Effects of Cannabis Therapy on Endogenous Cannabinoids

INVESTIGATOR: Daniele Piomelli, Pharm.D., Ph.D.

STUDY LOCATION: University of California, Irvine

PROJECT TITLE: Effects of Cannabis Therapy on Endogenous Cannabinoids

PROJECT TYPE: Pre-Clinical Study

STATUS: COMPLETE

RESULTS:

This study assessed the effect of acute and chronic treatment of rats with the cannabinoid agonist, WIN-55212-2, on the levels of anandamide in blood and brain tissue. No change was observed in plasma anandamide concentration after either acute or chronic treatment. Likewise, there was no significant change in anandamide levels in three brain regions: cerebellum, nucleus accumbens, and brainstem. Chronic, but not acute, treatment with WIN-55212-2 caused a marked increase in anandamide levels in the brain hippocampus, a region that is crucially involved in learning and memory.

In order to compare the actions of cannabinoids with those of other abused substances, the effects of acute administration of amphetamine and alcohol on brain anandamide levels in the rat were measured. It was found that amphetamine (2 mg/kg ip) significantly increases anandamide levels in the nucleus accumbens, but not in the hippocampus and cerebellum. Furthermore, it was found that acute alcohol administration (4 g/kg ip) decreased anandamide levels in the hippocampus, cerebellum, and nucleus accumbens. These finding suggest that the endogenous cannabinoid system may respond in selective ways to different drugs of abuse.

These experiments contributed preliminary data to work that was later published in the journal Neuropsychopharmacology.

ABSTRACT:

Despite a long history of use in traditional medicine, the therapeutic value of the cannabis remains uncertain. The active principle in cannabis, D9-tetrahydrocannabinol (D9-THC), exerts its effects by activating high-affinity receptors present on the surface of brain and immune cells. These receptors are called cannabinoid receptors and are normally engaged by a group of natural fat-derived substances called endocannabinoids. The endocannabinoids are a novel group of neurotransmitters that may contribute in important ways to movement, cognition, pain and other physiological processes. We have learned much on these molecules in recent years, but still don't know how they may be affected by treatment with cannabis and D9-THC. Yet, elucidating such interactions would be important to evaluate the consequences of medical treatment with these and other cannabinoid agents. Here, we propose to test the hypothesis that long-term cannabis and D9-THC administration interfere with activity of the endocannabinoid system. The first aim of the proposed research is to determine whether cannabis and D9-THC affect circulating levels of endocannabinoid compounds in humans. Initial analyses have shown that such measurements are feasible by using a technique known as high-performance liquid chromatography/mass spectrometry (HPLC/MS). The proposed studies will determine circulating endocannabinoid levels in persons treated with marijuana, D9-THC (dronabinol) or placebo. The plasma samples will be kindly provided by Dr. D. Abrams (at U.C. San Francisco) who is currently funded by the CMCR to investigate the effects of cannabinoid therapy in HIV patients. The second aim of the proposed research is to determine whether cannabis and D9-THC affect endocannabinoid formation and/or inactivation in rodents. We will examine the effects of acute and chronic D9-THC administration on (1) endocannabinoid levels in rat plasma and brain tissue; and (2) activities of endocannabinoid-metabolizing enzymes in rat brain tissue. The main purpose of these experiments, which will be conducted in collaboration with Dr. F. Rodríguez de Fonseca (at the Carlos Haya Hospital in Málaga, Spain), is to complement our human studies by providing mechanistic insight on how cannabinoid drugs affect the endocannabinoid system. Brain neurotransmitter systems are highly plastic and regulate their activity when they are challenged with exogenous drugs. We hypothesize that treatment with cannabis or D9-THC may produce compensatory changes in the activity of the endocannabinoid system. Such changes might in turn influence in important ways the therapeutic outcome of cannabinoid therapy and participate in withdrawal phenomena after drug cessation.

PUBLICATIONS:

Type:

Title:

Journal Article Giuffrida A, Leweke FM, Gerth CW, Schreiber D, Koethe D, Faulhaber J, Klosterkotter J, Piomelli D. Cerebrospinal Anandamide Levels are Elevated in Acute Schizophrenia and are Inversely Correlated with Psychotic Symptoms. Neuropsychopharmacology. 2004 Nov;29(11):2108-14.

San Diego company testing marijuana-derived multiple sclerosis therapy

Gary Robbins, San Diego Union Tribune, October 10, 2018

Emerald Health Pharmaceuticals of San Diego has begun using a marijuana-derived therapy to experimentally treat small numbers of people who suffer from multiple sclerosis and scleroderma, a pair of autoimmune diseases.

The small, phase 1 safety trial involves CBD, a compound found in marijuana. CBD has caught the attention of researchers because it does not get people high, and it has anti-inflammatory properties.

The trial is meant to determine whether the therapy is safe, what dose should be used, and if there are any side effects or related problems.

Emerald Health says it also is developing another non-psychoactive compound found in marijuana — CBG — for possible use in treating patients with Huntington’s disease and Parkinson’s disease.

UC San Diego is preparing to use CBD in a clinical trial that’s meant to people who suffer from epilepsy.

Read the story here


DEA slowly takes steps to affirm the medicinal value of marijuana

Gary Robbins, San Diego Union Tribune, October 2, 2018

Scientists and patients who've long held that marijuana can be used to treat illness and disease are finally getting some backing from the federal government.

The Drug Enforcement Agency currently lists marijuana as a Schedule 1 drug, meaning that it has no known medical use and a high potential for abuse.

But in a very narrow ruling, the DEA recently said that patients who suffer from two specific types of epilepsy could benefit from taking Epidiolex, a new anti-seizure medication derived from marijuana.

Epidiolex largely consists of cannabidiol, or CBD, a compound in cannabis that does not get people high.

The DEA decided to classify Epidiolex as a Schedule 5 drug, which would rank it with cough medicines.

The move has caused some confusion. The Union-Tribune sought clarity from Dr. Igor Grant, a psychiatrist who helps lead UC San Diego's Center for Medicinal Cannabis Research.

Read the interview here


Study to Examine Possible Effects of Cannabis Compound for Common Movement Disorder

Press Release, UC San Diego Health, September 18, 2018

Researchers at University of California School of Medicine are preparing to launch a novel clinical trial to examine the safety, efficacy and pharmacological properties of cannabis as a potential treatment for adults with essential tremor (ET). Currently, ET is treated using repurposed medications originally developed for high blood pressure or seizures. Surgery is another option.

Scheduled for early 2019, the phase I/II trial will assess efficacy and tolerability of an oral cannabis formulation comprised of cannabidiol (CBD) and low-dose tetrahydrocannabinol (THC). Researchers say it will be the first time this combination has been studied for treatment of ET.

“This study will provide key insights,” said Fatta Nahab, MD, neurologist at UC San Diego Health and associate professor of neurosciences at UC San Diego School of Medicine. “If found to be safe and effective, cannabis would not only serve as an exciting new addition to the limited treatment options currently available for patients with ET, but it might also provide scientists with new insights on essential tremor.”

Read the full press release here


More News

Click here to access the CMCR news archives.

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Introduction/Overview
CMCR Symposium, June 2018


Daniele Piomelli, MD, PhD, PharmD

The health impact of cannabis
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Ziva Cooper, PhD

Therapeutic potential of cannabis for pain alone and as an adjunct to opioids
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Iain McGregor, PhD

Medicinal cannabis research down under: Introducing the Lambert Initiative for Cannabinoid Therapeutics
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Thomas Marcotte, PhD

Cannabis and public safety: The challenge of cannabis-impaired driving
CMCR Symposium, June 2018


Alan Budney, PhD

Medicinal cannabis / legalization and the development of cannabis use problems
CMCR Symposium, June 2018


Ryan Vandrey, PhD

What's in real-world cannabis?
CMCR Symposium, June 2018


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