Synthetic Marijuana Compound Reduces Agitation, Improves Appetite in Alzheimer's Patients
August 21, 2003
Science Daily/Meridian Health System
Study results suggest dronabinol, a synthetic version of THC, the active ingredient in Cannabis sativa L (marijuana), may reduce agitation and lead to weight gain in patients with Alzheimer's disease, according to data presented today at the annual meeting of the International Psychogeriatric Association.
"Our research suggests dronabinol may reduce agitation and improve appetite in patients with Alzheimer's disease, when traditional therapies are not successful," said Joshua Shua-Haim, M.D., lead investigator in the study and medical director of the Meridian Institute for Aging, a continuum of senior health programs and services in Central New Jersey affiliated with Meridian Health System. "In the study, dronabinol appeared to be safe and effective for these patients. The results point to a promising direction for future research."
Dronabinol, marketed under the trade name Marinol, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-THC also is a naturally occurring component of Cannabis sativa L (marijuana). Dronabinol is the only cannabinoid approved by the U.S. Food and Drug Administration (FDA) and is indicated for the treatment of anorexia in patients with HIV/AIDS and for the treatment of nausea and vomiting associated with cancer chemotherapy.
An estimated four million Americans have Alzheimer's disease and the number will grow to 14 million by 2050, according to the Alzheimer's Association. In addition to memory loss, patients often experience agitation, loss of body weight, depression and restlessness.
Agitation is the most frequently encountered type of behavioral disturbance associated with Alzheimer's disease and affects an estimated 75 percent of people with the disease. Weight loss, a common problem in patients with Alzheimer's disease, is a predictive factor of mortality. Weight loss may derive from the deterioration of patients' cognitive abilities, resulting in an inability to recognize hunger and thirst.
"It's important to look at all the aspects of Alzheimer's disease that contribute to quality of life for patients, family members and caregivers," said Dr. Shua-Haim. "Agitation and weight loss are upsetting and stressful as the patient's needs become ever more demanding."
The study was a retrospective review and examined 48 patients (mean age = 77) residing in a dementia unit of an assisted living facility or a nursing home. All patients met the DSM-IV and NINCDS-ADRDA criteria for possible Alzheimer's disease and, according to their family or caregivers, had unsatisfactory control of their agitation. The mini mental status examination (MMSE), a test used to measure a person's basic cognitive skills, and an assessment of activities of daily living were used to evaluate patients prior to treatment with dronabinol and at one month. Patients initially received 5 mg/day of dronabinol in two doses. The treatment was titrated up to a maximum of 10 mg/day. In addition, all patients were treated with atypical neuroleptics and at least four medications to control behavior.
The evaluation by caregivers following one month of treatment found 31 patients (66 percent) experienced a significant improvement in agitation. Functional improvement was observed in 33 (69 percent) of the patients. Prior to the study, all patients experienced weight loss and had been diagnosed with anorexia. After treatment with dronabinol, all patients (100 percent) had gained weight. No adverse events, such as falls, syncope, seizures or exacerbation of agitation or depression, were reported as a result of treatment.
Meridian Health System is comprised of Jersey Shore Medical Center in Neptune, Medical Center of Ocean County in Brick, and Riverview Medical Center in Red Bank, in addition to long-term care and assisted living facilities, a home care agency, ambulatory care sites, ambulance services, and other related health services and affiliations throughout Monmouth and Ocean counties in New Jersey.
https://www.sciencedaily.com/releases/2003/08/030821072622.htm
Mouse Model Links Alcohol Intake to Marijuana-like Brain Compounds
January 21, 2003
Science Daily/NIH/National Institute On Alcohol Abuse And Alcoholism
Brain molecules similar to the active compound in marijuana help to regulate alcohol consumption, according to new reports by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, Maryland, and a separate NIAAA-supported group at several New York state research institutions.
In studies conducted with a strain of mice known to have a high preference for alcohol, the scientists found greatly reduced alcohol intake in mice specially bred to lack CB1, the brain receptor for innate marijuana-like substances known as endocannabinoids. The effect was age dependent, the Bethesda group found. The New York scientists showed that the endocannabinoid system activates a brain region known as the nucleus accumbens, which plays a major role in mediating the rewarding effects of alcohol. Both groups had shown that alcohol intake among normal mice of the same alcohol-preferring strain could be reduced by treating the animals with a drug that blocks CB1 receptors in the brain.
The new reports appear in the early online versions of the Proceedings of the National Academy of Sciences, Volume 20, Number 3, at www.pnas.org and the Journal of Neurochemistry, Volume 24, Number 4, at www.blackwell-synergy.com/servlet/useragent?func=showIssues&code=jnc in the week beginning January 20, 2003 (specific dates to be determined).
"These are important findings," notes NIAAA Director Ting-Kai Li, M.D. "Implicating yet another neurochemical mechanism in alcohol consumption opens another potential avenue for the development of new pharmacologic agents to prevent and treat alcohol problems."
The brain's multiple communication pathways employ a wide variety of signaling molecules known as neurotransmitters to relay messages from one brain cell to another. Researchers have found that alcohol affects numerous neurotransmitters and that a variety of brain pathways are involved in alcohol abuse and dependence. Determining precisely how alcohol interacts with brain cells and affects brain chemistry is an ongoing focus of research. Knowledge gained through this research helps scientists develop drugs to diminish the desire to consume alcohol and to counteract alcohol's effects.
Since their discovery in the early 1990's, endocannabinoids and endocannabinoid receptors have been studied intensely by alcohol and drug abuse researchers. Recent animal studies have suggested that the so-called "endocannabinoid system" is involved in some of the pharmacologic effects of alcohol and in drinking behavior.
In one of the current studies, researchers led by George Kunos, M.D., Ph.D., Scientific Director of NIAAA's Division of Intramural Biological and Clinical Research, found that, among the normal, alcohol-preferring mice–that is, those with intact CB1 receptors–the animals' appetite for both alcohol and food decreased with age. This occurred even though levels of endocannabinoids and the density of CB1 receptors were found to be similar in the brains of young and old mice.
"Although unexpected," says Dr. Kunos, "the observed age-dependent decline in alcohol preference in mice parallels observations in humans, in that only some teenage binge drinkers become alcoholics as adults, and that the onset of alcoholism declines with age."
The researchers found a possible explanation for this phenomenon by comparing the efficiency of the signal sent by the CB1 receptors in different regions of the brain in young and old mice. In old mice, they found diminished CB1 signaling in an area known as the limbic forebrain. The part of the limbic forebrain known as the nucleus accumbens plays a major role in mediating the rewarding properties of alcohol and cannabinoids and also is thought to help regulate appetite. The nucleus accumbens exerts its effects through the release of the neurotransmitter dopamine. Alcohol ingestion typically elicits a robust release of dopamine from the nucleus accumbens.
The second report by NIAAA-supported scientists led by Basalingappa L. Hungund, Ph.D., of the New York State Psychiatric Institute and Nathan S. Kline Institute for Psychiatric Research in Orangeburg, New York, complements the findings of the Kunos research team. Dr. Hungund and colleagues found that, in addition to showing a dramatic reduction in alcohol intake, alcohol-preferring mice that lack CB1 receptors release no dopamine from the nucleus accumbens after they drink alcohol. In mice with intact CB1 receptors, the researchers were able to abolish alcohol-induced release of dopamine from the nucleus accumbens by treating the animals with a drug that blocks CB1 receptors.
"Our results," says coauthor Balapal Basavarajappa, Ph.D., "clearly suggest that the CB1 receptor system is involved in ethanol-induced dopamine release in the nucleus accumbens and indicate that activation of the limbic dopamine system is required for the reinforcing effects of alcohol. They further suggest an interaction between the cannabinoidergic and dopaminergic systems in the reinforcing properties of drugs of abuse, including alcohol."
"Taken together," adds Dr. Kunos, "these findings provide unequivocal evidence for the role of endocannabinoids and CB1 in alcohol drinking behavior in rodents, and suggest that the CB1 receptor may be a promising pharmacotherapy target."
The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA disseminates research findings to scientists, practitioners, policy makers, and the general public.
https://www.sciencedaily.com/releases/2003/01/030121080758.htm
Marijuana's Distant Relative May Be The Next Prozac; Chemical Reduces Anxiety Using Novel Nerve System In Body
December 2, 2002
University of California - Irvine
Man-made chemicals that are distant relatives of marijuana may eventually become new drugs to combat anxiety and depression, according to a UC Irvine College of Medicine study. The study is the first to show how anxiety is controlled by the body's anandamide system, a network of natural compounds known for their roles in governing pain, mood and other psychological functions.
While marijuana relieves anxiety by working on the same system, laboratory rats given the new drugs don't seem to suffer the side effects produced by THC, marijuana's active ingredient. The study appears on Nature Medicine's Web site and will be published in the January 2003 issue.
After designing and testing a number of different chemicals, pharmacology professor Daniele Piomelli and his team found two, called URB532 and URB597, which relieved anxiety and worked in ways far gentler than THC.
"THC reduces anxiety by binding directly to receptors in the brain and resulting in its familiar 'high' sensation," Piomelli said. "This reaction is too strong, creating marijuana's side effects."
URB532 and URB597, on the other hand, inhibit the activity of an enzyme that breaks apart natural anandamide, leaving more of the neurotransmitter to help reduce anxiety and depression. This is similar to the way Prozac works on serotonin, another natural anti-depressant neurotransmitter. With this gentler biochemical approach, URB532 and URB597 were able to keep brain anandamide levels high for many hours after a single dose without producing visible side effects.
"While the study's results are promising, the road from laboratory discovery to available medication is years long, often winding, and definitely expensive," Piomelli said. "In fact, most drugs never make it beyond the discovery stage, for a number of scientific and commercial reasons. But nearly all drugs on the market today saw their start at the laboratory discovery phase."
https://www.sciencedaily.com/releases/2002/12/021202071928.htm
How Do You Solve Relief -- Structure Of Pain-Modulating Enzyme Described By Scripps Scientists
Science Daily/November 29, 2002
The Scripps Research Institute
A group of researchers from The Scripps Research Institute (TSRI) have solved the structure of an enzyme that modulates central nervous system (CNS) functions such as pain perception, cognition, feeding, sleep, and locomotor activity.
The enzyme, described in the latest issue of the journal Science, is called fatty acid amide hydrolase (FAAH), and it breaks down certain fatty signaling molecules that reside in the lipid membranes of CNS cells. The TSRI group reports that FAAH modulates the action of these fatty signaling molecules through an unusual mechanism of action whereby it scoops them out of the cell membranes and chews them up.
"I envision that if someone could make a specific inhibitor to FAAH, you could, in principal, get pain relief without any of the side effects," says Benjamin Cravatt, one of the paper’s lead authors and an investigator in TSRI's Department of Cell Biology, Department of Chemistry, and The Skaggs Institute for Chemical Biology.
"As soon as we had the view of the active site, we knew FAAH could be used to make lead clinical candidates," adds Raymond Stevens, who is a professor in the Department of Molecular Biology and Chemistry at TSRI and the other lead author on the paper. "The deep pocket with well-defined cavities provides the guidance to take the currently available tight binding inhibitors and improve on their specificity and pharmakokinetic properties."
Pain Management and FAAH
Easing pain is practically synonymous with practicing medicine, and since before the days of Hippocrates, doctors have sought the best ways of doing this--looking for compounds that not only ease pain, but do so as fast, effectively, and lastingly as possible--and without any unwanted side effects.
Every analgesic, from opiates to hypnotism to electroshocks to balms, have side effects, and therein lies the rub: whether relieving the pain or the side effects is more pressing.
One compound that has been hotly debated in the last 10 years is delta-9-tetrahydrocannabinol (THC), the active ingredient in marijuana. The reason THC works is that it mimics the action of natural cannabinoids that the body produces in signaling cascades in response to a peripheral pain stimulus. THC binds to "CB-1" receptors on cells on the rostral ventromedial medulla, a pain-modulating center of the brain, decreasing sensitivity to pain.
Unfortunately, the receptors that THC bind to are also widely expressed in other parts of the brain, such as in the memory and information-processing centers of the hippocampus. Binding to nerve cells of the hippocampus and other cells elsewhere in the body, THC creates a range of side effects as it activates CB-1 mediated signaling--including distorted perception, difficulty in problem-solving, loss of coordination, and increased heart rate and blood pressure, anxiety, and panic attacks.
The challenge posed by THC and other cannabinoids is to find a way to use them to produce effective, long-lasting relief from pain without the deleterious side effects. Now Cravatt and Stevens think they know just how to do that.
The solution, as they see it, is to increase the efficacy of the natural, endogenous cannabinoids ("endocannabinoids") the body produces to modulate pain sensations.
"When you feel pain, you release endocannabinoids [which provide some natural pain relief]," says Cravatt. "Then the amplitude and duration of their activity are regulated by how fast they are broken down."
In particular, the body releases an endogenous cannabinoid called anandamide, a name derived from the Sanskrit word meaning "internal bliss." When the body senses pain, anandamide binds to CB-1 and nullifies pain by blocking the signaling. However, this effect is weak and short-lived as FAAH quickly metabolizes the anandamide--the compound has a half-life of only a few minutes in vivo.
In some ways, THC is superior to anandamide as a pain reliever because it is not as readily metabolized by FAAH. But THC goes on to suppress cannabinoid receptor activity all over the body. This, coupled with the fact that it is a controlled substance, makes THC an unattractive target for developing therapeutics.
FAAH is much more attractive target for pain therapy because by inhibiting FAAH, you would increase the longevity of anandamide molecules--preventing their breakdown and allowing them to continue providing some natural pain relief.
The structure that Cravatt, Stevens, and their TSRI colleagues solved should form a template for designing specific inhibitors that control the action of FAAH when the body is sensing pain and releasing anandamide.
The research article, "Structural Adaptations in a Membrane Enzyme that Terminates Endocannabinoid Signaling" is authored by Michael H. Bracey, Michael A. Hanson, Kim R. Masuda, Raymond C. Stevens, and Benjamin F. Cravatt, and appears in the November 29, 2002 issue of the journal Science.
The research was funded by the National Institute on Drug Abuse, the Searle Scholars Program, The Skaggs Institute for Chemical Biology, a National Research Service Award, and a Jabinson graduate fellowship.
https://www.sciencedaily.com/releases/2002/11/021127072047.htm
Smoking Pot Alters More Than Mood — Human Immune System Affected
August 28, 2002
Science Daily/University Of South Florida Health Sciences Center
Marijuana may alter immune function in people -- but the jury is still out on whether it hurts or helps the body's ability to fight infection or other diseases, report researchers at the University of South Florida College of Medicine and the UCLA School of Medicine in Los Angeles. "The bottom line is you cannot routinely smoke marijuana without it affecting your immune system," said Thomas Klein, PhD, professor of medical microbiology and immunology at USF. "However, because of the complexity of the immune system, we can't say yet whether the effect we've observed in humans is good or bad."
A study by USF and UCLA is the first to show that healthy humans who smoke marijuana appear to alter the expression of marijuana receptors, or molecules, on immune cells in their blood. The findings were reported in the June issue of the Journal of Neuroimmunology.
Pot's influence on the immune system continues to be hotly debated. While more human studies are needed, overwhelming evidence from animal studies indicates that marijuana and its psychoactive compounds, known as cannabinoids, suppress immune function and inflammation.
"This suggests marijuana or cannabinoids might benefit someone with chronic inflammatory disease, but not someone who has a chronic infectious disease such as HIV infection," said Dr. Klein, lead investigator of the study.
The USF/UCLA group is one of few in the world conducting studies to define the role of cannabinoid receptors in regulating immunity in both drug abusers and nonusers.
If the results in animals hold true in humans, their work might lead to the development of safe and effective cannabinoid drugs for certain diseases, Dr. Klein said. "If the cannabinoids in marijuana are effective immune suppressors, this property might be harnessed to treat patients with overly aggressive immune responses or inflammatory diseases like multiple sclerosis and rheumatoid arthritis."
Receptors that react to delta-9 tetrahydrocannabinol or THC, the compound in marijuana that produces a high, have been found in tissues throughout the body and in the brain. A naturally circulating THC-like substance called anandamide also binds to and activates these marijuana, or cannabinoid, receptors, indicating that the body's own cannabinoid system plays a physiological role in normal immunity as well as defining moods, Dr. Klein said.
In the USF/UCLA study, researchers analyzed blood samples from 56 healthy volunteers -- including 10 chronic marijuana smokers, ages 22 to 46, participating in lung and immune function studies at UCLA. The marijuana smokers denied use of any other drugs, and the nonsmokers denied all illegal drug use. Because no accurate way yet exists to directly study the expression of cannabinoid receptors on immune cells, the researchers looked at the genetic material (messenger RNA) that is the direct predecessor, or precursor, of the receptor.
They found that the baseline genetic expression of precursor RNA was consistent across all age, gender and ethnic groups. But, the peripheral blood cells from the marijuana users expressed significantly higher levels of cannabinoid receptor messenger RNA than blood cells from non-users. The levels increased regardless of the amount of marijuana use, although all users in the study had a history of smoking pot several times or more a week.
https://www.sciencedaily.com/releases/2002/08/020828062229.htm
An Internal Cannabinoid-Signaling System Regulates Human Sperm, Fertilization Potential; Abusing Marijuana May Overload System, Inhibit Fertility
December 12, 2000
Science Daily/University at Buffalo
SAN FRANCISCO -- A cellular signaling system that responds to THC, the active substance in marijuana, as well as to anandamide, a cannabinoid-like molecule normally produced in the body, may regulate sperm functions required for fertilization in humans, a study headed by scientists from the University at Buffalo has found.
In addition, the findings suggest that men and women who abuse marijuana could jeopardize fertility by overloading this natural cannabinoid signaling system that regulates sperm structure, vigor and fertility.
Herbert Schuel, Ph.D., UB professor of anatomy and cell biology and lead author on the study, presented results of the research here today (Dec. 12, 2000) at the annual meeting of the American Society for Cell Biology.
Collaborating on the research were Lani Burkman, Ph.D., and Jack Lippes, M.D., of UB, and colleagues from the University of Connecticut, Eastern Virginia Medical School and University of California at Irvine.
The study presents the first evidence that anandamide exists in human seminal plasma, mid-cycle oviductal fluid and follicular fluid, and can regulate directly the human sperm's ability to fertilize an egg.
"These findings suggest that defects in the cannabinoid receptor-signaling system could account for certain types of infertility," Schuel said. "A better understanding of these mechanisms might lead to the development of novel drugs useful in reproductive medicine. For heavy marijuana users, the study results raise the possibility they are jeopardizing fertility by overloading this signaling system."
A receptor for cannabinoids was found in the human brain in the late 1980s. This finding suggested that the body must produce its own chemical version of THC to activate these receptors, and a substance called anandamide was found to be that chemical. Schuel and collaborators were the first to report cannabinoid receptors in sperm, using sea urchins as a model, and that anandamide also activated those receptors.
The regulatory mechanisms that prepare sperm to fertilize eggs within human reproductive tracts remain, for the most part, a scientific mystery. Human sperm are bathed in male reproductive-tract secretions when they are ejaculated into the female's vagina, and are not immediately capable of fertilizing eggs. However, once removed from the seminal plasma and exposed for several hours to secretions within the female reproductive tract, sperm become "capacitated" and can fertilize eggs.
Capacitated sperm exhibit a characteristic pattern of vigorous swimming called hyperactivated motility. When they bind to a specific protein in the egg's surface coat, sperm can be stimulated to secrete digestive enzymes that enable them to penetrate the egg coat during fertilization, a secretory process called the acrosome reaction.
"We know that sperm capacitation and fertilizing potential are tightly regulated within the female reproductive tract," Schuel said. "We also know that the cannabinoid receptor found in the human brain is expressed in the human testis, and that anandamide is produced in the testis and uterus of mammals. Within the uterus, anandamide regulates early development of the fertilized egg, and determines where the embryo will implant to initiate pregnancy. Cannabinoids also affect this process," he noted.
Now, Schuel and collaborators have the first evidence that anandamide can directly regulate human sperm's ability to fertilize an egg. Using a synthetic equivalent of natural anandamide called AM-356 and THC, the substance responsible for the "high" produced by marijuana smoke, the researchers showed that both chemicals regulate in vitro capacitation and fertilizing potential of human sperm in three ways:
• AM-356 produces opposite effects on hyperactivated sperm swimming, depending on the amount. Too much (a concentration of 2.5 nano Moles) inhibits hyperactivated motility, while at a 10-fold lower concentration, it stimulates hyperactivated swimming. Because anandamide is present in human-reproductive fluids and human sperm contain cannabinoid receptors, it is possible that localized differences in anandamide concentration may regulate sperm swimming patterns within the female-reproductive tract.
• Both AM-356 and THC inhibit structural changes over the acrosome. The structural integrity of the acrosome during capacitation is known to be a critical factor in sperm's ability to fertilize eggs.
• AM-356 significantly inhibits sperm binding to the zona, or egg coat. This observation provides the first evidence that anandamide (which AM-356 mimics) can regulate directly sperm fertilizing potential in humans.
"Defects in endocannabinoid signaling may be responsible for certain currently unexplained types of infertility," Schuel said. "Conversely, endocannabinoid signaling in human-reproductive tracts may provide potential targets for the future development of new drugs for use in reproductive medicine.
"In addition, the increased load of cannabinoids in people who abuse marijuana could flood natural endocannabinoid-signal systems in reproductive organs and adversely impact fertility," he said. "This possibility may explain observations made over the past 30-40 years that marijuana smoke drastically reduces sperm production in males."
Alexandros Makriyannis, Ph.D., and Robert Picone of the University of Connecticut; Mary C. Mahony, Ph.D., of Eastern Virginia Medical School, and Andrea Giuffrida, Ph.D., and Daniele Piomelli, Ph.D., of the University of California at Irvine, collaborated on this research.
https://www.sciencedaily.com/releases/2000/12/001212065509.htm
Center for Medicinal Cannabis Research Established at University of California
September 5, 2000
Science Daily/University of California, San Diego
A statewide, state-funded initiative to rigorously study the safety and efficacy of medicinal cannabis to treat certain diseases is being established at the University of California. The Center for Medicinal Cannabis Research (CMCR), headquartered at UCSD, will be a collaboration between UCSD and UCSF, two of the UC system's leading biomedical research campuses.
The CMCR will administer $3 million in first-year funding to support and coordinate scientific research at universities and research centers throughout California, assessing the use of cannabis as an alternative for treating specific medical conditions.
Funding of the CMCR is the result of SB847 (Vasconcellos), passed by the State Legislature and signed into law by Governor Gray Davis in October 1999. The legislation calls for a three-year program overseeing objective, high quality medical research that will "...enhance understanding of the efficacy and adverse effects of marijuana as a pharmacological agent," stressing that the project "should not be construed as encouraging or sanctioning the social or recreational use of marijuana."
Data from these studies will be used to develop guidelines for appropriate pharmaceutical use of medicinal cannabis. California voters approved such use in 1996, but exactly what role the substance should play in patient care, and how it should be administered as a pharmaceutical agent, is ambiguous because of the lack of definitive research, said Igor Grant, M.D., professor of psychiatry at UCSD and director of the CMCR. Grant is also executive vice chair of the department of psychiatry and director of UCSD's HIV Neurobehavioral Research Center.
Co-directors of the CMCR are Donald Abrams, M.D., professor of medicine at UCSF; and J. Hampton Atkinson, M.D., professor of psychiatry, and Andrew Mattison, Ph.D., associate clinical professor of psychiatry and family and preventive medicine, both of UCSD.
The CMCR plans to solicit applications this fall, to be reviewed by an independent Scientific Review Board of national experts. Funding will be awarded to support research focusing on diseases and conditions as defined in a report by the National Academy of Sciences/Institute of Medicine, and by a National Institutes of Health expert panel, according to Grant.
"The politics of medical marijuana are behind us as we begin the important work of researching the safety and efficacy of medical marijuana," said Senator John Vasconcellos (D-Santa Clara). "The National Institutes of Health and the Institute of Medicine of the National Academy of Sciences have independently called for further studies. Now, because of the vision of the Legislature, the Governor and the University of California, the issue of medical marijuana is properly in the hands of physicians and researchers."
The symptoms and conditions for which cannabis might be a useful treatment option include:
* Severe appetite suppression, weight loss and cachexia due to HIV infection and other medical conditions;
* Chronic pain resulting from certain types of injuries and diseases such as AIDS;
* Nausea associated with cancer and its treatment; and
* Severe muscle spasticity caused by diseases such as multiple sclerosis.
"This is an important opportunity to continue to evaluate the therapeutic potential of cannabis," said Abrams, a UCSF oncologist and AIDS expert who has just completed the first clinical trial of inhaled marijuana in patients with HIV infection. "The findings from our initial safety trial suggest that studies of the possible effectiveness of marijuana should be launched now. This state funding will allow that to happen quickly so that we may finally get some needed answers."
Support will be awarded on a competitive basis to those studies determined to be of the highest scientific quality, with studies anticipated to begin as early as January 2001. Most of the studies are anticipated to be patient trials, said Grant, though there is also interest in funding some basic research that has direct relevance to understanding safety, efficacy, and mechanisms of action of cannabis chemicals for the conditions in question.
The cannabis to be used in the studies will be obtained from the National Institute on Drug Abuse in accordance with procedures developed by the Public Health Service. Studies may also utilize alternative, non-smoked preparations of cannabis, as these become available through pharmaceutical research and are approved for clinical trials by the appropriate regulatory bodies.
In addition to the Scientific Review Board that will provide independent review of research proposals, the CMCR leadership is appointing an Advisory Board to provide input on how the CMCR can meet its objectives in the most scientifically sound, responsible and timely manner.
https://www.sciencedaily.com/releases/2000/09/000904122146.htm
New Class of Chemicals Found to Use Marijuana-Like System in Brain
May 4, 2000
Science Daily/University of California, Irvine
Researchers at UC Irvine's College of Medicine have developed a chemical that could form the basis of a new class of drugs to treat a number of psychiatric disorders, including schizophrenia, Parkinson's disease, autism and attention-deficit hyperactivity disorder.
The chemical, which has been tested on rats, affects brain cells that use chemicals similar to marijuana to counteract the actions of a neurotransmitter called dopamine. Dopamine has been implicated in schizophrenia, Parkinson's disease, Tourette's syndrome and many other psychiatric disorders. The researchers' findings appear in the May issue of the Journal of Neuroscience.
Daniele Piomelli, professor of pharmacology, led a team that found that a chemical called AM404 reversed the normal inactivation of a naturally occurring chemical in the brain called anandamide, which is related to marijuana's active ingredient and opposes the actions of dopamine. By reversing the inactivation of anandamide, AM404 is able to gently curb the exaggerated movements and other disorders caused by too much dopamine activity in nerve cells.
"We were excited to find this action of AM404 in the brain. It's very encouraging to see it work in a very subtle and effective way to counteract the effects of too much dopamine-induced activity," said Piomelli. "With further testing, we hope this eventually will result in new treatments that don't have the side effects of many current psychiatric drugs."
Piomelli and his colleagues found that AM404 targeted nerves that produced unusually high levels of dopamine and caused exaggerated movements andother problems in rats. Instead of directly encouraging the production of dopamine-curbing anandamide, AM404 was found to discourage the disintegration of existing anandamide. More anandamide was then available to bind to receptors on nerve cells and reduce the stimulation of nerve cells by dopamine.
If further research proves successful, the chemical could be used to treat schizophrenia, Tourette's, Parkinson's, autism and attention-deficit disorder, all of which are currently treated by drugs that attack the dopamine system in the brain.
Piomelli warns that their research on cannabinoid receptors has shown consistently that smoking marijuana may actually make these disorders worse. "Although AM404 helps to manipulate cannabinoid receptors, we think that using marijuana directly creates too severe a reaction and can create adverse reactions among people suffering from these diseases," he said.
The researchers, who have been working for several years on detailing the cannabinoid nerve cell system in the brain, are now looking at how AM404 selects the nerve cells it affects in the brain.
"AM404's selection of nerve cells may mean that treatments may not have the side effects of many current drugs, which aren't as selective about the nerve cells they impact," Piomelli said. "Once we see how the drug actually works in the brain, we'll have a better idea of what disorders it may be most effective at treating. Using brain scans and analyzing the uptake of AM404 in rats and other animals, we can have a better idea of where it's working."
Piomelli's colleagues in this study were Massimo Beltramo and Andrea Giuffrida at UCI; Fernando Rodriguez de Fonseca, Miguel A. Gorriti and Miguel Navarro at the Complutense University, Madrid, Spain, and Antonio Calignano, Gerasimos Grammatikopoulos and Antonio G. Sadile at the University of Naples, Italy.
The researchers' work was supported by a grant from the National Institute of Drug Abuse.
https://www.sciencedaily.com/releases/2000/05/000503183344.htm
Cannabinoids' Role in Retinal Function Described
December 8, 1999
Science Daily/University of California, San Diego
A team led by scientists from the University of California, San Diego (UCSD) has demonstrated the prevalence of cannabinoid receptors in the retina, indicating an important role for cannabinoids—a family of compounds which includes the psychoactive components of marijuana and hashish—in retinal function and perhaps vision in general.
The UCSD researchers, in collaboration with colleagues from The Neurosciences Institute in San Diego and the University of Washington in Seattle, have described for the first time the specific distribution and effects on retinal function of the cellular receptor proteins activated by cannabinoids.
These findings, published in the December 7 issue of the Proceedings of the National Academy of Sciences (PNAS), may provide a missing link in efforts to unravel the complicated and fascinating machinery by which the retina turns light into meaningful information in the brain. The work also provides greater understanding of the effects of marijuana and hashish, drugs which have been used by man for millennia.
“The retina is incredibly complex, highly sensitive to shifts in light levels, and responsive to contrasts, colors and lines,” said Alex Straiker, principal author of the PNAS paper and a graduate student in UCSD's neuroscience program. “We understand very little about how the retina works. By demonstrating that this receptor system is present, we add another piece to the puzzle, opening one more window into how the eye works. It also suggests that marijuana affects vision because it plugs into an existing signaling system that is abundant in the retina.”
Cannabinoids are naturally occurring compounds in vertebrates, and are known to play an important role in intercellular signaling. The chemical THC found in marijuana is a cannabinoid, though different from the ones produced by the body. Two cannabinoid receptors, CB1 and CB2, were discovered only the last ten years. CB1 exists primarily in the central nervous system, while CB2 is found primarily in the peripheral nervous system.
The PNAS paper reports that the retinal cells of rhesus monkeys, chicks, salamanders, goldfish, mice and rats, all similar in many respects to the human eye, contain high levels of CB1. The researchers also found CB1 receptors localized in both rod and cone photoreceptors, the retinal structures that respond to light, processing colors and black and white images. The extensive and consistent localization of these receptors in the retinas of a variety of species suggests that they play a fundamental role in modulating the transmission of signals critical for visual perception.
“The fact that this system is so highly conserved in species separated by hundreds of millions of years of evolution suggests that it's important,” said Straiker. “Nature likes to tinker, so any time you see something this consistent, it raises eyebrows.” The paper also points to a functional role of cannabinoids in the inhibition of calcium channels involved in visual signaling.
“Two key players in the processing of light information in the retina are photoreceptors, which catch light and turn it into a signal that can be interpreted by other cells, and bipolar cells, which are next in line in the flow of information,” said Straiker. “Communication between the cells requires the release of a neurotransmitter called glutamate, triggered by calcium currents passing through a specific calcium channel. Cannabinoids are known to inhibit calcium channels. If you shut down the channel, you shut down the release of glutamate, and profoundly alter the cell's ability to signal.”
Some of the reported effects of the use of marijuana and hashish include the perception of a snowy visual field, increased light intensity and altered vision. In fact, Straiker said his interest in seeking CB1 receptors in the retina was sparked in part by accounts of dramatic alterations in visual perception following marijuana use.
These findings suggest that at least some of the visual effects of marijuana and hashish use occur at the earliest stage of visual processing, as the calcium channels critical for the normal processing of visual information are inhibited.
Co-authors of the paper are Harvey Karten, professor of neurosciences, and Greg Maguire, formerly assistant adjunct professor of ophthalmology, both of the UCSD School of Medicine; Nephi Stella and Daniele Piomelli, formerly at The Neurosciences Institute, and Ken Mackie of the University of Washington.
The research was supported by the National Institutes of Health, The Glaucoma Foundation, and the Neurosciences Institute, which receives major support from Novartis.
Straiker is a graduate student in the UCSD Graduate Program in Neurosciences, ranked as the premier neuroscience graduate program in the country by a National Research Council survey of the National Academy of Sciences. Straiker is presently continuing his work as a graduate student and researcher in the Molecular Neurobiology Laboratory at The Salk Institute, a participating institution.
https://www.sciencedaily.com/releases/1999/12/991208061213.htm
UC Irvine Researchers Demonstrate How Marijuana-Like Chemicals Work in the Brain
March 23, 1999
Science Daily/University of California, Irvine
Findings Could Lead to New Treatments for Schizophrenia, Parkinson's, Other Diseases
Researchers at UC Irvine's College of Medicine have discovered how chemicals in the brain that are related to the active ingredient of marijuana help regulate body movements and other motor activity in rats.
In the April issue of the journal Nature Neuroscience, the researchers also report finding a network of these chemicals within the brain that prevents the overactive motor behavior found in schizophrenia, Parkinson's disease and Tourette's syndrome. The discoveries ultimately could result in new treatments for these and other neurological diseases.
Daniele Piomelli, associate professor of pharmacology, and Andrea Giuffrida, a post-doctoral researcher, found that a marijuana-like chemical called anandamide (the Sanskrit word for "bliss") inhibits the effects of nerve cells that transmit dopamine, which is largely responsible for stimulating movement and other motor behavior in the brain. For years, scientists have linked the uncontrolled production of dopamine to schizophrenia, Tourette's syndrome (which causes severe "nervous tics") and Parkinson's disease.
"This shows for the first time how anandamides work in the brain to produce normal motor activity," Piomelli said. "Patients with schizophrenia and other diseases have reported that marijuana appears to relieve some of their symptoms, but scientists have never found a physiological reason why. By understanding how the anandamide system works similarly to marijuana, we can explore new ways to treat these diseases more effectively."
But Piomelli said his research group will not consider marijuana in future research aimed at developing new treatments, because its chemical activity doesn't produce the effects on dopamine that are useful for treating these diseases. "Marijuana doesn't provide the regulatory effects on dopamine in the brain that we're looking for," he said.
The researchers found that anandamide is part of a network of nerve cells in an area of the brain called the striatum, which coordinates all body movements and other motor behavior. In the striatum, the anandamide network inhibited dopamine's attempts to stimulate the body's motor nerves. Normally, nerve cells regulate this behavior by releasing anandamides at the same time they release dopamine. In order to temper the effects of dopamine, the anandamides bind to nerve cell sites called cannabinoid receptors, so-named because they are targets of tetrahydrocannabinol (marijuana's active ingredient) as well as related chemicals like anandamides. When anandamides were bound to these receptors, body movement in the rats decreased.
But when the researchers prevented the cannabinoid receptors from binding to anandamides, the blocked nerve cells could no longer inhibit dopamine's effects. In such a state, the rats experienced severe nervous tics and other uncontrolled motor activity. In humans, such exaggerated activity brought on by unregulated dopamine production can result in diseases such as schizophrenia, Tourette's and Parkinson's.
By enhancing the nerve cells' sensitivity to anandamide, new medicines could treat these diseases without the side effects of current medicines, Piomelli said. "Current drugs certainly halt the actions of dopamine, but the side effects, including sedation and dizziness, are very severe," he said. "Drugs that exploit the anandamide system can provide a gentler way of reducing the hyperactivity in the brain caused by too much dopamine."
But Piomelli said it will be many years before any drugs will be available on the market. "We're just beginning to map out where this system works in rats' brains. We still are a long way from knowing how anandamides work in humans, and any potential drugs would have to be tested rigorously for their effectiveness and safety."
Piomelli's research group discovered the existence of anandamides in the brain and has spent several years exploring how these chemicals and their nerve-cell receptors work in the central nervous system. Piomelli and Giuffrida were assisted in their research by Loren H. Parsons and Toni Kerr at the Scripps Research Institute, La Jolla, Calif., and Fernando Rodriguez de Fonseca and Miguel Navarro of the Universidad Complutense, Madrid.
https://www.sciencedaily.com/releases/1999/03/990323050735.htm