Cannabis: Non-addictive pathway to pain relief?

Medicinal properties of cannabis examined

January 12, 2017

Science Daily/Oregon Health & Science University

OHSU research suggests an avenue for developing treatments for chronic pain that harness the medicinal properties of cannabis while minimizing the threat of addiction.

The study, conducted in a rodent model, provides additional rationale for the development of therapeutics using cannabinoid receptors to treat chronic pain, which afflicts about 30 percent of the U.S. population. OHSU investigators studied the function of two forms of cell membrane receptors that bind cannabinoids that occur naturally within the body, called endocannabinoids.

"It may be an avenue where we can get better pain medications that are not addictive," said senior author Susan Ingram, Ph.D., an associate professor of neurosurgery in the OHSU School of Medicine.

Ingram and colleagues report the treatment of chronic pain has challenged the medical system, with medications that are ineffective or create serious side effects: "However, emerging data indicate that drugs that target the endocannabinoid system might produce analgesia with fewer side effects compared with opioids."

The body's endocannabinoid system comprises receptors, endocannabinoid molecules and enzymes that make and degrade the endocannabinoids located in the brain and throughout the central and peripheral nervous system. The research team focused on two cannabinoid receptors, known as CB1 and CB2, in the rostral ventromedial medulla -- a group of neurons located in the brainstem known to modulate pain. The study is the first to examine CB1 and CB2 receptor function at the membrane level in late adolescent and adult neurons.

The researchers observed that chronic inflammatory pain increased activity of CB2 receptors and decreased CB1 activity. Cannabis activates both CB1 and CB2 receptors equally. The study suggests that selective activation of CB2 receptors contributes to the medicinal benefit of cannabis while minimizing the propensity of the other cannabinoid receptor, CB1, to induce tolerance and withdrawal. Ingram said the next phase of the research will further explore this area of brain circuitry, which ultimately could lead to the development of a new class of pain medications.

Co-authors include lead author Ming-Hua Li, Ph.D., and Katherine L. Suchland, both with the Department of Neurological Surgery, OHSU School of Medicine.

The study was funded by grants from the National Institutes of Health (DA035316 and R56NS093894) and American Heart Association (13SDG14590005, MH.L.).

https://www.sciencedaily.com/releases/2017/01/170112130145.htm

Pain relief without the high

January 4, 2017

Science Daily/Leiden, Universiteit

Researchers at Leiden University led by Mario van der Stelt (Leiden Institute for Chemistry) have set ‘gold standards’ for developing new painkillers based on the medicinal effects of cannabis.

Medicinal marijuana

Medicinal marijuana is in frequent use as a painkiller, but its psycho-active side-effects are a major disadvantage. The pharmaceutical industry is desperately seeking a synthetic form of cannabis that inhibits inflammation and pain, but without the high. Leiden researchers have now brought the development of such drugs a step closer. In an article in Nature Communications they set out 'gold standards' for the use of reference substances, to improve trials with synthetic cannabis.

Many of the clinical trials carried out to date with with synthetic cannabis have failed, with no measurable effect being recorded in patients. One of the causes of these failures can be found in the pre-clinical lab, during testing with animals. Substances are often used in these tests whose biochemical and molecular-pharmaceutical effects have never been properly characterised. As a result, there have been a lot of contradictory publications on research findings, the results of which cannot be reproduced. This is having a major effect on the allocation of research funding, the use of animal testing and the exposure of patients to non-active substances.

International and public-private collaboration

Marjolein Soethoudt, a PhD candidate in Van der Stelt's research group, studied together with 12 international academic groups, the National Institute of Health (US) and pharmaceuticals concern Hoffman-LaRoche (Switzerland), the 18 most commonly used reference substances, including the psychoactive ingredient in marijuana, Δ9-THC. They carried out their studies under standardised conditions in 36 different tests, to analyse the molecular pharmacological characteristics of the substances. They hoped to be able to identify the most suitable reference sustances for the research on synthetic cannabis. The research led to three 'gold standards' that should make it possible to give an impetus to the development of new painkillers and anti-inflammatories.

Cannabinoid CB2 receptor

Δ9-THC binds to two types of proteins in the human body: the cannabinoid CB1 receptor in the brain and the cannabinoid CB2 receptor in the immune system. Activating the CB1 receptor in the brain makes you high, while activating the CB2 receptor has an anti-inflammatory effect. The three 'gold standards' are molecules that are highly selective in activating only the CB2 receptor and ignoring the CB1 receptor. These three gold standards also appeared to cause the fewest side-effects, nor did they give the mice a high. Earlier studies have shown that these substances do have an analgesic and anti-inflammatory effect. The researchers advise that these three gold standards should be used in future in research on new medicines that rely on the activation of the cannabinoid CB2 receptor for their effectiveness.

Marijuana-like chemicals inhibit human immunodeficiency virus (HIV) in late-state AIDS

March 20, 2012

Science Daily/Mount Sinai Medical Center

Mount Sinai School of Medicine researchers have discovered that marijuana-like chemicals trigger receptors on human immune cells that can directly inhibit a type of human immunodeficiency virus (HIV) found in late-stage AIDS, according to new findings published online in the journal PLoS ONE.

Medical marijuana is prescribed to treat pain, debilitating weight loss and appetite suppression, side effects that are common in advanced AIDS. This is the first study to reveal how the marijuana receptors found on immune cells -- called cannabinoid receptors CB1 and CB2 -- can influence the spread of the virus. Understanding the effect of these receptors on the virus could help scientists develop new drugs to slow the progression of AIDS.

"We knew that cannabinoid drugs like marijuana can have a therapeutic effect in AIDS patients, but did not understand how they influence the spread of the virus itself," said study author Cristina Costantino, PhD, Postdoctoral Fellow in the Department of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine. "We wanted to explore cannabinoid receptors as a target for pharmaceutical interventions that treat the symptoms of late-stage AIDS and prevent further progression of the disease without the undesirable side effects of medical marijuana."

HIV infects active immune cells that carry the viral receptor CD4, which makes these cells unable to fight off the infection. In order to spread, the virus requires that "resting" immune cells be activated. In advanced AIDS, HIV mutates so it can infect these resting cells, gaining entry into the cell by using a signaling receptor called CXCR4. By treating the cells with a cannabinoid agonist that triggers CB2, Dr. Costantino and the Mount Sinai team found that CB2 blocked the signaling process, and suppressed infection in resting immune cells.

Triggering CB1 causes the drug high associated with marijuana, making it undesirable for physicians to prescribe. The researchers wanted to explore therapies that would target CB2 only. The Mount Sinai team infected healthy immune cells with HIV, then treated them with a chemical that triggers CB2 called an agonist. They found that the drug reduced the infection of the remaining cells.

"Developing a drug that triggers only CB2 as an adjunctive treatment to standard antiviral medication may help alleviate the symptoms of late-stage AIDS and prevent the virus from spreading," said Dr. Costantino. Because HIV does not use CXCR4 to enhance immune cell infection in the early stages of infection, CB2 agonists appear to be an effective antiviral drug only in late-stage disease.

As a result of this discovery, the research team led by Benjamin Chen, MD, PhD, Associate Professor of Infectious Diseases, and Lakshmi Devi, PhD, Professor of Pharmacology and Systems Therapeutics at Mount Sinai School of Medicine, plans to develop a mouse model of late-stage AIDS in order to test the efficacy of a drug that triggers CB2 in vivo. In 2009 Dr. Chen was part of a team that captured on video for the first time the transfer of HIV from infected T-cells to uninfected T-cells.

Funding for this study was provided to Drs. Chen and Devi by the National Institutes of Health in Bethesda, Maryland. Dr. Costantino is supported by a National Institutes of Health Clinical and Translational Science Award grant awarded to Mount Sinai School of Medicine.

https://www.sciencedaily.com/releases/2012/03/120320195252.htm