Patient use of cannabis in epilepsy

December 8, 2014

Science Daily/American Epilepsy Society (AES)

Three studies offer new insights into diverse patient experiences with CBD. Despite all the media and legislative attention, there is little scientific evidence about its effectiveness.

There may have been many anecdotal reports about cannabis and its derivative cannabidiol (CBD) in the treatment of people with epilepsy, especially in very young children who have catastrophic forms of epilepsy such as Lennox Gastaut Syndrome (LGS) or Dravet Syndrome (DS). Despite all the media and legislative attention, there is little scientific evidence about its effectiveness. Three studies presented at the American Epilepsy Society's 68th Annual Meeting offer new insights into diverse patient experiences with CBD.

The first of three studies is from Colorado, where much of the nation's attention has been captured by issues surrounding cannabis. The physicians and researchers at Children's Hospital Colorado and the University of Colorado have a unique perspective on CBD given the large number of cases they have treated. In addition to the many children already in their care, these professionals are now caring for many of the patients who have ventured to Colorado in search of cannabis treatment.

Dr. Kevin Chapman, associate professor of pediatrics and neurology at the University of Colorado, and his colleagues conducted a retrospective review of the 58 children and adolescents (average age of 7) with catastrophic forms of epilepsy who were receiving artisanal oral cannabis extracts when they came under the care of the hospital-based team. Chapman's team found that in only one-third of patients did the parents report a seizure reduction of 50% or more, and this did not correlate with an improvement in their electroencephalograms (EEGs). Of the sixteen patients who had baseline EEGs prior to and during treatment with cannabis, only two showed any signs of improvement. The researchers also noted that the response rate did not change with various strains of cannabis. Notably, families who moved to Colorado for CBD treatment were three times as likely to report a reduction greater than 50% than families who were already in Colorado.

Adverse effects occurred in 47% of patients, with increased seizures or new seizures in 21%, somnolence/fatigue in 14%, and rare adverse events of developmental regression in 10% with one patient needing intubation, and one death.

"This substantial gap between the clinical observations and various anecdotal reports highlighted in popular media underscores the desperate need shared by the entire epilepsy community for robust scientific evidence regarding the potential benefit and risks of marijuana in people with epilepsy," said Dr. Chapman.

A second study documents the experiences reported by parents of children with infantile spasms (IS) or LGS who were treated with artisanal CBD-enriched cannabis preparations. Through a survey of 53 parents whose children had IS and/or LGS (n = 53), the UCLA based researchers found that 92% of parents reported a reduction in seizures and 13% reported complete seizure-freedom. The majority of respondents reported using a CBD preparation with a CBD:THC ratio of at least 15:1. Prior to starting CBD, the parents reported that their children (median age for 3.6 years) had typically tried and failed 8 medications prior to CBD. Most patients with IS had failed both hormonal therapy (prednisolone and/or ACTH) and vagabtrin. The median length of other therapies was 6.9 months. The survey participants reported that side effects of treatment were also less than those with other medications. Benefits reported included improvements in sleep, alertness and mood during the CBD treatment.

"Although this study suggests a potential role for CBD in the treatment of IS and LGS, it is important to note that this study does not represent compelling evidence of efficacy or safety," said Raymond Zhou, research associate, UCLA Infantile Spasms Project. "From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and placebo effect as our data is self-reported by parents and did not use objective measures such as EEG. Our hope in presenting this data is to emphasize the need for controlled clinical trials to establish safety and efficacy."

A third study is a single case of a child with Doose Syndrome whose family initiated independent CBD treatment. A child aged 4 experiencing multiple seizure types tried several medications with various and limited benefits. Baseline video EEG showed that the child had at least 10 seizures per day while awake and asleep. Immediately after starting on CBD the child continued to have seizures and Valproic acid levels increased substantially. When the dosage of Valproic acid was reduced the blood level returned to the previous range, and over 4 months seizures disappeared clinically and a repeat EEG was normal in both awake and asleep periods.

"We cannot recommend CBD treatment based on the limited evidence at this time, but do hope that families who independently seek CBD treatment will continue conventional therapies and remain in close contact with their healthcare providers," said Jeffery Gold, MD, Ph.D., Rady Children's Hospital of San Diego. "Establishing EEG measures before and after CBD treatment will provide the best possible insight into the benefits of the treatment. Further, since the effect of CBD treatment on other medications is undetermined, we recommend that physicians work with families to determine if adjustments to other medications are necessary."

https://www.sciencedaily.com/releases/2014/12/141208144146.htm

Cannabis extract can have dramatic effect on brain cancer

November 14, 2014

Science Daily/University of St George's London

Experts have shown that when certain parts of cannabis are used to treat cancer tumours alongside radio therapy treatment the growths can virtually disappear.

The new research by specialists at St George's, University of London, studied the treatment of brain cancer tumours in the laboratory and discovered that the most effective treatment was to combine active chemical components of the cannabis plant which are called cannabinoids.

Two of these called tetrahydrocannabinol (THC) and cannabidiol (CBD) were tested as part of the research into brain cancer which is particularly difficult to treat and claims the lives of about 5,200 each year. It also has a particularly poor prognosis as the rate of survival after five years of patients' diagnosis is around 10%.

Cannabinoids are the active chemicals in cannabis and are also known more specifically as phytocannabinoids. There are 85 known cannabinoids in the cannabis plant.

The new research is the first to show a drastic effect when combining THC and CBD with irradiation. Tumours growing in the brains of mice were drastically slowed down when THC/CBD was used with irradiation.

Dr Wai Liu, Senior Research Fellow and lead researcher on the project, said: "The results are extremely exciting. The tumours were treated in a variety of ways, either with no treatment, the cannabinoids alone, and irradiation alone or with both the cannabinoids and irradiation at the same time.

"Those treated with both irradiation and the cannabinoids saw the most beneficial results and a drastic reduction in size. In some cases, the tumours effectively disappeared in the animals. This augurs well for further research in humans in the future. At the moment this is a mostly fatal disease.

"The benefits of the cannabis plant elements were known before but the drastic reduction of brain cancers if used with irradiation is something new and may well prove promising for patients who are in gravely serious situations with such cancers in the future."

The research team are discussing the possibility of combining cannabinoids with irradiation in a human clinical trial.

The research has been published in the Molecular Cancer Therapeutics journal.

Cannabinoids are the active chemicals in cannabis and are also known more specifically as phytocannabinoids. There are 85 known cannabinoids in the cannabis plant. The primary psychoactive component of cannabis is called tetrahydrocannabinol (THC).

https://www.sciencedaily.com/releases/2014/11/141114085629.htm

Effectiveness of cannibidiol in epilepsy: Three studies shed new light

October 14, 2014

Science Daily/American Epilepsy Society (AES)

In advance of the American Epilepsy Society's (AES) Annual Meeting in December, the organization has offered highlights of groundbreaking research being studied at a number of institutions regarding the effectiveness of cannibidiol (CBD) and its derivatives as a viable treatment for people with epilepsy.

The first of three studies (Abstract#1.326) to be presented in full at the Annual Meeting is from Colorado, where much of the nation's attention has been captured by issues surrounding cannabis. The physicians and researchers at Children's Hospital Colorado and the University of Colorado have a unique perspective on CBD given the large number of cases they have treated. In addition to the many children already in their care, these professionals are now caring for many of the patients who have ventured to Colorado in search of cannabis treatment.

Dr. Kevin Chapman, associate professor of pediatrics and neurology at the University of Colorado, and his colleagues conducted a retrospective review of the 58 children and adolescents (average age of 7) who had catastrophic forms of epilepsy and were receiving artisanal oral cannabis extracts when they came under the care of the hospital-based team. Chapman's team found that in only one-third of patients did the parents report a seizure reduction of 50% or more, and this did not correlate with an improvement in their electroencephalograms (EEGs). Of the sixteen patients who had baseline EEGs prior to and during treatment with cannabis, only two showed any signs of improvement. The researchers also noted that the response rate did not change with various strains of cannabis. Notably, families who moved to Colorado for CBD treatment were three times as likely to report a reduction greater than 50% than families who were already in Colorado.

Adverse effects occurred in 47% of patients, with increased seizures or new seizures in 21%, somnolence/fatigue in 14%, and rare adverse events of developmental regression in 10% with one patient needing intubation, and one death.

"This substantial gap between the clinical observations and various anecdotal reports highlighted in popular media underscores the desperate need shared by the entire epilepsy community for robust scientific evidence regarding the potential benefit and risks of marijuana in people with epilepsy," said Dr. Chapman.

Two additional studies that will be featured at the Annual Meeting provide updates on the development of Epidiolex (GW Pharmaceuticals), a purified and formulated form of CBD. The first study (Abstract #3.303) explores initial data from an efficacy and safety study, a precursor to a randomized clinical trial. Twenty-three patients with treatment-resistant epilepsies, especially Dravet Syndrome, with an average age of 10, were enrolled in two sites at New York University and the University of California San Francisco. After establishing a 4-week baseline of frequency, type of seizures and existing antiepileptic drug (AED) regimes, patients received a purified 98% oil-based CBD extract, of known and constant composition at a dose of 5mg/kg/day in addition to their baseline AED regimen. The daily dose was gradually increased until intolerance occurred or a maximum dose of 25 mg/kg/day was achieved. After three months of therapy, 39% of patients had a greater than 50% reduction in seizures with a median reduction of 32%. Seizure freedom occurred in 3/9 Dravet patients and 1/14 patients with other forms of epilepsy. Adverse effects were mostly mild or moderate and included somnolence, fatigue, AED level increases, decreased appetite, weight gain, diarrhea, increased appetite and weight loss.

"These results are encouraging, especially since they involved a group of children and young adults with very treatment-resistant epilepsy. However, we await the planned double-blind study to truly assess the safety and efficacy of Epidiolex," said Orrin Devinsky, M.D., director of the NYU Comprehensive Epilepsy Center and professor of neurology, neurosurgery and psychiatry at the NYU School of Medicine.

The second abstract related to Epidiolex (Abstract #2.309) examined the drug interactions between existing AEDs and the CBD extract Epidiolex. In this study, 33 patients (with an average age of 10) were taking an average of three different AEDs including clobazam (54.5% of patients), valproate (36.4%) and levetiracetam (30.3%), felbamate (21.2%), Lamotrigine (18.2%) and zonisamide (18.2%). Baseline AED concentrations were established and then taken again after the addition of CBD. Patients were given a purified 98% CBD extract, of known and constant composition at a dose of 5mg/kg/day in addition to their baseline AEDs. The study found that in patients on multiple AEDs, the addition of CBD may be associated with changes in serum concentrations of some concomitant AEDs. A subset of patients experienced an increase in clobazam concentrations requiring a dose adjustment and suggesting CBD's effects on the major metabolic pathway of clobazam.

"These results support experimental findings that CBD can affect metabolism of some common anti-epileptic drugs though the effects may not be seen in all patients. More studies are needed to understand the potentially complex interactions between CBD and other drugs but in the meantime, frequent monitoring of drug levels is warranted in children taking CBD-containing products, including medicinal cannabis," Daniel Friedman, M.D., epileptologist and a clinical neurophysiologist at the NYU Comprehensive Epilepsy Center.

https://www.sciencedaily.com/releases/2014/10/141014112710.htm

Estrogen increases cannabis sensitivity

September 3, 2014

Science Daily/Washington State University

Smoking today's concentrated pot might be risky business for women, according to new research from Washington State University. The study is the first to demonstrate sex differences in the development of tolerance to THC.

Psychology professor Rebecca Craft showed that, thanks to their estrogen levels, female rats are at least 30 percent more sensitive than males to the pain-relieving qualities of THC -- the key active ingredient in cannabis. Females also develop tolerance to THC more quickly. These sensitivities could increase vulnerability to negative side effects like anxiety, paranoia and addiction.

The findings were recently published in the journal Drug and Alcohol Dependence.

The research was supported by a grant from the National Institute on Drug Abuse.

Many unknowns

Craft said other researchers, like Margaret Haney at the Columbia University Medical Center, have shown that women are more susceptible to cannabis abuse and dependence than men. Haney has documented a cannabis withdrawal syndrome of irritability, sleep disruption and decreased food intake that Craft said tends to be more severe in women. Women also have a greater tendency to relapse when trying to stop using the drug.

Despite the known differences in how marijuana affects the sexes, Craft said most THC tolerance studies have been done on males.

With recent legalization of recreational marijuana in Washington and Colorado -- and many more states allowing medicinal use -- Craft said there is greater burden on researchers to understand the effects of cannabis and ferret out differences between males and females.

She said the "munchie effect" appears to be the only THC reaction where males show more sensitivity than females. Studies in California found that THC stimulated the appetites of male animals more than those of females.

Cannabis complex

The marijuana plant contains more than 60 compounds known as cannabinoids. THC, or tetrahydrocannabinol, is the psychoactive ingredient behind the characteristic mental high. Cannabidiol and cannabinol occur in smaller amounts but may be useful for medical purposes.

All three compounds are present in the most common species of marijuana, Cannabis sativa and C. indica, but in varying proportions.

Craft said most medical marijuana patients prefer a balance between the cannabinoids. But when it comes to recreational pot, selective breeding has resulted in THC concentrations double or triple those seen in the 1960s and 70s.

"Marijuana is very different than it was 40 years ago," she said. "It's much higher in THC and lower in cannabidiol, so a little bit goes a very long way.

"We're more likely to see negative side effects today like anxiety, confusion, panic attacks, hallucinations or extreme paranoia," she said. "And women are at higher risk."

One of the few female studies

Most clinical drug trials have been conducted on men due to their more stable hormonal profile. Despite the recommendation of the National Institutes of Health in 1993 to include more women in studies or give good reasons not to, many researchers still avoid dealing with the hormone swings inherent in a woman's biology.

But Craft has been studying drug sensitivities in females for years.

Working with rats in her laboratory, Craft said she and her team "routinely manipulate hormones and follow females across their cycles to see if their drug sensitivities change along with their hormones. And they do…very frequently." Estrogen is the culprit.

"What we're finding with THC is that you get a very clear spike in drug sensitivity right when the females are ovulating -- right when their estrogen levels have peaked and are coming down," she said.

Surprise finding

In the current study, Craft and her team examined the pain relieving effects of THC in male and female rats. After 10 days of treatment, tolerance to THC was shown to be significantly greater in females than males.

Tolerance occurs when the rat "adapts" to THC so that larger doses are required to produce the same pain-relieving effects initially seen with the first dose.

Because Craft already knew that females were more sensitive to THC, she adjusted their doses to be 30 percent lower than doses for males. The females still developed more tolerance.

"This is the lowest dose anyone has ever used to induce tolerance," she said.

The team also found that a low dose of THC did not disrupt the reproductive cycle in female rats, something that has been under debate and, Craft said, needs more study.

Medical marijuana

Hoping to gain greater insights into marijuana's medical potential, Craft and her team are also studying the effects of cannabidiol, which can counter some of THC's negative side effects.

The THC and cannabidiol studies will be extended to include chronic types of pain typically seen in people who request medical marijuana -- such as those with debilitating back or joint pain, cancer, Crohn's disease, multiple sclerosis, severe muscle spasms and more.

"These people have pain that lasts for months or years," Craft said. "Tolerance develops differently and sometimes you get a lot less tolerance to a drug when people are in chronic pain."

Craft uses a standard research formulation of delta-9-THC for her studies and is approved by the U.S. Drug Enforcement Administration to work with Schedule I drugs such as cannabis.

https://www.sciencedaily.com/releases/2014/09/140903092153.htm

Medicinal oil reduces debilitating epileptic seizures associated with Glut1 deficiency, trial shows

August 11, 2014

Science Daily/UT Southwestern Medical Center

A rare metabolic disease that caused hundreds of seizures daily for a 6-year-old is now significantly under control as part of a clinical trial that uses a medicinal oil for treatment. Within hours, treatment with an edible oil dramatically reduced the number of seizures for then-4-year-old.

Two years ago, the parents of Chloe Olivarez watched painfully as their daughter experienced epileptic seizures hundreds of times a day. The seizures, caused by a rare metabolic disease that depleted her brain of needed glucose, left Chloe nearly unresponsive, and slow to develop.

Within hours, treatment with an edible oil dramatically reduced the number of seizures for then-4-year-old Chloe, one of 14 participants in a small UT Southwestern Medical Center clinical trial.

"Immediately we noticed fewer seizures. From the Chloe we knew two years ago to today, this is a completely different child. She has done amazingly well," said Brandi Olivarez, Chloe's mother.

For Chloe and the other trial participants who suffer from the disease called Glut1 deficiency (G1D), seizure frequency declined significantly. Most showed a rapid increase in brain metabolism and improved neuropsychological performance, findings that suggested the oil derived from castor beans called triheptanoin, ameliorated the brain glucose-depletion associated with this genetic disorder, which is often undiagnosed.

"This study paves the way for a medical food designation for triheptanoin, thus significantly expanding therapeutic options for many patients," said Dr. Juan Pascual, Associate Professor of Neurology and Neurotherapeutics, Physiology, and Pediatrics at UT Southwestern and lead author of a study on the findings, published in JAMA Neurology.

For the estimated 38,000 Americans suffering from this disease, the only proven treatment has been a high-fat ketogenic diet, which only works for about two-thirds of patients. In addition, this diet carries long-term risks, such as development of kidney stones and metabolic abnormalities.

Based on the results of this trial, triheptanoin appears to work as efficiently as the ketogenic diet; however, more research needs to be done before the oil is made available as a medical food therapy, researchers said.

"Triheptanoin byproducts produced in the liver and also in the brain refill brain chemicals that we found are preferentially diminished in the disorder, and this effect is precisely what defines a medical food rather than a drug," said Dr. Pascual, who heads UT Southwestern's Rare Brain Disorders Program, maintains an appointment in the Eugene McDermott Center for Human Growth and Development, and holds The Once Upon a Time Foundation Professorship in Pediatric Neurologic Diseases.

The oil, approved for use in research only, is an ingredient in some cosmetic products and is added to butter in some European countries. It is not commercially available in the U.S. for clinical use.

Triheptanoin's success as an experimental treatment for other metabolic diseases, along with preclinical success in G1D mice, led Dr. Pascual and his trial collaborator, Dr. Charles Roe, Clinical Professor of Neurology and Neurotherapeutics, to first conceive the idea and then launch this trial for G1D patients. The 14 pediatric and adult patients in the study consumed varying amounts of the oil, based on their body weight, four times a day. Given the trial's success, Dr. Pascual plans further research to refine the optimal dosage toward the goal of facilitating medical food designation of triheptanoin as a new G1D treatment.

While some trial participants reported mild stomach upset as a side effect, for Chloe the oil has been a miracle medicine without negative effects. Her parents, Brandi and Josh Olivarez of Waco, Texas, continue to be amazed by her progress.

"Before, she was having so many seizures a day that she couldn't even talk. Now she sings all the time, she can eat whatever she wants, and her speech is greatly improved. She still has some learning delays, but has come a long way," said Mrs. Olivarez.

Many Glut1 patients suffer from movement disorders that limit their physical capabilities, but that does not appear to be the case with Chloe. As for the seizures, she still has minor ones occasionally, but they are not debilitating.

"She is now able to run a solid mile without stopping. This would not have been possible without the oil," Mrs. Olivarez said. "Before, she had almost no muscle tone, was lethargic and had a very wide gait due to trying to balance herself while walking, which was very tiring for her."

To better understand this disease, UT Southwestern established a patient-completed registry to track G1D incidence and what treatments work or do not work for those registered.

Study author Dr. Hanzhang Lu, Associate Professor in the Advanced Imaging Research Center and of Psychiatry and Radiology, a TI Scholar in Advanced Imaging Technologies, devised a novel MRI technique used in the trial to measure brain metabolism.

https://www.sciencedaily.com/releases/2014/08/140811165819.htm

Trends in substance use among high school athletes suggests increase of prescription pain medication usage

July 28, 2014

Science Daily/Taylor & Francis

Newly published research from Journal of Child & Adolescent Substance Abuse (Routledge) reports on the current trends of substance use by high school student athletes and notes an increase in the use of prescription pain medications among football players. "High School Sports Participation and Substance Use: Differences by Sport, Race, and Gender," conducted by Bryan E. Denham of Clemson University, is now available online with Free Access.

In the United States, alcohol and marijuana use continue to threaten the collective health of American teenagers. At least half of the students enrolled in U.S. high schools consume alcohol. Furthermore, while the term "hard drug" often applies to illicit substances such as cocaine or LSD, it also now pertains to prescription pain relievers or analgesics (e.g. methadone, opium, morphine, and codeine). "The study seeks to account for multiple determinants of substance use before attempting to draw substantive conclusions about sport-specific patterns," wrote Denham.

For the research, Denham cross-tabulated quantitative data collected from the answers of 2273 high school seniors who participated in the 2009 Monitoring the Future survey, sponsored by the National Institute on Drug Abuse (NIDA) and conducted at the Institute for Social Research at the University of Michigan. This study divided the data based on gender and included two categorical factors -- race and competitive sports participation. Male participants in these sports were interviewed: baseball, basketball, football, soccer, swimming and diving, and track and field. Female participants in these sports were interviewed: softball, basketball, soccer, swimming and diving, track and field, and volleyball.

The results did find a few common trends, some of which included: student athletes generally partake in illicit substance use more frequently than non-competitors, potentially due to assimilation with their peer groups. Among all of the sports studied, football players use the most illegal substances. Males consume more illegal substances than females. White students use substances more than African American and Hispanic classmates. Most revealing, 12 percent of males and 8 percent of females reported using analgesics in the past year, an increase from previous surveys.

"I've studied the use of performance-enhancing substances in sports for about 15 years, and this study extended that line of research to mind-altering substances," said Denham. "Alcohol has always been available, as has marijuana, but young people also may look to stronger drugs for euphoric effects. If prescription pain relievers are over-prescribed in certain regions, their use may trickle down to adolescents. Use of narcotic pain relievers may become a habit with some adolescent athletes."

https://www.sciencedaily.com/releases/2014/07/140728104601.htm

Biological basis for magic mushroom 'mind expansion' discovered

July 3, 2014

Science Daily/Imperial College London

New research shows that our brain displays a similar pattern of activity during dreams as it does during a mind-expanding drug trip. The study found that under psilocybin, activity in the more primitive brain network linked to emotional thinking became more pronounced, with several different areas in this network -- such as the hippocampus and anterior cingulate cortex -- active at the same time. This pattern of activity is similar to the pattern observed in people who are dreaming.

Psychedelic drugs such as LSD and magic mushrooms can profoundly alter the way we experience the world but little is known about what physically happens in the brain. New research, published in Human Brain Mapping, has examined the brain effects of the psychedelic chemical in magic mushrooms, called psilocybin, using data from brain scans of volunteers who had been injected with the drug.

The study found that under psilocybin, activity in the more primitive brain network linked to emotional thinking became more pronounced, with several different areas in this network -- such as the hippocampus and anterior cingulate cortex -- active at the same time. This pattern of activity is similar to the pattern observed in people who are dreaming. Conversely, volunteers who had taken psilocybin had more disjointed and uncoordinated activity in the brain network that is linked to high-level thinking, including self-consciousness.

Psychedelic drugs are unique among other psychoactive chemicals in that users often describe 'expanded consciousness,' including enhanced associations, vivid imagination and dream-like states. To explore the biological basis for this experience, researchers analysed brain imaging data from 15 volunteers who were given psilocybin intravenously while they lay in a functional magnetic resonance imaging (fMRI) scanner. Volunteers were scanned under the influence of psilocybin and when they had been injected with a placebo.

"What we have done in this research is begin to identify the biological basis of the reported mind expansion associated with psychedelic drugs," said Dr Robin Carhart-Harris from the Department of Medicine, Imperial College London. "I was fascinated to see similarities between the pattern of brain activity in a psychedelic state and the pattern of brain activity during dream sleep, especially as both involve the primitive areas of the brain linked to emotions and memory. People often describe taking psilocybin as producing a dream-like state and our findings have, for the first time, provided a physical representation for the experience in the brain."

The new study examined variation in the amplitude of fluctuations in what is called the blood-oxygen level dependent (BOLD) signal, which tracks activity levels in the brain. This revealed that activity in important brain networks linked to high-level thinking in humans becomes unsynchronised and disorganised under psilocybin. One particular network that was especially affected plays a central role in the brain, essentially 'holding it all together', and is linked to our sense of self.

In comparison, activity in the different areas of a more primitive brain network became more synchronised under the drug, indicating they were working in a more co-ordinated, 'louder' fashion. The network involves areas of the hippocampus, associated with memory and emotion, and the anterior cingulate cortex which is related to states of arousal.

Lead author Dr Enzo Tagliazucchi from Goethe University, Germany said: "A good way to understand how the brain works is to perturb the system in a marked and novel way. Psychedelic drugs do precisely this and so are powerful tools for exploring what happens in the brain when consciousness is profoundly altered. It is the first time we have used these methods to look at brain imaging data and it has given some fascinating insight into how psychedelic drugs expand the mind. It really provides a window through which to study the doors of perception."

Dr. Carhart-Harris added: "Learning about the mechanisms that underlie what happens under the influence of psychedelic drugs can also help to understand their possible uses. We are currently studying the effect of LSD on creative thinking and we will also be looking at the possibility that psilocybin may help alleviate symptoms of depression by allowing patients to change their rigidly pessimistic patterns of thinking. Psychedelics were used for therapeutic purposes in the 1950s and 1960s but now we are finally beginning to understand their action in the brain and how this can inform how to put them to good use."

The data was originally collected at Imperial College London in 2012 by a research group led by Dr Carhart-Harris and Professor David Nutt from the Department of Medicine, Imperial College London. Initial results revealed a variety of changes in the brain associated with drug intake. To explore the data further Dr. Carhart-Harris recruited specialists in the mathematical modelling of brain networks, Professor Dante Chialvo and Dr Enzo Tagliazucchi to investigate how psilocybin alters brain activity to produce its unusual psychological effects.

As part of the new study, the researchers applied a measure called entropy. This was originally developed by physicists to quantify lost energy in mechanical systems, such as a steam engine, but entropy can also be used to measure the range or randomness of a system. For the first time, researchers computed the level of entropy for different networks in the brain during the psychedelic state. This revealed a remarkable increase in entropy in the more primitive network, indicating there was an increased number of patterns of activity that were possible under the influence of psilocybin. It seemed the volunteers had a much larger range of potential brain states that were available to them, which may be the biophysical counterpart of 'mind expansion' reported by users of psychedelic drugs.

Previous research has suggested that there may be an optimal number of dynamic networks active in the brain, neither too many nor too few. This may provide evolutionary advantages in terms of optimising the balance between the stability and flexibility of consciousness. The mind works best at a critical point when there is a balance between order and disorder and the brain maintains this optimal number of networks. However, when the number goes above this point, the mind tips into a more chaotic regime where there are more networks available than normal. Collectively, the present results suggest that psilocybin can manipulate this critical operating point.

The research was funded and intellectually supported by the Beckley Foundation. Professor Chialvo is from the Consejo Nacional de Investigaciones Cientificas y Tecnologicas (CONICET), Argentina and Dr Tagliazucchi is based at Goethe University, Germany.

https://www.sciencedaily.com/releases/2014/07/140703102649.htm

Ecstasy, Molly can be fatal in warm environments

June 4, 2014

Science Daily/NIH/National Institute on Drug Abuse

A moderate dose of MDMA, commonly known as Ecstasy or Molly, that is typically nonfatal in cool, quiet environments can be lethal in rats exposed to conditions that mimic the hot, crowded, social settings where the drug is often used by people, a study finds. Scientists have identified the therapeutically-relevant cooling mechanism to enable effective interventions when faced with MDMA-induced hyperthermia. The study, in the Journal of Neuroscience, was conducted by researchers at the National Institute on Drug Abuse's Intramural Research Program (NIDA IRP). NIDA is a part of the National Institutes of Health.

While MDMA can have a range of adverse health effects, previous studies have shown that high doses of MDMA increase body temperature, while results with moderate doses were inconsistent. This has led some people to assume that the drug is harmless if taken in moderation. However, this study shows that in rats even moderate doses of MDMA in certain environments can be dangerous because it interferes with the body's ability to regulate temperature.

"We know that high doses of MDMA can sharply increase body temperature to potentially lead to organ failure or even death," said NIDA Director Dr. Nora D. Volkow. "However, this current study opens the possibility that even moderate doses could be deadly in certain conditions."

It is impossible to predict who will have an adverse reaction even to a low dose of MDMA. However, in this study scientists gave the rats low to moderate doses that have been shown in past studies to not be fatal. They monitored the rats to determine drug-induced changes in brain and body temperature and in the body's ability to cool itself through blood vessel dilation. When rats were alone and in a room-temperature environment, a moderate dose of MDMA modestly increased brain and body temperature and moderately diminished the rats' ability to eliminate excessive heat. However, when researchers injected the same dose in rats that were either in a warmer environment or in the presence of another rat in the cage, brain temperature increased, causing death in some rats. These fatal temperature increases were because the drug interfered with the body's ability to eliminate heat.

"These results demonstrate that the use of MDMA in certain warm, social settings could be more dangerous than commonly believed," said Dr. Eugene Kiyatkin, first author on the study and NIDA IRP scientist. "Even with moderate doses, we saw drug-induced, fatal brain hyperthermia during conditions of social interaction and in warm environments."

These findings further suggest that medical interventions aimed at increasing the efficiency of whole-body cooling by targeting blood vessel constriction in the skin could be therapeutically relevant for counteracting the development of MDMA-induced hyperthermia.

https://www.sciencedaily.com/releases/2014/06/140604094116.htm

Marijuana shows potential in treating autoimmune disease

June 2, 2014

Science Daily/University of South Carolina

A team of University of South Carolina researchers led by Mitzi Nagarkatti, Prakash Nagarkatti and Xiaoming Yang have discovered a novel pathway through which marijuana's main active constituent, THC, can suppress the body's immune functions.

Their research has been published online in the Journal of Biological Chemistry.

Marijuana is the most frequently used illicit drug in the United States, but as more states legalize the drug for medical and even recreational purposes, research studies like this one are discovering new and innovative potential health applications for the federal Schedule I drug.

Marijuana is now regularly and successfully used to alleviate the nausea and vomiting many cancer patients experience as side effects to chemotherapy, combat the wasting syndrome that causes some AIDS patients to lose significant amounts of weight and muscle mass and ease chronic pain that is unresponsive to opioids, among other applications.

The university study has uncovered yet another potential application for marijuana, in the suppression of immune response to treat autoimmune diseases. The work builds on recent scientific discoveries that the environment in which humans live can actually trigger changes that occur outside of human DNA, but nevertheless can cause alterations to the function of genes controlled by DNA. These outside molecules that have the ability to alter DNA function are known collectively as the epigenome. In this study, the investigators wanted to find out if the tetrahydrocannabinol (THC) found in marijuana has the capacity to affect DNA expression through epigenetic pathways outside of the DNA itself.

The recent findings show that THC can change critical molecules of epigenome called histones, leading to suppression of inflammation. These results suggest that one potential negative impact of marijuana smoking could be suppression of beneficial inflammation in the body. But they also suggest that, because of its epigenetic influence toward inflammation suppression, marijuana use could be efficacious in the treatment of autoimmune diseases such as arthritis, lupus, colitis, multiple sclerosis and the like, in which chronic inflammation plays a central role.

https://www.sciencedaily.com/releases/2014/06/140602150914.htm

Could cannabis active substance curb seizures? Experts weed through evidence

May 22, 2014

Science Daily/Wiley

The therapeutic potential of medical marijuana and pure cannabidiol (CBD), an active substance in the cannabis plant, for neurologic conditions is highly debated. A series of articles published in Epilepsia, a journal of the International League Against Epilepsy (ILAE), examine the potential use of medical marijuana and CBD in treating severe forms of epilepsy such as Dravet syndrome.

In a case study, Dr. Edward Maa, Chief of the Comprehensive Epilepsy Program at Denver Health in Denver, Colo., details one mother's experience of providing medical marijuana to her child with Dravet syndrome. The adjunct therapy, a strain of cannabis high in CBD and tetrahydrocannabinol (THC) known as Charlotte's Web, was given in conjunction with the patient's antiepileptic drug regimen. The child's seizure frequency was reduced from 50 convulsions per day to 2 to 3 nighttime convulsions per month.

"Colorado is "ground zero" of the medical marijuana debate," says Dr. Maa. "As medical professionals it is important that we further the evidence of whether CBD in cannabis is an effective antiepileptic therapy." Currently, 21 states and the District of Columbia (DC) have legalized marijuana for medical purposes according to GOVERNING magazine.

A counter-point article summarizes current scientific evidence of CBD use in epilepsy and other neurological or psychiatric disorders including anxiety, schizophrenia and addiction. Previous studies found that THC, the primary psychoactive substance and CBD the main non-psychoactive ingredient in cannabis, display anticonvulsive properties in animals. However, this research was conducted in acute animal models and data is limited for chronic recurrent seizures. Recent studies claim medical marijuana with high ratios of CBD to THC are more effective in seizure control, but the data was anecdotal and not well controlled.

"While cannabis has been used to treat epilepsy for centuries, data from double-blind randomized, controlled trials of CBD or THC in epilepsy is lacking," explains Dr. Orrin Devinsky, Director of the Comprehensive Epilepsy Center at NYU Langone Medical Center in New York and Saint Barnabas Institute of Neurology and Neurosurgery in New Jersey. "Randomized controlled studies of CBD in targeted epilepsy groups, such as patients with Dravet or Lennox-Gastaut syndromes, are in the planning stages."

Dr. Maria Roberta Cilio, Director of Research in Pediatric Epilepsy of the Comprehensive Epilepsy Center at UCSF Benioff Children's Hospital in San Francisco, agrees, "There is a critical need for new therapies, especially for childhood-onset treatment-resistant epilepsies that impair quality of life and contribute to learning and behavioral disorders. Rigorous investigation of the safety and efficacy of medical marijuana or individual components such as CBD are necessary for patients with epilepsy before any conclusion is made. "

"There is much interest in the therapeutic potential of medical marijuana and CBD in treating epilepsy," say Drs. Gary Mathern and Astrid Nehlig, Editors-in-Chief of Epilepsia. "We would like your perspective on this important issue and ask that patients, clinicians, and medical professionals visit http://surveys.verticalresponse.com/a/show/1539433/ea840f4206/0 to provide feedback on the use of medical marijuana in epilepsy."

https://www.sciencedaily.com/releases/2014/05/140522074747.htm