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Big Alzheimer's research roadblock: Federal government

Promising new research conducted last year at the Salk Institute for Biological Studies has shown that marijuana extracts may hold a key to treating Alzheimer's disease. The next step: To conduct tests on mice and, if the results are promising, move on to human trials.

Jim Hill looks over the marijuana he grows for medical purposes at his farm in Potter Valley, Calif. Hill believes passionately in marijuana's purported ability to treat the symptoms of diseases ranging from cancer to Alzheimer's.
Eric Risberg | AP
Jim Hill looks over the marijuana he grows for medical purposes at his farm in Potter Valley, Calif. Hill believes passionately in marijuana's purported ability to treat the symptoms of diseases ranging from cancer to Alzheimer's.

But Salk Institute researchers have run into a major hurdle, and not a scientific one: the federal government. The Salk Institute is based in La Jolla, California — a state that legalized marijuana last November — but it is a federally funded research institute.

Marijuana is still listed as a Schedule I controlled substance under the Controlled Substances Act (CSA) of 1970. A substance is placed in Schedule I if it is determined to have no currently accepted medical use, a lack of accepted safety for use under medical supervision and a high potential for abuse. Other Schedule I classified drugs include heroin and LSD. Because the Salk institute receives money from the National Institutes of Health, an agency of the U.S. Department of Health and Human Services, the lab must abide by federal law, which prohibits it from having any unapproved strains of cannabis in its facility without the proper registration.

The researchers at the Salk lab were able to conduct the initial phase of their research without obtaining the proper Schedule I registration, by working with only about a milligram of cannabinoids — chemical compounds found in the marijuana plant — from chromatography standards that are found in methanol, a toxic alcohol solution. These solutions are normally used by labs that do drug testing on individuals as positive controls in the assays, and Salk purifies it from that.

In order to acquire marijuana for further studies, the lab must first apply to the Drug Enforcement Agency, which carries out the application process jointly with the U.S. Department of Health and Human Services. The Salk researchers sent in their application in December. They are still waiting for approval, with their research at a standstill.

"It's so blatantly obvious that this plant should be studied in greater detail, and yet we have this major roadblock stopping it," said Dr. David Schubert, a professor at The Salk Institute and the senior scientist on the study. "It's hard enough to get funding without having to worry about legal issues on top of it. It's odd and somewhat demoralizing."

Barbara Carreno, a spokesperson for the DEA, said it can take three to six months for the agency to review the research work and approve an application.

New Trump administration Attorney General Jeff Sessions is known to be against legalization. But White House spokesman Sean Spicer recently voiced a much sterner view of prosecuting recreational use of marijuana as compared to medical use.

"It's so blatantly obvious that this plant should be studied in greater detail, and yet we have this major roadblock stopping it." -Dr. David Schubert, professor at the Salk Institute for Biological Studies

Preliminary evidence from the study done on human neurons indicates that tetrahydrocannabinol (THC) and other compounds found in cannabis promote the removal of a toxic plaque protein, amyloid beta, found inside neurons in the brains of Alzheimer's patients. It is this plaque that causes inflammation and neuron cell death, contributing to the loss of memory and mental abilities in Alzheimer's patients.

The Salk scientists believe that if they are able to use cannabis compounds to target and attack the buildup of amyloid beta before people start showing the symptoms of the disease, they may be able to stop the cells from making the inflammatory molecules, Schubert said.

Devastating costs 

Time is of the essence, given the rise in Alzheimer's cases and the associated costs, measured in both loss of human life and dollars.

Alzheimer's disease is the most common form of dementia. It is also the sixth-leading cause of death in the nation, according to the Alzheimer's Association. In 2016 there were more than 5 million Americans living with Alzheimer's. One in 9 Americans age 65 and older have the disease. The organization also estimates that 1 in 3 seniors will eventually die while battling some form of dementia. As the baby boomer generation continues to age, incidences of the disease are expected to increase. Currently, somebody in the United States develops Alzheimer's disease every 66 seconds.

The cost to the economy of caring for Alzheimer's and dementia patients was estimated to be about $236 billion in 2016. In 2015 a study funded by the National Institutes of Health estimated that the costs associated with late-stage dementia are greater than for any other disease.

During the last five years of a person with dementia's life, total health-care spending was more than a quarter of a million dollars per person ($287,038), about 57 percent greater than costs associated with death from other diseases, including cancer ($173,383) and heart disease ($175,136).

Between 2002 and 2012, just one of the 244 Alzheimer's drugs that were evaluated in clinical trials went on to win U.S. Food and Drug Administration approval, according to the Alzheimer's Association. From 2000 to 2013, death's attributed to Alzheimer's disease increased by 71 percent.

A Big Drug problem

Recent promising research efforts from major pharmaceutical companies have failed.

In November, Eli Lilly said its experimental Alzheimer's drug, solanezumab, which had shown hopes of slowing the deterioration of thinking and memory in Alzheimer patients by attacking the amyloid plaques in a patient's brain, had failed in clinical trials. It is now in Phase 1 trials in collaboration with AstraZeneca to develop another Alzheimer's drug, known as MEDI1814.

Merck recently abandoned an Alzheimer's drug trial after saying it offered "no chance of finding a positive clinical effect."

Biogen has also been conducting clinical trials for its experimental Alzheimer drug, aducanumab. The drug is currently being evaluated in two global Phase 3 studies, ENGAGE and EMERGE. During earlier trials the drug was shown to cause a swelling in the brain in some patients, so the company is incrementally increasing the dosage in the most recent trials in order to reduce the percentage of people who will suffer from this side effect.

Currently, there are just five prescription medications approved for use in the United States, which aim to slow down the worsening of symptoms in people with Alzheimer's, but they have proved to only be effective in some people and for a limited period of time.

Schubert contends that the pharmaceutical lobby in Washington, D.C., is part of the problem. "The pharmaceutical companies want to stop the use of cannabis in the research community because it's a natural product, so it can't be patented," he said. "That's the reason they don't have any incentive to use it (cannabis) in the development of new drugs. They can't make money on it, so they are against it."

Salk researchers believe the reason so many Alzheimer's drugs are failing may be explained by the widely held belief in the scientific community that simply removing or preventing the accumulation of amyloid plaques that occur outside of the brain's cell can help alleviate some of the symptoms of dementia. But the scientists at the Salk lab believe that this is the wrong approach.

"They are trying to use antibodies to get rid of plaque that is outside the cell, but that is too late in the disease," Schubert said. By the time the plaque has developed, the damage to the patient's brain cells may already be too extensive. "What we are trying to do is get rid of the plaque amyloid protein while it is still inside the cell, at a much earlier stage in the progression of the disease," Schubert said.

Neurons in the brain naturally make THC-like compounds, called endocannabanoids, to protect them from dying. These endocannabanoids, a class of lipid molecules, affect both inflammation and other functions of the cells, such as intercellular signaling in the brain. The Salk lab's scientists were able to demonstrate that one of their Alzheimer's drug candidates removed amyloid from inside the cells, in part by activating one of the binding partners (receptors) for endocannabinoids in neurons.

THC, an active ingredient in marijuana, it turns out, acts similarly to the endocannabinoids molecules the body naturally makes to activate the receptors in the brain's cells. What the scientists discovered was that by exposing those cells to THC, they were able to stop the inflammation and death of the cells, which they believe may stop the loss and deterioration of memory in Alzheimer's patients.

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So far, all requests for a removal or rescheduling of the marijuana plant to a Schedule II or III drug have been denied. The DEA denied two of the latest petitions last August, stating that the CSA mandates that scheduling decisions be based on medical, scientific and other data showing the relative abuse potential of a drug. The agency turns to the FDA, in consultation with the National Institute on Drug Abuse, to provide it with a recommendation on such decisions, and the FDA again recommended it not be removed.

"Ongoing scientific and medical evaluation determined at this time that the marijuana plant continues to have high potential for abuse and does not meet the criteria outlined by the DEA for currently accepted medical use, requiring its continued placement in Schedule I under the law," said Michael Felberbaum, a spokesperson for the FDA.

The agency's claims that marijuana has "dose-dependent reinforcing effects" which can result in dependence brings out Schubert's palpable frustration. "Marijuana is not physically addictive, although it can be psychologically addictive like, sugar, salt and fat, none of which are classified as Schedule I drugs," he said. "It's ridiculous when in California anyone can legally go down to the corner store and just buy marijuana."

In November, California voted to pass Proposition 64, legalizing the recreational use of the marijuana — in a state that has long allowed for the use of medicinal marijuana. Legalizing pot means that local growers are now able to grow all different types of strains of marijuana and in abundance. "I can go to a medical marijuana dispensary and buy marijuana, or I can grow it, but I can't bring it into a lab to study it, because of the federal restriction," Schubert said.

The FDA is aware that marijuana and marijuana-derived products are currently being prescribed by doctors to treat a number of medical conditions including AIDS wasting, epilepsy, neuropathic pain, multiple sclerosis, cancer and chemotherapy-induced nausea. But to date, the agency has not approved a marketing application for a drug product containing or derived from botanical marijuana and has not found any such product to be safe and effective for any indication.

"It's a totally unexplored area, because researchers have been stopped by the DEA, due to the way the agency classifies marijuana," Schubert said. "The result is that basically no clinical trials have been held to test the use of marijuana-based drugs in the treatment of Alzheimer's or any other neurodegenerative disease. It's not right that they have that type of say over something that could be very useful." He added, "People are dying of this disease, and there is nothing out there for them."

By Leslie Kramer, special to CNBC.com

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