MARIJUANA IS INFAMOUS for its ability to muddle thoughts and dull reactions. What is less well known is that it may also blunt the progression of Alzheimer's disease, which relentlessly robs its sufferers of their memories and personality. Families and individuals tormented by this deterioration may welcome such an alternative therapy, no matter how they feel about marijuana's illegal status.
“I went through several years of a son on marijuana and had him placed in a facility to be ‘dried out,’” says Ruth, age 69, of St. Louis. Even so, she says she would consider giving the drug to her 79-year-old husband, Joe, who now suffers from Alzheimer's, if it stopped his combativeness and helped to slow his memory loss. Joe is just one of 4.5 million Americans who have the neurodegenerative disorder, which usually strikes after the age of 60 and is found in nearly half of those older than 85.
Several laboratories around the world are now investigating how marijuana may stave off Alzheimer's. It is a new field, and research has not reached clinical testing, but scientists are beginning to understand several biochemical mechanisms by which marijuana may stall the disease—perhaps even more successfully than the most frequently prescribed medications.
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Ounce of Prevention
A century ago German doctor Alois Alzheimer first described the disease when he found sticky plaques in the autopsied brains of patients who had exhibited extreme memory loss and confusion. We now know that the senile plaques he observed are composed of beta-amyloid protein and a slew of other toxins, which together form a poisonous gunk that kills cells and causes hemorrhaging. Doctors had no means to treat the disease until 1993, when the Food and Drug Administration approved the cholinesterase inhibitor Cognex, a drug that blocks the enzyme acetylcholinesterase from breaking down acetylcholine, a neurotransmitter that relays signals in the memory areas of the brain.
Plaques produced by Alzheimer's rapidly kill so-called cholinergic neurons, those that synthesize acetylcholine. By raising levels of this neurotransmitter in the brain, Cognex keeps these cells alive longer and slows plaque formation. A newer cholinesterase inhibitor, called Aricept, works in the same way. Research has shown, however, that cholinesterase inhibitors are only moderately effective. In a review of 22 clinical trials, published in the August 6, 2005, edition of the British Medical Journal, Hanna Kaduszkiewicz and her colleagues at the University Medical Center Hamburg-Eppendorf in Germany concluded that “because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable.”
Many experts believe these drugs simply offer too little too late. By the time a doctor can make a diagnosis and prescribe medication, so many brain cells have been destroyed that boosting the amount of acetylcholine is as futile as tossing a bandage on a massive head wound. Preventing Alzheimer's at an earlier stage may be the only hope for those predisposed to the disease. To that end, new research reveals that the active ingredient in marijuana, tetrahydrocannabinol (THC), may outperform cholinesterase inhibitors. According to Kim D. Janda of the Scripps Research Institute in La Jolla, Calif., THC prevents the degradation of acetylcholine just as Cognex and Aricept do, and it may also hinder toxic proteins from forming plaques.
“We found this mechanism while trying to find a ‘vaccine’ against pot,” Janda says. He has been using computer modeling to study small synthetic molecules he dubs “credit cards” because of their flat shape. THC is a natural “credit card,” which enables it to slip between acetylcholine and acetylcholinesterase and impede their interaction. Janda's team reported in the December 2006 issue of Molecular Pharmaceutics that the THC molecule binds to a unique location on the acetylcholinesterase enzyme. If you picture the enzyme as a doughnut, Janda explains, Alzheimer's drugs bind to the hole, but THC binds instead to the lip of the hole, blocking the enzyme's actions even more efficiently. “We don't know why it does, it just does,” Janda says.
Cannabinoids—the class of drugs to which marijuana belongs—may offer other potential benefits to Alzheimer's patients. According to Maria de Ceballos, a neurology researcher at the Cajal Institute in Madrid, they prevent inflammation caused by overactive microglia and astrocytes, the sanitation workers of the central nervous system. These cells swarm around Alzheimer's plaques and try to rid the brain of the toxins. To do so, however, they secrete additional toxins—nitric oxide and tumor necrosis factor-alpha—that cause swelling and kill neurons.
Microglia and astrocytes sport CB1 cannabinoid receptors (the same receptors responsible for making people feel “stoned”). According to de Ceballos's research, cannabinoids can plug these receptors, preventing the microglia and astrocytes from producing nitric oxide and tumor necrosis factor-alpha. As with the cholinesterase inhibitors, the key may be acting in time. As the disease progresses, it destroys the neurons that have CB1 receptors, leaving no target on which the cannabinoids can act. The best course of action is prevention, not therapy once “it's too late,” de Ceballos says.
Pipe Dreams?
The notion that cannabinoids can help Alzheimer's patients has its critics, among them Lawrence Honig, a neurologist who studies the disease at Columbia University's Sergievsky Center. He maintains that little evidence shows definitively that acetylcholinesterase is involved in beta-amyloid clustering. And looking at Janda's computer models, Honig does not believe that THC works more efficiently than prescription drugs in preventing acetylcholine degradation. He also dismisses the idea that receptors are the key to preventing inflammation or plaque formation.
De Ceballos and Janda are frustrated that their findings are generally unnoticed by the Alzheimer's research field and that their work is stigmatized because the active compound is found in an illegal drug. “Look, we are not advocating that people start smoking dope,” Janda asserts. “The only people who take notice of this research are people who are looking for another reason to legalize pot.” He believes that prestigious journals have not published his results for this reason.
De Ceballos feels that her research will get the attention it deserves only through communication with the public and physicians so that the message is not misunderstood. Although she is not recommending it, she says that people with a family history of Alzheimer's and who test positive for high-risk genes might consider smoking marijuana at moderate levels over a long period before symptoms arise. “Just like with wine, doctors say ‘one glass a day' [for heart health]—not a whole bottle. But it is not something we have data on yet,” she points out. In fact, smoking the plant may not even be necessary. De Ceballos notes that another cannabinoid receptor also found in the brain recognizes cannabinoids but does not confer the psychoactive effects. Perhaps one day there will be a pill that targets these receptors instead.
In the meantime, her lab is designing a study of populations from the Netherlands, where marijuana smoking has been decriminalized since 1976. She wants to see if those who indulge in the herb have lower rates of Alzheimer's. If so, the results might finally generate some serious buzz.