Brookhaven Scientists Explore Brain's Reaction to Potent Hallucinogen

Brain-imaging studies performed in animals at the U.S. Department of Energy's (DOE) Brookhaven National Laboratory provide researchers with clues about why an increasingly popular recreational drug that causes hallucinations and motor-function impairment in humans is abused. Using trace amounts of Salvia divinorum - also known as "salvia," a Mexican mint plant that can be smoked in the form of dried leaves or serum - Brookhaven scientists found that the drug's behavior in the brains of primates mimics the extremely fast and brief "high" observed in humans. Their results are now published online in the journal NeuroImage.

Quickly gaining popularity among teenagers and young adults, salvia is legal in most states, but is grabbing the attention of municipal lawmakers. Numerous states have placed controls on salvia or salvinorin A - the plant's active component - and others, including New York, are considering restrictions.

"This is probably one of the most potent hallucinogens known," says Brookhaven chemist Jacob Hooker, the lead author of the study, which is the first to look at how the drug travels through the brain. "It's really important that we study drugs like salvia and how they affect the brain in order to understand why they are abused and to investigate their medicinal relevance, both of which can inform policy makers."

Hooker and fellow researchers used positron emission tomography, or PET scanning, to watch the distribution of salvinorin A in the brains of anesthetized primates. In this technique, the scientists administer a radioactively labeled form of salvinorin A (at concentrations far below
pharmacologically active doses) and use the PET scanner to track its site-specific concentrations in various brain regions.

Within 40 seconds of administration, the researchers found a peak concentration of salvinorin A in the brain -- nearly 10 times faster than the rate at which cocaine enters the brain. About 16 minutes later, the drug was essentially gone. This pattern parallels the effects described by human users, who experience an almost immediate high that starts fading away within 5 to 10 minutes.

High concentrations of the drug were localized to the cerebellum and visual cortex, which are parts of the brain responsible for motor function and vision, respectively. Based on their results and published data from human use, the scientists estimate that just 10 micrograms of salvia in the brain is needed to cause psychoactive effects in humans.

Salvia doesn't cause the typical euphoric state associated with other hallucinogens like LSD, Hooker says. The drug targets a receptor that is known to modulate pain and could be important for therapies as far reaching as mood disorders.

"Most people don't find this class of drugs very pleasurable," Hooker says. "So perhaps the main draw or reason for its appeal relates to the rapid onset and short duration of its effects, which are incredibly unique. The kinetics are often as important as the abused drug itself."

The Brookhaven team says it plans to conduct further studies related to salvia's abuse
potential. The scientists also hope to develop radioactive tracers that can better probe the brain receptors to which salvia binds. Such studies could possibly lead to therapies for chronic pain and mood disorders.

This research was funded by the Office of Biological and Environmental Research within DOE's Office of Science. DOE has a long-standing interest in research on brain chemistry gained through brain-imaging studies. Brain-imaging techniques such as PET are a direct outgrowth of DOE's support of basic physics and chemistry research.

Brookhaven says that all research involving laboratory animals at Brookhaven National Laboratory is conducted under the jurisdiction of the lab's Institutional Animal Care and Use Committee in compliance with the Public Heath Service (PHS) Policy on Humane Care and Use of Laboratory Animals, the U.S. Department of Agriculture's Animal Welfare Act, and the National Academy of Sciences' Guide for the Care and Use of Laboratory Animals.

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Drug Dosages Often Incorrect for Obese Patients

As if severely overweight people didn’t already have enough health concerns, experts are raising another red flag – the possibility that some of their prescription medications, especially antibiotics, may not be prescribed at the appropriate dosage and could be ineffective.

Because most adult antibiotics are produced in a “one size fits all” dosage and some doctors are not attuned to this issue, the societal trend towards severe obesity is resulting in more individuals who get inappropriate drug therapies for infectious disease, a new study in the journal Pharmacotherapy suggests.

“The number of individuals with the highest body mass index, very obese people, is up 600 percent between 1986 and 2000,” says David Bearden, a clinical associate professor in the College of Pharmacy at Oregon State University.

“Very obese individuals in some cases, even those with severe infections, may be getting only half the necessary dose of a prescription drug such as an antibiotic,” Bearden said. “That’s a problem. It could lead not only to antibiotic failure but also an increase in antibiotic resistance, another serious issue.”

The problem is somewhat less of a concern with dosages of medications that patients take for extended periods, such as blood pressure or cholesterol medications, because the results of taking those medications are more routinely monitored and dosages can be increased as necessary. It’s a particular concern with antibiotics, Bearden says, because they are often used to treat severe or even life-threatening infections, and “bad things can happen quickly if the drug is ineffective.”

Drug companies are just now becoming more aware of this issue and beginning to test and recommend dosages more appropriate for adults of varying weights, Bearden says. But with older drugs that are commonly used, there often is very little or no data for adjusting dosages. In actual practice the issue is often ignored outright, or “educated guesses” are made with whatever data is available.

Without more attention, the issue may only get worse, and it’s not just a U.S. phenomenon. The World Health Organization estimates that 400 million people were obese in 2005 and that the total will increase to 700 million by 2015. It considers these numbers a “global pandemic” that is affecting low, middle and high-income nations around the world. Obesity is also considered an independent risk factor for surgical site infections and is associated with higher mortality rates in critically ill patients.

Even if the problem is carefully considered, Bearden says, it’s not simple.

“It would be nice if we could just use a simple multiplier to adjust drug dosages for overweight people,” Bearden says. “But it’s not that easy. There are a lot of factors that affect drug distribution in the body, including age, weight, kidney function, other disease problems and the type of antibiotic or other drug.”

Adipose tissue, or body fat, affects how the human body interacts with drugs. With some drugs it absorbs large amounts of a prescription medication, but with others, it doesn’t. And sometimes there is a very fine line between a drug being effective at one dose, ineffective if the dose is too low, and toxic if it’s too high. All of these issues affect appropriate dosages, and in many situations, the data needed to evaluate the problem simply doesn’t exist.

The issue of adjusted drug dosages has been known and addressed in children for decades, experts say, because of the obvious distinction between a 30-pound toddler and a 120-pound youngster. But with adults, far less attention has been given the problem. The medical and pharmaceutical industries often just assume that everyone weighs about 150-170 pounds.

“This is enough of an issue that if I were a very obese person being given an antibiotic, I would discuss it with my doctor,” Bearden says. “Hopefully the doctor will already have considered it and will be able to address your concerns. If not, then it’s a conversation you need to have, and more medical specialists, including pharmacists, may need to be consulted.”

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Alzheimer's Drug Begins Clinical Trials

A drug based on the design of a Purdue University researcher to treat Alzheimer's disease began the first phase of human clinical trials this week.

"Millions of people suffer from this devastating disease and treatment options are very limited," says Arun Ghosh, the Purdue professor who led the creation of the treatment molecule. "Current drugs manage the symptoms, but this could be the first disease-modifying therapy. It may be able to prevent and reverse the disease."

CoMentis Inc., a biopharmaceutical company based in San Francisco, is initiating the clinical trials of the experimental drug CTS-21166. Ghosh, who has dual appointments in the departments of chemistry and medicinal chemistry, is a scientific co-founder of the company with Jordan Tang, the J.G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation.

The collaborative work of Ghosh and Tang led to the development of a treatment that could intercept and disable the disease at an early stage.

In 2000, Tang identified beta-secretase, a key enzyme in the progression of Alzheimer's that triggers the formation of amyloid plaques in the brain. Various stages in plaque formation produce toxic proteins that harm the brain, causing damage that eventually leads to dementia.
Later that year, Ghosh built a molecule that binds to this key enzyme and inhibits its activity, a beta-secretase inhibitor.

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Drug Slows and May Halt Parkinson's Disease

Northwestern University researchers have discovered a drug that slows – and may even halt – the progression of Parkinson’s disease. The drug rejuvenates aging dopamine cells, whose death in the brain causes the symptoms of this devastating and widespread disease.

D. James Surmeier, the Nathan Smith Davis professor and chair of physiology at Northwestern University’s Feinberg School of Medicine, and his team of researchers have found that isradipine, a drug widely used for hypertension and stroke, restores stressed-out dopamine neurons to their vigorous younger selves. The study is described in a feature article in the international journal Nature, which will be published online June 10.

Dopamine is a critical chemical messenger in the brain that affects a person’s ability to direct his movements. In Parkinson’s disease, the neurons that release dopamine die, causing movement to become more and more difficult.

Ultimately, a person loses the ability to walk, talk or pick up a glass of water. The illness is the second most common neurodegenenerative disease in the country, affecting about 1 million people. The incidence of Parkinson’s disease increases with age, soaring after age 60.

“Our hope is that this drug will protect dopamine neurons, so that if you began taking it early enough, you won’t get Parkinson’s disease, even if you were at risk. ” says Surmeier, who heads the Morris K. Udall Center of Excellence for Parkinson’s Disease Research at Northwestern. “It would be like taking a baby aspirin everyday to protect your heart.”

Isradipine may also significantly benefit people who already have Parkinson’s disease. In animal models of the disease, Surmeier’s team found the drug protected dopamine neurons from toxins that would normally kill them by restoring the neurons to a younger state in which they are less vulnerable.

The principal therapy for Parkinson’s disease patients currently is L-DOPA, which is converted in the brain to dopamine. Although L-DOPA relieves many symptoms of the disease in its early stages, the drug becomes less effective over time. As the disease progresses, higher doses of L-DOPA are required to help patients, leading to unwanted side-effects that include involuntary movements. The hope is that by slowing the death of dopamine neurons, isradipine could significantly extend the time in which L-DOPA works effectively.

“If we could double or triple the therapeutic window for L-DOPA, it would be a huge advance,” Surmeier says.

The work by Surmeier’s group is particularly exciting because nothing is known to prevent or slow the progression of Parkinson’s disease.


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