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Can CBD Really Do All That? It seems to be true!

https://medium.com/new-york-times-magazine/can-cbd-really-do-all-that-374fec6a7327 Can CBD Really Do All That?

How one molecule from the cannabis plant came to be seen as a therapeutic cure-all

New York Times Magazine

May 21
By Moises Velasquez-Manoff

When Catherine Jacobson first heard about the promise of cannabis, she was at wits’ end. Her 3-year-old son, Ben, had suffered from epileptic seizures since he was 3 months old, a result of a brain malformation called polymicrogyria. Over the years, Jacobson and her husband, Aaron, have tried giving him at least 16 different drugs, but none provided lasting relief. They lived with the grim prognosis that their son — whose cognitive abilities never advanced beyond those of a 1-year-old — would likely continue to endure seizures until the cumulative brain injuries led to his death.

In early 2012, when Jacobson learned about cannabis at a San Francisco conference organized by the Epilepsy Therapy Project, she felt a flicker of hope. The tip came from a father named Jason David, with whom Jacobson began talking by chance outside a presentation hall. He had mostly lost faith in conventional medicine during his own family’s ordeal. But he claimed to have successfully treated his son’s seizures with a cannabis extract, and now he was trying to spread the word to anyone who would listen.

The idea to try cannabis extract came to David after he found out that the federal government held a patent on cannabidiol, a molecule derived from the cannabis plant that is commonly referred to as CBD. Unlike the better-known marijuana molecule delta-9-tetrahydrocannabinol, or THC, CBD isn’t psychoactive; it doesn’t get users high. But in the late 1990s, scientists at the National Institutes of Health discovered that it could produce remarkable medicinal effects. In test tubes, the molecule shielded neurons from oxidative stress, a damaging process common in many neurological disorders, including epilepsy.

Jacobson had a Ph.D. in neuroscience. She had started her postdoctoral research at the University of California, San Francisco, by studying how cancer cells metastasize and spread, but after Ben was born she moved to Stanford and switched her focus to epilepsy. After meeting David and reading through the small body of published work on CBD, Jacobson changed postdoctoral directions once again, from primary research to the study of this community of parents who were treating their epileptic children with cannabis extracts.

One small, double-blind study particularly caught her attention. In 1980, scientists in Brazil treated eight epileptic patients with CBD and eight patients with sugar pills as a placebo. For half the group that received CBD, the seizures almost completely disappeared; another three experienced a reduction in the intensity of their seizures. Only one person in the placebo group got better.

None of the epilepsy drugs that had been approved to date had helped Ben much. But CBD worked on different and still somewhat mysterious pathways. If she could find a suitable CBD extract, Jacobson thought, she might have a truly new class of drug for Ben. The other experimental drugs and devices she had heard about at epilepsy conferences were under development, unapproved by the Food and Drug Administration and thus largely unavailable. But medical marijuana had been legal in California since 1996, so CBD was theoretically accessible right away.

Seven years later, cannabidiol is everywhere. We are bombarded by a dizzying variety of CBD-infused products: beers, gummies, chocolates and marshmallows; lotions to rub on aching joints; oils to swallow; vaginal suppositories. CVS and Walgreens each recently announced plans to sell CBD products in certain states. Jason David now sells a cannabis extract called Jayden’s Juice, named for his son — one of several extracts on the market, including Haleigh’s Hope and Charlotte’s Web, that are named after children who are said to have benefited from being treated with CBD.

Many of these products are vague about what exactly CBD can do. (The FDA prohibits unproven health claims.) Yet promises abound on the internet, where numerous articles and testimonials suggest that CBD can effectively treat not just epilepsy but also anxiety, pain, sleeplessness, Crohn’s disease, arthritis and even anger. Plenty of legitimate, if still inconclusive, research is being done on CBD. Many scientists are truly excited about it.

Amid the current deluge of products, it now seems almost quaint that, back in 2012, after deciding to try treating Ben with CBD, Jacobson couldn’t actually locate the stuff. Ben’s seizures could strike at any time. He was at high risk of what epileptologists callSudep, or sudden unexpected death in epilepsy. “I would have done anything to save Ben,” Jacobson told me. And so one day in 2012 she found herself driving her black SUV to a rundown Oakland neighborhood, past a police car, to purchase a kilo of what she had been told was CBD-rich cannabis.

For millenniums people have used cannabis with relatively few side effects. CBD seems to interact with multiple systems: increasing the quantity of native cannabinoids in the human body; binding with serotonin receptors, part of the “feel good” molecular machinery targeted by conventional SSRIs; and stimulating GABA receptors, responsible for calming the nervous system. With more than 65 cellular targets, CBD may provide a kind of full-body massage at the molecular level.

This biochemical promiscuity is one reason CBD seems so medically promising, according to Yasmin Hurd, a neuroscientist at Mount Sinai, in New York. Modern neuroscience often tries to target one pathway or receptor, Hurd told me; that approach is easier to study scientifically, but it may not address what are often network-wide problems. “The brain is about a symphony,” she says. And CBD, she suspects, can “bring the entire symphony into harmony.”

With her black-market stash in hand, Jacobson entered what she calls her R. & D. phase. She set up a lab in her garage — and then proceeded to fail miserably, for months, to extract anything of much use. Only under the tutelage of two University of California, Davis, scientists did she make progress. Nearly a year after starting, she had a cannabis extract that was high in CBD and lacked measurable THC.

Ben improved somewhat after taking it, but it was another boy with severe epilepsy, 11-year-old Sam Vogelstein, who responded most significantly. Jacobson and Sam’s mother, Evelyn Nussenbaum, had met and become close friends as together they sought a safe and reliable source of CBD for their children.

Across the Atlantic, Geoffrey Guy, the founder of a company called GW Pharmaceuticals, had successfully brought one cannabis-derived medicine, called Sativex, to market in Britain and other European countries. The first such medication permitted by a government, it was approved to treat the symptoms of spasticity (as well as pain) caused by multiple sclerosis. It contained both CBD and THC. Guy was intrigued when, through a mutual acquaintance, a California family seeking CBD to treat epilepsy reached out to him — Evelyn Nussenbaum and her son Sam.

Guy agreed to treat Sam. Jacobson had her extract analyzed and the results sent to Guy. In December 2012, Sam and Nussenbaum flew to London for two weeks to try a purified CBD drug that Guy had created just for him. He started with a small dose and, as it was gradually increased, his seizures faded. Before his trip, Sam was taking three conventional medications and still having dozens of seizures daily. But after he reached the highest daily dose of CBD — 250 milligrams — his seizures stopped almost entirely for a week. He became more articulate and coherent than he had been since he was 5.

After he returned to the United States, it was six months before Sam could take Guy’s extract again. Medical marijuana is illegal under federal law, but Sam gained access to Guy’s extract through the FDA’s compassionate-use program, which makes still-unapproved drugs available to patients with serious conditions. (In 2015 Sam’s father, Fred Vogelstein, a journalist, detailed Sam’s story in Wired magazine.) With a petition from a UCSF epileptologist, Roberta Cilio, who was the doctor for both boys, Ben also received the medicine through the FDA’s compassionate-use program. It helped, Jacobson thought, particularly with the most severe fits, which caused him to lose consciousness. But he was by no means seizure-free.

Jacobson and Nussenbaum knew many other families struggling with epilepsy. They were aware of the suffering and desperation of those who belonged to this “club that no one wanted to join,” as Nussenbaum puts it. Everyone should have access to the drug that had so helped Sam, they thought. But that meant the FDA would have to approve CBD for epilepsy. For that to happen, real trials had to take place.

The Drug Enforcement Administration’s classification of cannabis as a Schedule 1 drug, alongside heroin, peyote, ecstasy and LSD, has made it difficult for American scientists to study. Much of the research into its therapeutic potential comes from other countries, including Brazil. In the 1970s, Antonio Zuardi, a neuroscientist at the University of São Paulo, began looking into how cannabinoids affect mental states. Large quantities of THC could cause anxiety and paranoia in volunteers, he discovered, but CBD could attenuate those effects.

Later studies by Zuardi and his colleagues showed that a large dose of CBD, when given to volunteers who feared public speaking — that is, who suffer from social anxiety — blunted the flight-or-fight response, measured by increases in heart rate, blood pressure and skin conductivity, prompted by having to address others. And scientists at King’s College London have found evidence that CBD can lessen the psychosis-producing effects of THC and maybe help treat schizophrenia, a disorder whose main symptom is psychosis. The scientists are now testing CBD as a prophylactic to prevent schizophrenia from even emerging.

Some years ago, Hurd, who is the director of the Addiction Institute at Mount Sinai, discovered that THC could (as opponents of marijuana legalization have long maintained) prompt heroin-seeking behavior in rodents, acting as a proverbial “gateway drug.” But she also found that CBD reduced drug-seeking behavior, which led her to change the focus of her work. Now she studies how CBD could help opioid addicts kick the habit.

Hurd’s research, replicated by others, indicates that CBD might help recovering opioid addicts avoid relapse, perhaps the greatest challenge they face. She’s not sure why but suspects that by reducing anxiety and craving — major triggers of relapse — CBD helps patients stay the course. And because it’s not habit-forming, like other anti-anxiety medications, CBD might be a badly needed new weapon with which to fight an epidemic that claims more than 130 lives daily in the United States.

Other possible applications of plant-derived cannabinoids could be just as groundbreaking. Scientists at New York University are studying CBD as a possible treatment for autism spectrum disorders. Spanish researchers are testing both THC and CBD on an aggressive brain cancer called glioblastoma. Israeli scientists have found that CBD can lessen the incidence of graft-versus-host disease in bone-marrow transplant patients, presumably because the cannabinoid calms the immune system and deters it from attacking the patient.

How could one family of molecules help so many maladies? The most obvious response is that they might not; all this research is preliminary and might not pan out. But scientists often propose a counter-explanation: Many chronic disorders, even though they seem distinct, are characterized by dysfunction in the same few pathways. Inflammation and oxidative stress, for example, occur in schizophrenia, metabolic disorders, heart disease and other ailments. The therapeutic magic of CBD and, in some cases, THC — and maybe some of the more than 100 other cannabinoids in cannabis — may come from the ways that, by tweaking the endocannabinoid system, they push the body away from disease toward the unruffled state scientists call homeostasis.

In early 2013, just a few weeks after Sam Vogelstein returned from Britain, Catherine Jacobson organized a brainstorming session at N.Y.U., which included Geoffrey Guy, epilepsy researchers and a consultant with a DEA background, in order to figure out how to make FDA-sanctioned trials happen. What followed the meeting surpassed Jacobson’s expectations. The FDA first expanded the ability of doctors to prescribe CBD and then fast-tracked the approval process.

In June 2018, just five years after that meeting — an instant in drug-development time — the FDA approved GW Pharmaceutical’s CBD extract as a treatment for two rare forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. And three months later the DEA rescheduled this first CBD drug (but not THC) to Schedule 5, meaning it was now considered to have low potential for abuse. The drug, called Epidiolex, is the first to contain only CBD and the first derived directly from the cannabis plant itself.

Because so many people already use cannabis and think it helps, patients might be, in effect, pioneering new uses through self-experimentation. This trend concerns many physicians, who worry that patients may be deluding themselves, but some scientists interested in cannabinoids have begun to look to “vernacular” applications for clues about what to study formally. CBD is generally considered safe, even at the high doses tested so far — and the quantities in chocolates, teas and other edibles tend to be far below the concentrations tested experimentally.

Many who have direct experience with CBD, including a few scientists, do not think it should be available only by prescription. They point out that long before the 1970 Controlled Substances Act, which made marijuana illegal, people used the plant medicinally. Cannabis should not only take its place as an FDA-approved drug, they contend. It should also reclaim its role as a folk remedy.

Some scientists are concerned by how far the CBD craze has moved beyond the science. But Staci Gruber, associate professor of psychiatry at Harvard Medical School, does not think the two are necessarily in conflict. This might seem odd, given her work. She has found that recreational users, particularly those who begin using cannabis earlier in life, exhibit some cognitive difficulties and altered brain structure and function.

In 2014, Gruber started the Marijuana Investigations for Neuroscientific Discovery, or MIND, program to examine the effects of medical cannabis, and so far, she has found exactly the opposite in people who use cannabis as medicine. Their cognitive function appears to improve over time and preliminary evidence suggests that, after initiation of medical-cannabis treatment, their brain activity begins to normalize.

Gruber has also observed that medical cannabis patients tend to reduce their use of conventional medications over time, which might itself be beneficial to brain structure and function. Whatever the explanation, Gruber believes greater scientific engagement with the CBD phenomenon is as important as more careful regulation. “People have been using cannabis forever,” she told me. “The question now is, How do we as scientists catch up?”