Marijuana-like Brain Chemicals Work as Antidepressant
November 7, 2007
Science Daily/University of California - Irvine
American and Italian researchers have found that boosting the amounts of a marijuana-like brain transmitter called anandamide produces antidepressant effects in test rats.
Led by Daniele Piomelli, the Louise Turner Arnold Chair in Neurosciences and director of the Center for Drug Discovery at the University of California, Irvine, the researchers used a drug they created, called URB597, which blocks anandamide degradation in the brain, thereby increasing the levels of this chemical.
“These findings raise the hope that the mood-elevating properties of marijuana can be harnessed to treat depression,” Piomelli said. “Marijuana itself has shown no clinical use for depression. However, specific drugs that amplify the actions of natural marijuana-like transmitters in the brain are showing great promise.”
The researchers administered URB597 to chronically stressed rats which showed behaviors similar to those seen in depressed human patients. After five weeks of treatment, the stressed rats treated with the drug were behaving similarly to a comparison group of unstressed animals.
URB597 works by inhibiting FAAH, an enzyme in the body that breaks down anandamide. Dubbed “the bliss molecule” for its similarities to the active ingredient in marijuana, anandamide is a neurotransmitter that is part of the brain’s endocannabinoid system and it has been shown in studies by Piomelli and others to play analgesic, anti-anxiety and antidepressant roles. It also is involved in regulating feeding and obesity. Blocking FAAH activity boosts the effects of anandamide without producing the “high” seen with marijuana.
Piomelli and colleagues at the Universities of Urbino and Parma in Italy created URB597. A patent was issued in 2007. The European pharmaceutical company Organon holds the license to the patent and will begin clinical studies on the drug in 2008, according to Piomelli.
Marco Bortolato, Regina Mangieri, Jin Fu, Janet Kim and Oliver Arguello of UC Irvine; Andrea Duranti, Andrea Tontini and Giorgio Tarzia of the University of Urbino; and Marco Mor of the University of Parma also participated in the study. It was supported by the National Institute on Drug Abuse, the University of California Discovery Program and the National Alliance for Research on Schizophrenia and Depression.
https://www.sciencedaily.com/releases/2007/11/071105120556.htm
Cannabis: Potent Anti-depressant In Low Doses, Worsens Depression at High Doses
October 24, 2007
Science Daily/McGill University
A new neurobiological study has found that a synthetic form of THC, the active ingredient in cannabis, is an effective anti-depressant at low doses. However, at higher doses, the effect reverses itself and can actually worsen depression and other psychiatric conditions like psychosis.
It has been known for many years that depletion of the neurotransmitter serotonin in the brain leads to depression, so SSRI-class anti-depressants like Prozac and Celexa work by enhancing the available concentration of serotonin in the brain. However, this study offers the first evidence that cannabis can also increase serotonin, at least at lower doses.
Laboratory animals were injected with the synthetic cannabinoid WIN55,212-2 and then tested with the Forced Swim test -- a test to measure "depression" in animals; the researchers observed an antidepressant effect of cannabinoids paralleled by an increased activity in the neurons that produce serotonin. However, increasing the cannabinoid dose beyond a set point completely undid the benefits, said Dr. Gabriella Gobbi of McGill University.
"Low doses had a potent anti-depressant effect, but when we increased the dose, the serotonin in the rats' brains actually dropped below the level of those in the control group. So we actually demonstrated a double effect: At low doses it increases serotonin, but at higher doses the effect is devastating, completely reversed."
The anti-depressant and intoxicating effects of cannabis are due to its chemical similarity to natural substances in the brain known as "endo-cannabinoids," which are released under conditions of high stress or pain, explained Dr. Gobbi. They interact with the brain through structures called cannabinoid CB1 receptors. This study demonstrates for the first time that these receptors have a direct effect on the cells producing serotonin, which is a neurotransmitter that regulates the mood.
Dr. Gobbi and her colleagues were prompted to explore cannabis' potential as an anti-depressant through anecdotal clinical evidence, she said. "As a psychiatrist, I noticed that several of my patients suffering from depression used to smoke cannabis. And in the scientific literature, we had some evidence that people treated with cannabis for multiple sclerosis or AIDS showed a big improvement in mood disorders. But there were no laboratory studies demonstrating the anti-depressant mechanism of action of cannabis."
Because controlling the dosage of natural cannabis is difficult -- particularly when it is smoked in the form of marijuana joints -- there are perils associated with using it directly as an anti-depressant.
"Excessive cannabis use in people with depression poses high risk of psychosis," said Dr. Gobbi. Instead, she and her colleagues are focusing their research on a new class of drugs which enhance the effects of the brain's natural endo-cannabinoids.
"We know that it's entirely possible to produce drugs which will enhance endo-cannabinoids for the treatment of pain, depression and anxiety," she said.
The study, published in the October 24 issue of The Journal of Neuroscience, was led by Dr. Gabriella Gobbi of McGill University and Le Centre de Recherche Fernand Seguin of Hôpital Louis-H. Lafontaine, affiliated with l'Université de Montréal. First author is Dr. Gobbi's McGill PhD student Francis Bambico, along with Noam Katz and the late Dr. Guy Debonnel* of McGill's Department of Psychiatry.
https://www.sciencedaily.com/releases/2007/10/071023183937.htm