Biological Psychiatry, showing that treatment with cannabidiol facilitates serotonergic neurotransmission in the central nervous system and that combining it with low doses of selective serotonin reuptake inhibitor antidepressant drugs, or SSRIs, such as fluoxetine induces a significant antidepressant effect," Joca said.

"So there's a possibility that combining cannabidiol with SSRIs might allow the latter to be used in lower doses, perhaps reducing their adverse side-effects while maintaining the therapeutic effect of higher doses."

According to the authors, therefore, cannabidiol may not only be a faster-acting antidepressant than conventional drugs but also improve the response to such drugs when taken in combination with them.

"Our evidence suggests these effects occur by inducing neuroplastic alterations in the prefrontal cortex and hippocampus, which are brain structures involved in the development of depression. Because cannabidiol is used in humans to treat other conditions, we believe it can also be studied in humans for the treatment of depression in the near future," Joca said.

https://www.sciencedaily.com/releases/2018/08/180830113004.htm

Differences between combined, isolated use of cannabis, nicotine on brain networks

August 28, 2018

Science Daily/Center for BrainHealth

Researchers at the Center for BrainHealth® at the University of Texas at Dallas investigated the effects on the brain of concurrent cannabis and nicotine use, versus the use of solely cannabis and solely nicotine.

The results, recently published in the journal Brain Structure and Function, show that not only were the effects in these three categories different, but also that the group using both nicotine and cannabis more closely resembled the control (non-user) group in brain connectivity. The isolated nicotine and isolated cannabis users showed equally less connectivity in general.

Previous research in rats has suggested that nicotine may be a "gateway drug" leading to cannabis and other drug use. Studies performed with rats exposed to THC -- the main psychoactive compound found in marijuana -- demonstrated an increased likelihood to self-administer nicotine that was not observed with rats exposed to heroin or cocaine, suggesting that there is something unique about the cannabis-nicotine interaction.

"Most of the literature to date has focused on associations of isolated cannabis and nicotine use, even though concurrent cannabis and nicotine use is more prevalent in society than cannabis use alone," said the study's lead author, Dr. Francesca M. Filbey, the Bert Moore Chair in BrainHealth at UT Dallas. "Our findings confirm the limitations of existing research."

While the outcome of the study could be, in part, due to the opposing effects nicotine and cannabis have on the brain, the difference in the brains of concurrent users versus isolated users of each product begs for further research in functional connectivity metrics in these populations, Filbey said.

MRI scans were used to evaluate resting state functions in 12 different regions of the brain among four groups of participants: 28 nicotine users, 53 cannabis users, 26 nicotine and cannabis users, and 30 non-users in a control group. These scans revealed that the control group displayed greater connectivity in almost all of the networks compared to the nicotine and cannabis groups, while the combined nicotine plus cannabis group had greater connectivity than the only-nicotine and only-cannabis groups. Notably, this study did not demonstrate a correlation between substance use severity and functional connectivity.

Differences in brain network connectivity suggest alterations in the underlying neural architecture of the brain that support brain function. Overall, Filbey said the study suggests unique and combined contributions of cannabis and nicotine on brain network connectivity, which could be helpful knowledge for intervention programs.

https://www.sciencedaily.com/releases/2018/08/180828133934.htm