Study: Non-Psychoactive Cannabis Could Treat OCD

Leaf Science

“A non-psychoactive chemical in marijuana may be able to control symptoms of obsessive-compulsive disorder, according to new research out of Brazil.

Cannabidiol (CBD) is one of the major compounds found in marijuana, but lacks the high caused by THC.

Previous studies suggest that it can be used to combat anxiety and other obsessive-compulsive behaviors.

While research has mostly involved simple animal models, a team led by Dr. Francisco Guimarães of the University of Sao Paulo’s School of Medicine decided to test cannabidiol in rats that were given mCPP – a drug that blocks the effects of traditional OCD treatments.

Interestingly, even at low doses, CBD was able to reverse the obsessive-compulsive behavior caused by mCPP. Published in the journal Fundamental & Clinical Pharmacology, the authors conclude that the study adds support to “a possible anti-compulsive effect of CBD.””

http://www.leafscience.com/2013/10/22/study-non-psychoactive-cannabis-treat-ocd/

“Cannabidiol reverses the mCPP-induced increase in marble-burying behavior.”  http://www.ncbi.nlm.nih.gov/pubmed/24118015

Cannabidiol reverses the mCPP-induced increase in marble-burying behavior

Fundamental & Clinical Pharmacology

“Cannabidiol (CBD), one of the main components of Cannabis sp., presents clinical and preclinical anxiolytic properties.

Recent results using the marble-burying test (MBT) suggest that CBD can also induce anticompulsive-like effects.

The results, in addition to reinforcing a possible anticompulsive effect of CBD, also suggest that mCPP-induced repetitive burying could be a useful test for the screening of compounds with presumed anticompulsive properties.”

http://onlinelibrary.wiley.com/doi/10.1111/fcp.12051/abstract

Cannabinoid Receptor Found to Help Suppress Habitual Behavior

“A mouse study finds that CB1 protein in orbitofrontal cortex neurons mediates the ability to switch between habitual and active-learning behaviors when needed.

Everyone carries out daily habits and routines. As David Lovinger, Ph.D., chief of the Laboratory for Integrative Neuroscience at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), explained, “If your brain does not habitualize familiar tasks or places, it would be very difficult to focus because you’re constantly processing all these sensory inputs.”

Nonetheless, it’s important that the brain can shift from habit mode to a more active, goal-directed mindset. While an occasional lapse is normal, a chronic inability to exit from habitual behavior is a critical element of both addiction and obsessive-compulsive disorders. A new study carried out by Lovinger and colleagues adds to the understanding of the brain circuits responsible for the habitual/goal-directed shift.

The results, published June 15 in Neuron, also point to a receptor called cannabinoid type 1 (CB1) as a key regulator of this circuitry.

The findings were made possible using a training strategy that enabled mice to push levers for food in both a habitual and goal-directed manner. The mice were placed in enclosures with differing visual decorations; the lever in the first dropped a food reward after it was pressed a certain number of times, while the lever in the second would drop a reward at a random time after the lever had been pressed once.

“In the first scenario, the mouse makes the connection quickly that pressing the lever 20 times, for example, gets it a reward,” Lovinger told Psychiatric News. “In the second enclosure, that contiguity is disrupted. The mouse knows that pressing will eventually lead to reward, but it doesn’t know how many, so it will just start pressing at a periodic rate.”

On alternate testing days, the mice were allowed to eat their treats prior to the testing, and on these days—termed the devalued state because the desire for the reward is lessened—mice pressed the lever far less in the goal-directed enclosure, but still roughly the same amount in the random-time enclosure—much like a habit.

The researchers then tried these tests out on mice in which the neurons that travel between the orbitofrontal cortex (OFC) and dorsal striatum (DS, which links decision making and reward behaviors) were blocked and observed that the mice kept pressing a lot in both enclosures, suggesting an inability to switch out of habit mode.

“Normally, on devalued days the urge to default to the habit of pressing the lever repeatedly gets suppressed in some way because the brain is providing information that the food isn’t as valuable,” Lovinger said.

With the OFC-DS connection identified, the next question was what part of these neurons was responsible for suppressing habits? Some previous work by Lovinger’s colleague and study coauthor Rui Costa, Ph.D., an investigator at the Champalimaud Institute for the Unknown in Lisbon, Portugal, pointed to CB1 as a potential candidate; the CB1 receptor interacts with endocannabinoids, natural messenger molecules in the body that are strikingly similar to THC, the active compound in marijuana.

When mice lacking the CB1 receptor in their OFC neurons were trained, they reduced their lever pressing in both enclosures on devalued days, reflective of a state in which the mice always used goal-directed behaviors because they could not form habits.

Having found CB1 as the receptor that Helps suppress habits, Lovinger said the next step would be to find the agent in the OFC-DS neural circuit that strengthens habits—and that should provide major clues about how drugs of abuse like alcohol and marijuana disrupt the normal process of habituation.

While the NIAAA is more focused on the addiction side, Lovinger thinks the current knowledge gained on weakened habits could be valuable in neuropsychiatry as well.

“It may be a bit of a stretch, but ADHD could be mediated in part by reduced habit-forming potential,” he said. “If someone is trying to pay attention to all potential outcomes in every decision, it could explain the lack of focus displayed by people with ADHD.””

http://psychnews.psychiatryonline.org/doi/full/10.1176/appi.pn.2016.7b25

New Study Finds Endocannabinoids May Help OCD

OCD and cannabis research

“Obsessive-Compulsive Disorder (OCD) may look different in each affected individual. One person might feel it is necessary to wash their hands constantly while others might feel obligated to count something over and over.

According to the National Institute of Mental Health, OCD is a common disorder in which a person has uncontrollable and reoccurring obsessions and compulsions. Obsessions often cause anxiety in a person, so they feel by doing compulsions, or certain behaviors, they might relieve their anxiety.

There are many treatments and medications used to combat OCD, however research is now showing that endocannabinoids can also play a huge role in OCD. The new study was funded by the The National Institute of Alcohol Abuse and Alcoholism (NIAA) and was conducted with mice. Researchers probed the brain mechanisms that are used when a mouse transitions from goal-directed behavior to habitual behaviors. They then led the mouse to receive food two ways. One way the mice received food was through doing a goal-directed behavior while the second way was through doing a habitual behavior. They then found that by deleting a certain endocannabinoid receptor, mice didn’t form habits.

This discovery led scientists to the conclusion that endocannabinoids, which are natural messengers in our bodies similar to cannabinoids found in cannabis, have a lot to do with how our brains make decisions.

George F. Koob, Ph.D. is the Director of the NIAA stated that their study revealed a mechanism in the brain that controls the transition between goal-directed behaviors and habitual behaviors. He went on to explain, “As we learn more about this mechanism, it could reveal how the brain forms habits and, more specifically, how both endocannabinoids and cannabinoid abuse can influence habitual behavior pathophysiology.”

This conclusion that our bodies natural endocannabinoids and the active ingredients in cannabis can affect memory and decision-making may give scientists a glimpse into new medications and treatments for OCD.” http://ireadculture.com/new-study-finds-endocannabinoids-may-help-ocd/

New Study Finds Endocannabinoids May Help OCD

Study reveals central role of endocannabinoids in habit formation

National Institutes of Health (NIH) - Turning Discovery into Health

“Daily activities involve frequent transitions between habitual behaviors, such as driving home, and goal-directed behaviors, such as driving to a new destination on unfamiliar roads. An inability to shift between habitual and non-habitual behaviors has been implicated in obsessive-compulsive disorder (OCD), addiction, and other disorders characterized by impaired decision-making.

In a new study conducted with mice, scientists report that endocannabinoids, natural messengers in the body that are chemically similar to the active compound in marijuana, play an important role in how the brain controls this fundamental process.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, funded the study.

“The new findings point to a previously unknown mechanism in the brain that regulates the transition between goal-directed and habitual behaviors,” said George F. Koob, Ph.D., NIAAA director. “As we learn more about this mechanism, it could reveal how the brain forms habits and, more specifically, how both endocannabinoids and cannabinoid abuse can influence habitual behavior pathophysiology.” A report of the findings is now online in the journal Neuron.

Previous work in NIAAA’s Laboratory for Integrative Neuroscience suggested that reduced activity in the brain’s orbitofrontal cortex (OFC) underlies habit formation. Endocannabinoids are known to generally reduce the activity of neurons. In the current study, the authors, hypothesized that endocannabinoids in the OFC could be playing a key role in habit formation. The researchers used a newly developed procedure that allowed them to probe the brain mechanisms involved when a mouse shifts from goal-directed to habitual actions. By chemically inhibiting the activity of neurons in the OFC, they disrupted goal-directed behaviors and the mice relied on habitual actions instead. David Lovinger, Ph.D., chief of the NIAAA Laboratory for Integrative Neuroscience, Rui Costa, Ph.D., D.V.M., from the Champalimaud Centre for the Unknown in Lisbon, Portugal, and first author Christina Gremel, Ph.D. from NIAAA and the University of California, San Diego led the research team.

“Mice were trained to receive a food reward in two different ways,” said Dr. Lovinger. “One way required the animal to respond out of habit, while the second way demanded it to perform behaviors that were goal-directed.”

When Dr. Lovinger and his colleagues selectively deleted a particular endocannabinoid receptor, called cannabinoid type 1 (CB1), from OFC neurons, they found that mice that lacked these receptors did not form habits, but used goal-directed responses to receive the food reward. Animals with intact CB1 receptors preferentially used habitual responses to obtain the food reward. The authors say the new study points to a molecular mechanism through which endocannabinoids promote the formation of habits by reducing the flow of information in the OFC.

“Endocannabinoids appear to act as a brake in the OFC, allowing for habit formation,” said Dr. Gremel, an assistant professor of psychology and affiliated with the Neurosciences Graduate program at UCSD. “Our results suggest that alterations in the brain’s endocannabinoid system could be blocking the brain’s capacity to ‘break habits’ as observed in disorders that affect switching between goal-directed and habitual behaviors.”

The authors concluded that their findings demonstrate the existence of parallel brain circuits that mediate goal-directed and habitual behaviors. Drugs of abuse and neuropsychiatric disorders can affect decision-making by changing the balance between habitual and goal-directed actions. In particular, these mechanisms could help explain how cannabis drugs such as marijuana affect memory and decision-making.

The new findings suggest that strategies that target the brain’s endocannabinoid system might restore this balance and alleviate suffering in disorders involving these processes.”

https://www.nih.gov/news-events/news-releases/study-reveals-central-role-endocannabinoids-habit-formation?source=acsh.org

Endocannabinoid Modulation of Orbitostriatal Circuits Gates Habit Formation.

“Everyday function demands efficient and flexible decision-making that allows for habitual and goal-directed action control. An inability to shift has been implicated in disorders with impaired decision-making, including obsessive-compulsive disorder and addiction. Despite this, our understanding of the specific molecular mechanisms and circuitry involved in shifting action control remains limited. Here we identify an endogenous molecular mechanism in a specific cortical-striatal pathway that mediates the transition between goal-directed and habitual action strategies. Deletion of cannabinoid type 1 (CB1) receptors from cortical projections originating in the orbital frontal cortex (OFC) prevents mice from shifting from goal-directed to habitual instrumental lever pressing. Activity of OFC neurons projecting to dorsal striatum (OFC-DS) and, specifically, activity of OFC-DS terminals is necessary for goal-directed action control. Lastly, CB1 deletion from OFC-DS neurons prevents the shift from goal-directed to habitual action control. These data suggest that the emergence of habits depends on endocannabinoid-mediated attenuation of a competing circuit controlling goal-directed behaviors.”

http://www.ncbi.nlm.nih.gov/pubmed/27238866

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

The endocannabinoid system and its therapeutic exploitation.

Image result for Nat Rev Drug Discov.

“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”  http://www.ncbi.nlm.nih.gov/pubmed/15340387

http://www.nature.com/nrd/journal/v3/n9/full/nrd1495.html