Natural 'high' could avoid chronic marijuana use

December 1, 2014

Science Daily/Vanderbilt University Medical Center

Replenishing the supply of a molecule that normally activates cannabinoid receptors in the brain could relieve mood and anxiety disorders and enable some people to quit using marijuana, a Vanderbilt University study suggests.

Cannabinoid receptors are normally activated by compounds in the brain called endocannabinoids, the most abundant of which is 2-AG. They also are "turned on" by the active ingredient in marijuana.

Sachin Patel, M.D., Ph.D., and his colleagues developed a genetically modified mouse with impaired ability to produce 2-AG in the brain. The mice exhibited anxiety-like behaviors, and female mice also displayed behaviors suggestive of depression.

When an enzyme that normally breaks down 2-AG was blocked, and the supply of the endocannabinoid was restored to normal levels, these behaviors were reversed, the researchers reported on Nov. 26 in the online edition of the journal Cell Reports.

If further research confirms that some people who are anxious and depressed have low levels of 2-AG, this method of "normalizing 2-AG deficiency could represent a viable ... therapeutic strategy for the treatment of mood and anxiety disorders," they concluded.

However, this approach has not been tested in humans, they cautioned.

Relief of tension and anxiety is the most common reason cited for chronic marijuana use. Thus, restoring depleted levels of 2-AG also "could be a way to help people using marijuana," added Patel, the paper's senior author and professor of Psychiatry and of Molecular Physiology and Biophysics.

Chronic use of marijuana down-regulates cannabinoid receptors, and thus paradoxically increases anxiety. This can lead to a "vicious cycle" of increasing marijuana use that in some cases leads to addiction.

Patel and his colleagues previously have found cannabinoid receptors in the central nucleus of the amygdala of the mouse. The amygdala is a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response.

They also have found that chemically modified inhibitors of the COX-2 enzyme they developed relieve anxiety behaviors in mice by activating natural "endocannabinoids" without gastrointestinal side effects. Clinical trials of some of these potential drugs could begin in the next several years.

Cyclooxygenase (COX) enzymes produce pro-inflammatory prostaglandins and are the target of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), used to relieve pain and inflammation. It has been known for several years that COX-2 inhibition also activates endocannabinoids.

https://www.sciencedaily.com/releases/2014/12/141201113253.htm

Cannabis prevents negative behavioral, physiological effects of traumatic events

September 4, 2014

Science Daily/University of Haifa

Administering synthetic marijuana (cannabinoids) soon after a traumatic event can prevent PTSD-like (post-traumatic stress disorder) symptoms in rats, caused by the trauma and by trauma reminders. This is according to a new study conducted by Nachshon Korem and Irit Akirav of the Department of Psychology at the University of Haifa, which was published in the journal Neuropsychopharmacology. "The importance of this study is that it contributes to the understanding of the brain basis of the positive effect cannabis has on PTSD and thus supports the necessity to perform human trials to examine potential ways to prevent the development of PTSD and anxiety disorders in response to a traumatic event," the researchers noted.

According to the Israel Medical Association approximately nine percent of the population suffers from post-traumatic stress disorder, whereas among at-risk populations such as combat soldiers, prisoners, victims of assault, citizens in lines of confrontation, etc., the percentages are even higher. A common phenomenon among those who suffer from trauma is that exposure to a "trauma reminder" -- an event that is not traumatic in essence but that evokes the memory of the experience of the traumatic event -- can further heighten the negative effects of the trauma. For example, for a person who has developed post-traumatic syndromes as a result of "Color Red" sirens (air raid sirens), a trauma reminder can occur following a loud car alarm.

In previous studies performed by Dr. Irit Akirav, she discovered that the use of cannabinoids within a specific time window after the traumatic event has occurred reduces PTSD symptoms in rats. In this current study, conducted by Dr. Irit Akirav together with the doctoral student Nachshon Korem, the researchers aimed to examine whether the use of cannabinoids may also moderate the effects of trauma in cases of exposure to trauma reminders. The researchers chose rats because of their great physiological similarity to humans in the way they respond to stressful and traumatic events.

During the first half of the experiment, the rats underwent the traumatic event of receiving an electric shock and were exposed to trauma reminders on the third and fifth days of the trial. After the event, and within the time window found in earlier studies, some of the rats were injected with a cannabinoid substance. The rats then went through extinction procedures for trauma (a conditional psychological procedure similar to exposure therapy in humans, the purpose of which is to cope with post-trauma symptoms).

From the findings it became clear that the rats that were injected with the cannabinoid substance showed no PTSD symptoms such as impaired extinction learning, increased startle response, changes in sensitivity to pain and impaired plasticity in the brain's reward center (the nucleus accumbens), compared to those not injected with the drug. The researchers added that the rats that were injected with the drug showed better results compared to rats who received sertraline (an antidepressant of the SSRI group) a substance that is used in the treatment of PTSD with limited success in reducing symptoms. In fact, for some of the symptoms, the rats that were injected with the drug showed similar behavior to rats exposed to trauma but that were not exposed to trauma reminders. In other words -- cannabis made the effects of trauma reminders "disappear."

Once they found the moderating effect of cannabis on behavioral aspects, the study aimed to examine the neurobiological basis for the improvement caused by the drug. It was found that rats who were exposed to trauma and to trauma reminders showed an increase in the expression of two receptors in the brain associated with emotional processing: the CB1 receptor, a receptor in the brain that cannabinoids are known to bind to, and receptor GR, the receptor associated with exposure to stress. On the other hand, in rats that received cannabinoids, the increase in the expression of these two receptors was prevented in the hippocampus and prefrontal cortex, areas involved in forming and saving traumatic memories.

"The findings of our study suggest that the connectivity within the brain's fear circuit changes following trauma, and the administration of cannabinoids prevents this change from happening. This study can lead to future trials in humans regarding possible ways to prevent the development of PTSD and anxiety disorders in response to a traumatic event," the researchers concluded.

https://www.sciencedaily.com/releases/2014/09/140904084252.htm

Marijuana compound may offer treatment for Alzheimer's disease

August 27, 2014

Science Daily/University of South Florida (USF Health)

Extremely low levels of the compound in marijuana known as delta-9-tetrahydrocannabinol, or THC, may slow or halt the progression of Alzheimer's disease, a recent study from neuroscientists at the University of South Florida shows.

Findings from the experiments, using a cellular model of Alzheimer's disease, were reported online in the Journal of Alzheimer's Disease.

Researchers from the USF Health Byrd Alzheimer's Institute showed that extremely low doses of THC reduce the production of amyloid beta, found in a soluble form in most aging brains, and prevent abnormal accumulation of this protein -- a process considered one of the pathological hallmarks evident early in the memory-robbing disease. These low concentrations of THC also selectively enhanced mitochondrial function, which is needed to help supply energy, transmit signals, and maintain a healthy brain.

"THC is known to be a potent antioxidant with neuroprotective properties, but this is the first report that the compound directly affects Alzheimer's pathology by decreasing amyloid beta levels, inhibiting its aggregation, and enhancing mitochondrial function," said study lead author Chuanhai Cao, PhD and a neuroscientist at the Byrd Alzheimer's Institute and the USF College of Pharmacy.

"Decreased levels of amyloid beta means less aggregation, which may protect against the progression of Alzheimer's disease. Since THC is a natural and relatively safe amyloid inhibitor, THC or its analogs may help us develop an effective treatment in the future."

The researchers point out that at the low doses studied, the therapeutic benefits of THC appear to prevail over the associated risks of THC toxicity and memory impairment.

Neel Nabar, a study co-author and MD/PhD candidate, recognized the rapidly changing political climate surrounding the debate over medical marijuana.

"While we are still far from a consensus, this study indicates that THC and THC-related compounds may be of therapeutic value in Alzheimer's disease," Nabar said. "Are we advocating that people use illicit drugs to prevent the disease? No. It's important to keep in mind that just because a drug may be effective doesn't mean it can be safely used by anyone. However, these findings may lead to the development of related compounds that are safe, legal, and useful in the treatment of Alzheimer's disease."

The body's own system of cannabinoid receptors interacts with naturally-occurring cannabinoid molecules, and these molecules function similarly to the THC isolated from the cannabis (marijuana) plant.

Dr. Cao's laboratory at the Byrd Alzheimer's Institute is currently investigating the effects of a drug cocktail that includes THC, caffeine as well as other natural compounds in a cellular model of Alzheimer's disease, and will advance to a genetically-engineered mouse model of Alzheimer's shortly.

"The dose and target population are critically important for any drug, so careful monitoring and control of drug levels in the blood and system are very important for therapeutic use, especially for a compound such as THC," Dr. Cao said.

https://www.sciencedaily.com/releases/2014/08/140827131801.htm

Increased levels of the body's own cannabinoids impair embryonic brain development

July 17, 2014

Science Daily/Medical University of Vienna

The human body produces substances, called endocannabinoids, that work in a similar way to cannabis. These endocannabinoids may not produce a "high," but are of tremendous importance for the functioning of the neural network in the brain -- especially during the embryonic stage. If this network is interfered with as a result of too many circulating endocannabinoids, the development of the embryonic brain can be impaired. Researchers at the Medical University of Vienna's Centre for Brain Research have now discovered what mechanism underlies the development of this impairment.

"Stimulation storm" in the brain

The protein "Slit" and its receptor "Robo" (roundabout) are important signaling molecules in the developing brain. Slits can regulate directional guidance of nerve cell processes (called axons), by binding to Robo receptors, directing the formation of embryonic brain circuitry. Researchers at the Medical University of Vienna have now shown that endocannabinoids can regulate Slit and Robo levels in both nerve cells and oligodendrocytes, which support nerve cells, through cannabinoid receptors CB1 and CB2.

This signaling system is important for correct embryonic brain development. If this system goes haywire due to increased levels of endocannabinoids, a kind of "stimulation storm" occurs. "In this case, both Slit and Robo are produced in greater quantities, leading to changes in axonal guidance decisions," explains Erik Keimpema. If the endocannabinoid system is in balance, however, this type of over-stimulation does not occur.

Human relevance

The researchers from MedUni Vienna also found this signalling system, and its regulation by cannabinoids, in human embryonic brains. Since, increased endocannabinoid levels are found in metabolic syndromes such as obesity and insulin resistance, as well as during maternal infections, "it is important to normalize altered endocannabinoid levels during pregnancy to ensure correct embryonic brain development," says the MedUni Vienna researcher. "We have demonstrated that the body's own cannabinoids are able to regulate an important signalling system in the development of embryonic brain circuitry."

https://www.sciencedaily.com/releases/2014/07/140717094826.htm

How cannabis compound could slow tumor growth

July 14, 2014

Science Daily/University of East Anglia

Scientists have shown how the main psychoactive ingredient in cannabis, THC, could reduce tumor growth in cancer patients. New research reveals the existence of previously unknown signaling platforms which are responsible for the drug's success in shrinking tumors.

Research published today reveals the existence of previously unknown signaling platforms which are responsible for the drug's success in shrinking tumours.

It is hoped that the findings could help develop a synthetic equivalent with anti-cancer properties.

The research was co-led with the Universidad Complutense de Madridin, Spain. The team used samples of human breast cancer cells to induce tumours in mice. They then targeted the tumours with doses of the cannabis compound THC (Tetrahydrocannabinol). They found that two cell receptors in particular were responsible for the drug's anti-tumour effects.

Dr Peter McCormick, from UEA's school of Pharmacy, said: "THC, the major active component of marijuana, has anti-cancer properties. This compound is known to act through a specific family of cell receptors called cannabinoid receptors. However, it was unclear which of these receptors were responsible for the anti-tumour effects of THC.

"We show that these effects are mediated via the joint interaction of CB2 and GPR55 -- two members of the cannabinoid receptor family. Our findings help explain some of the well-known but still poorly understood effects of THC at low and high doses on tumour growth.

"There has been a great deal of interest in understanding the molecular mechanisms behind how marijuana, and specifically THC, influence cancer pathology.

"There has also been a drive in the pharmaceutical industry to create synthetic equivalents that might have anti-cancer properties.

"By identifying the receptors involved we have provided an important step towards the future development of therapeutics that can take advantage of the interactions we have discovered to reduce tumour growth."

Dr McCormick added that cancer sufferers should not be tempted to self-medicate.

"Our research uses an isolated chemical compound and using the correct concentration is vital. Cancer patients should not use cannabis to self-medicate, but I hope that our research will lead to a safe synthetic equivalent being available in the future."

https://www.sciencedaily.com/releases/2014/07/140714100339.htm

Blocking brain's 'internal marijuana' may trigger early Alzheimer's deficits

June 18, 2014

Science Daily/Stanford University Medical Center

A new study led by investigators at the Stanford University School of Medicine has implicated the blocking of endocannabinoids -- signaling substances that are the brain's internal versions of the psychoactive chemicals in marijuana and hashish -- in the early pathology of Alzheimer's disease.

A substance called A-beta -- strongly suspected to play a key role in Alzheimer's because it's the chief constituent of the hallmark clumps dotting the brains of people with Alzheimer's -- may, in the disease's earliest stages, impair learning and memory by blocking the natural, beneficial action of endocannabinoids in the brain, the study demonstrates. The Stanford group is now trying to figure out the molecular details of how and where this interference occurs. Pinning down those details could pave the path to new drugs to stave off the defects in learning ability and memory that characterize Alzheimer's.

In the study, published June 18 in Neuron, researchers analyzed A-beta's effects on a brain structure known as the hippocampus. In all mammals, this midbrain structure serves as a combination GPS system and memory-filing assistant, along with other duties.

"The hippocampus tells us where we are in space at any given time," said Daniel Madison, PhD, associate professor of molecular and cellular physiology and the study's senior author. "It also processes new experiences so that our memories of them can be stored in other parts of the brain. It's the filing secretary, not the filing cabinet."

Surprise finding

Applying electrophysiological techniques to brain slices from rats, Madison and his associates examined a key hippocampal circuit, one of whose chief elements is a class of nerve cells called pyramidal cells. They wanted to see how the circuit's different elements reacted to small amounts of A-beta, which is produced throughout the body but whose normal physiological functions have until now been ill-defined.

A surprise finding by Madison's group suggests that in small, physiologically normal concentrations, A-beta tamps down a signal-boosting process that under certain conditions increases the odds that pyramidal nerve cells will transmit information they've received to other nerve cells down the line.

When incoming signals to the pyramidal tract build to high intensity, pyramidal cells adapt by becoming more inclined to fire than they normally are. This phenomenon, which neuroscientists call plasticity, is thought to underpin learning and memory. It ensures that volleys of high-intensity input -- such as might accompany falling into a hole, burning one's finger with a match, suddenly remembering where you buried the treasure or learning for the first time how to spell "cat" -- are firmly stored in the brain's memory vaults and more accessible to retrieval.

These intense bursts of incoming signals are the exception, not the rule. Pyramidal nerve cells constantly receive random beeps and burps from upstream nerve cells -- effectively, noise in a highly complex, electrochemical signaling system. This calls for some quality control. Pyramidal cells are encouraged to ignore mere noise by another set of "wet blanket" nerve cells called interneurons. Like the proverbial spouse reading a newspaper at the kitchen table, interneurons continuously discourage pyramidal cells' transmission of impulses to downstream nerve cells by steadily secreting an inhibitory substance -- the molecular equivalent of yawning, eye-rolling and oft-muttered suggestions that this or that chatter is really not worth repeating to the world at large, so why not just shut up.

Passing along the message

But when the news is particularly significant, pyramidal cells squirt out their own "no, this is important, you shut up!" chemical -- endocannabinoids -- which bind to specialized receptors on the hippocampal interneurons, temporarily suppressing them and allowing impulses to continue coursing along the pyramidal cells to their follow-on peers.

A-beta is known to impair pyramidal-cell plasticity. But Madison's research team showed for the first time how it does so. Small clusters consisting of just a few A-beta molecules render the interneuron's endocannabinoid receptors powerless, leaving inhibition intact even in the face of important news and thus squashing plasticity.

While small A-beta clusters have been known for a decade to be toxic to nerve cells, this toxicity requires relatively long-term exposure, said Madison. The endocannabinoid-nullifying effect the new study revealed is much more transient. A possible physiological role for A-beta in the normal, healthy brain, he said, is that of supplying that organ's sophisticated circuits with yet another, beneficial layer of discretion in processing information. Madison thinks this normal, everyday A-beta mechanism run wild may represent an entry point to the progressive and destructive stages of Alzheimer's disease.

Exactly how A-beta blocks endocannabinoids' action is not yet known. But, Madison's group demonstrated, A-beta doesn't stop them from reaching and binding to their receptors on interneurons. Rather, it interferes with something that binding ordinarily generates. (By analogy, turning the key in your car's ignition switch won't do much good if your battery is dead.)

Madison said it would be wildly off the mark to assume that, just because A-beta interferes with a valuable neurophysiological process mediated by endocannabinoids, smoking pot would be a great way to counter or prevent A-beta's nefarious effects on memory and learning ability. Smoking or ingesting marijuana results in long-acting inhibition of interneurons by the herb's active chemical, tetrahydrocannabinol. That is vastly different from short-acting endocannabinoid bursts precisely timed to occur only when a signal is truly worthy of attention.

"Endocannabinoids in the brain are very transient and act only when important inputs come in," said Madison, who is also a member of the interdisciplinary Stanford Bio-X institute. "Exposure to marijuana over minutes or hours is different: more like enhancing everything indiscriminately, so you lose the filtering effect. It's like listening to five radio stations at once."

Besides, flooding the brain with external cannabinoids induces tolerance -- it may reduce the number of endocannabinoid receptors on interneurons, impeding endocannabinoids' ability to do their crucial job of opening the gates of learning and memory.

The study's lead author was postdoctoral scholar Adrienne Orr, PhD. Other co-authors were postdoctoral scholars Jesse Hanson, PhD (now at Genentech) and Dong Li, PhD; and former undergraduate Adam Klotz, now a student at Stanford's Graduate School of Business. The study was funded by the National Institute for Mental Health (grant MH065541), the Harold and Leila Y. Mathers Charitable Foundation and Elan Pharmaceuticals.

https://www.sciencedaily.com/releases/2014/06/140618131955.htm

Protection from osteoarthritis may lie in our own joints

May 18, 2014

Science Daily/European Calcified Tissue Society

A recent study conducted by researchers at the University of Edinburgh is suggesting a strong link between osteoarthritis, which causes pain and stiffness in the joints and is the most common form of arthritis, and the endocannabioid system, which is found in the synovial tissue and fluid that surround joints. The endocannabinoid system is composed of cannabinoid receptors (which are more popularly known for managing the body's response to the psychoactive effects of cannabis) and endocannabinoid ligands. The type 2 cannabinoid receptor (CB2), is proving to be a significant source of defence against this potentially debilitating disease, which can affect all ages and is particularly common among the elderly.

The findings, which offer the eventual promise of new forms of protection, were presented at the 41st European Calcified Tissue Society Congress, held in Prague on May 17 -- 20, 2014, by Professor Stuart Ralston, Arthritis Research UK Professor of Rheumatology at the University of Edinburgh. Prof Ralston described how a study of mice with destabilised knee joints showed that cartilage degeneration, which lies at the heart of osteoarthritis, was up to 40% more severe in mice who were deficient in CB2 receptors, when compared to 'normal' mice, with the figure reaching up to 60% more severe among aged mice that developed spontaneous osteoarthritis and were deficient in CB2 receptors, when compared to their aged 'normal' counterparts.

The study also showed that a synthesised cannabinoid ligand, HU308, significantly inhibited the progression of arthritis in younger mice with normal levels of CB2 and had no effect on those with CB2 receptor deficiency.

Professor Ralston said: "Learning what provides natural protection against osteoarthritis can potentially give us a much greater insight into how we can develop treatments. We know from this study that, in mice, a CB2 receptor deficiency means a much higher likelihood of developing osteoarthritis and that the use of the synthesised cannabinoid, HU308, in normal mice offers additional protection against the disease.

"Our next step, we hope, is to investigate the role of the CB2 pathway in humans with osteoarthritis."

https://www.sciencedaily.com/releases/2014/05/140518092722.htm

No relief yet for brutal oral cancer pain, but cannabinoids may offer some hope

May 3, 2014

Science Daily/American Pain Society

Many cancer patients endure severe pain and, by far, one of the most excruciating pain conditions is caused by oral cancer, for which even the strongest available pain medications are largely ineffective. One of the nation's leading oral cancer treating clinicians, speaking at the American Pain Society's annual meeting, said he believes that while prospects for major treatment advances remain bleak, a new cannabinoid-based medication may have some promise for providing meaningful pain relief.

Brian Schmidt, DDS, MD, PhD, professor, New York University College of Dentistry and School of Medicine, delivered the Global Year Against Pain Lecture and reported that today, more than 100 years since President Ulysses S. Grant died from oral cancer, there is only modest improvement in patient survival. Grant is the only American president to die from cancer.

"Oral cancer is one of the most painful and debilitating of all malignancies," said Schmidt, " and opioids, the strongest pain medications we have, are an imperfect solution. They become dramatically less effective as tolerance to these drugs develops."

Now considered to be the fastest increasing cancer in the United States, oral and oropharyngeal malignancies usually begin in the tongue. Human papillomavirus transmitted through oral sex, tobacco use and excessive alcohol consumption are the leading causes of this increase in oropharyngeal cancer. In the United States, some 43,000 new cases of oral cancer are diagnosed every year and the disease is more widespread worldwide with 640,000 new cases a year.

Schmidt said oral cancer patients often undergo multiple surgeries as tumors recur and also are treated with radiation and chemotherapy. The disease is difficult to diagnose at early stages and spreads quickly, leaving patients in gruesome pain and unable to speak or swallow. "Our inability to effectively treat oral cancer stems from lack of knowledge. We know that cancer pain is caused by a unique biological mechanism, but more research is needed to develop medications that are effective in treating oral cancer pain," Schmidt said.

"The only way we can hope to reduce the devastating impact of oral cancer pain is to fund more research to help those who suffer or will suffer from this ruthless disease," Schmidt told the APS audience. He added that half of oral cancer patients do not survive five years after diagnosis.

Schmidt noted that perhaps some good news is on the horizon, as clinical trials proceed for a drug produced directly from a marijuana plants (Sativex). It is administered as an oral spray and shows promise for treating cancer pain. The drug is available in Canada and Europe for treating spasticity from multiple sclerosis and is in Phase 3 clinical trials in the United States for treatment of cancer pain. Schmidt is a clinical investigator for Sativex trials.

"While it's too early to conclude the cannabinoid medication will provide effective cancer pain relief, we do know that humans possess numerous cannabinoid receptors in the brain and body which regulate a significant amount of human physiology. So, there is hope that cannabinoid-based medications can become effective pain relievers for cancer patients."

https://www.sciencedaily.com/releases/2014/05/140503141201.htm

Key protein enhances memory, learning

May 2, 2014

Science Daily/Case Western Reserve University

Case Western Reserve researchers have discovered that a protein previously implicated in disease plays such a positive role in learning and memory that it may someday contribute to cures of cognitive impairments. The findings regarding the potential virtues of fatty acid binding protein 5 (FABP5) -- usually associated with cancer and psoriasis -- appear in the May 2 edition of The Journal of Biological Chemistry.

"Overall, our data show that FABP5 enhances cognitive function and that FABP5 deficiency impairs learning and memory functions in the brain hippocampus region," said senior author Noa Noy, PhD, a professor of pharmacology at the School of Medicine. "We believe if we could find a way to upregulate the expression of FABP5 in the brain, we might have a therapeutic handle on cognitive dysfunction or memory impairment in some human diseases."

FABP5 resides in many tissues and is especially highly expressed in the brain. Noy and her Case Western Reserve School of Medicine and National Institute on Alcohol Abuse and Alcoholism colleagues particularly wanted to understand how this protein functioned in neurons. They performed imaging studies comparing the activation of a key transcription factor in the brain tissue of normal mice and in FABP5-deficient mice. (Transcription factor is a protein the controls the flow of genetic information). The investigations revealed that FABP5 performs two different functions in neurons. First, it facilitates the degradation of endocannabinoids, which are neurological modulators controlling appetite, pain sensation, mood and memory. Second, FABP5 regulates gene expression, a process that essentially gives cells their marching orders on structure, appearance and function.

"FABP5 improves learning and memory both because it delivers endocannabinoids to cellular machinery that breaks them down and because it shuttles compounds to a transcription factor that increases the expression of cognition-associated genes," Noy said.

Even though endocannabinoids affect essential physiological processes from appetite to memory, the "cannabinoid" part of the word signifies that these natural biological compounds act similarly to drugs such as marijuana and hashish. Too much endocannabinoid can lead to impaired learning and memory.

In simple terms, FABP5 transports endocannabinoids for processing. FABP5 functions like a bus and carries the brain's endocannabinoids and their biological products to two stations within the neuron cell. FABP5 captures endocannabinoids entering the neuron and delivers them to an enzyme that degrades them (station 1). Then, that degraded product is picked up by the same protein (FABP5) and shuttled to the cell nucleus -- specifically, to a transcription factor within it (station 2). Binding of the degraded product activates the transcription factor and allows it to induce expression of multiple genes. The genes that are induced in this case tell the cells to take steps that promote learning and memory.

Noy and associates also compared memory and learning in FABP5-deficient mice and in normal ones. In one test, both sets of mice repeatedly swam in mazes that had a platform in one established location where they could climb out of the water. During subsequent swims, the wild-type mice reached the platform quickly because they had learned -- and remembered -- its location. Their FABP5-deficient counterparts took much longer, typically finding the platform's location by chance.

"In addition to regulating cell growth as in skin and in cancer cells, for example, FABP5 also plays a key role in neurons of the brain," Noy said. "FABP5 controls the biological actions of small compounds that affect memory and learning and that activate a transcription factor, which regulates neuronal function."

https://www.sciencedaily.com/releases/2014/05/140502132458.htm

Casual marijuana use linked to brain abnormalities in students: Dramatic effects of small time use; more 'joints' equal more damage

April 15, 2014

Science Daily/Northwestern University

Young adults who used marijuana only recreationally showed significant abnormalities in two key brain regions that are important in emotion and motivation, scientists report. The study was a collaboration between Northwestern Medicine® and Massachusetts General Hospital/Harvard Medical School.

This is the first study to show casual use of marijuana is related to major brain changes. It showed the degree of brain abnormalities in these regions is directly related to the number of joints a person smoked per week. The more joints a person smoked, the more abnormal the shape, volume and density of the brain regions.

"This study raises a strong challenge to the idea that casual marijuana use isn't associated with bad consequences," said corresponding and co-senior study author Hans Breiter, M.D. He is a professor of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine and a psychiatrist at Northwestern Memorial Hospital.

"Some of these people only used marijuana to get high once or twice a week," Breiter said. "People think a little recreational use shouldn't cause a problem, if someone is doing OK with work or school. Our data directly says this is not the case."

The study will be published April 16 in the Journal of Neuroscience.

Scientists examined the nucleus accumbens and the amygdala -- key regions for emotion and motivation, and associated with addiction -- in the brains of casual marijuana users and non-users. Researchers analyzed three measures: volume, shape and density of grey matter (i.e., where most cells are located in brain tissue) to obtain a comprehensive view of how each region was affected.

Both these regions in recreational pot users were abnormally altered for at least two of these structural measures. The degree of those alterations was directly related to how much marijuana the subjects used.

Of particular note, the nucleus acccumbens was abnormally large, and its alteration in size, shape and density was directly related to how many joints an individual smoked.

"One unique strength of this study is that we looked at the nucleus accumbens in three different ways to get a detailed and consistent picture of the problem," said lead author Jodi Gilman, a researcher in the Massachusetts General Center for Addiction Medicine and an instructor in psychology at Harvard Medical School. "It allows a more nuanced picture of the results."

Examining the three different measures also was important because no single measure is the gold standard. Some abnormalities may be more detectable using one type of neuroimaging analysis method than another. Breiter said the three measures provide a multidimensional view when integrated together for evaluating the effects of marijuana on the brain.

"These are core, fundamental structures of the brain," said co-senior study author Anne Blood, director of the Mood and Motor Control Laboratory at Massachusetts General and assistant professor of psychiatry at Harvard Medical School. "They form the basis for how you assess positive and negative features about things in the environment and make decisions about them."

Through different methods of neuroimaging, scientists examined the brains of young adults, ages 18 to 25, from Boston-area colleges; 20 who smoked marijuana and 20 who didn't. Each group had nine males and 11 females. The users underwent a psychiatric interview to confirm they were not dependent on marijuana. They did not meet criteria for abuse of any other illegal drugs during their lifetime.

The changes in brain structures indicate the marijuana users' brains are adapting to low-level exposure to marijuana, the scientists said.

The study results fit with animal studies that show when rats are given tetrahydrocannabinol (THC) their brains rewire and form many new connections. THC is the mind-altering ingredient found in marijuana.

"It may be that we're seeing a type of drug learning in the brain," Gilman said. "We think when people are in the process of becoming addicted, their brains form these new connections."

In animals, these new connections indicate the brain is adapting to the unnatural level of reward and stimulation from marijuana. These connections make other natural rewards less satisfying.

"Drugs of abuse can cause more dopamine release than natural rewards like food, sex and social interaction," Gilman said. "In those you also get a burst of dopamine but not as much as in many drugs of abuse. That is why drugs take on so much salience, and everything else loses its importance."

The brain changes suggest that structural changes to the brain are an important early result of casual drug use, Breiter said. "Further work, including longitudinal studies, is needed to determine if these findings can be linked to animal studies showing marijuana can be a gateway drug for stronger substances," he noted.

Because the study was retrospective, researchers did not know the THC content of the marijuana, which can range from 5 to 9 percent or even higher in the currently available drug. The THC content is much higher today than the marijuana during the 1960s and 1970s, which was often about 1 to 3 percent, Gilman said.

Marijuana is the most commonly used illicit drug in the U.S. with an estimated 15.2 million users, the study reports, based on the National Survey on Drug Use and Health in 2008. The drug's use is increasing among adolescents and young adults, partially due to society's changing beliefs about cannabis use and its legal status.

A recent Northwestern study showed chronic use of marijuana was linked to brain abnormalities. "With the findings of these two papers," Breiter said, "I've developed a severe worry about whether we should be allowing anybody under age 30 to use pot unless they have a terminal illness and need it for pain."

https://www.sciencedaily.com/releases/2014/04/140415203807.htm