Can CBD Really Do All That?

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 conference organized by the Epilepsy Therapy Project, she felt a flicker of hope. The meeting, in downtown San Francisco, was unlike others she had attended, which were usually geared toward lab scientists and not directly focused on helping patients. This gathering aimed to get new treatments into patients’ hands as quickly as possible. Attendees weren’t just scientists and people from the pharmaceutical industry. They also included, on one day of the event, families of patients with epilepsy.

The tip came from a father named Jason David, with whom Jacobson began talking by chance outside a presentation hall. He wasn’t a presenter or even very interested in the goings-on at the conference. 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 — a shift that compounded her anguish. She often wept in the parking lot before heading into the lab, overwhelmed by dread at the prospect of deliberately causing epilepsy in rodents. “I couldn’t watch animals seize all day and then watch Ben seize all night,” she told me. “It was just too much.”

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. In reality, she was preparing to join it herself. 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.

The epilepsy drugs that had been approved to date, none of which had helped Ben much, typically targeted the same few ion channels and receptors on the surface of neurons. 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 F.D.A. and thus largely unavailable. But medical marijuana had been legal in California since 1996, so CBD was theoretically accessible right away.

[Read more on why CBD is everywhere.]

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 for “soothing,” in one company’s words, “the area that needs it most.” 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 F.D.A. 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. A confluence of factors has led to this strange moment. Plenty of legitimate, if still inconclusive, research is being done on CBD. Many scientists are truly excited about it. The laws governing cannabis and its chemical components have loosened up. And the anecdotes that have emerged from what Elizabeth Thiele, an epileptologist at Harvard, calls the “vernacular” cannabis movement have lent emotional force to the claims made for CBD.

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. Other parents of epileptic children were using D.I.Y. techniques to treat their children: tinctures; cannabis-infused butter in baked goods; crushed cannabis buds in capsule form; even cannabis suppositories. Some reported positive results. Over the years, Jacobson has had many of these products tested at labs; almost invariably they contained very little or no CBD and too much THC. It has psychoactive effects, and there wasn’t much science suggesting THC could treat seizures.

Jacobson describes her family’s existence as akin to living under the threat of terrorism. Ben’s seizures could strike at any time. He was at high risk of what epileptologists call Sudep, 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 S.U.V. to a rundown Oakland neighborhood, past a police car, to purchase a kilo of what she had been told was CBD-rich cannabis.

In the early 1960s, a Bulgarian-born Israeli chemist named Raphael Mechoulam asked a simple question: How does marijuana make you high? The biochemistry of major psychoactive molecules from other recreationally used drugs, like cocaine and opium, was already understood. But scientists still didn’t know how cannabis worked. Mechoulam was the first scientist to map the chemical structure of both cannabidiol and delta-9-tetrahydrocannabinol, or THC. Two decades later, Allyn Howlett, a scientist then at St. Louis University Medical School, used a radioactive THC equivalent to trace where cannabinoids ended up in the brain and discovered what she would later call CB1 receptors. They were subsequently found in the kidneys, lungs and liver, too. White blood cells of the immune system, the gut and the spleen also have another type of cannabinoid receptor, known as CB2.

There is a long history of scientists gaining insight into human physiology by studying how plants interact with our bodies. Poppy flowers and the opium derived from them led to the discovery of the body’s native opioid receptors, which help regulate pain, stress responses and more. Nicotine, a stimulant found in tobacco, long used by Native Americans, taught scientists about the existence of our own nicotinic receptors, which influence neuronal excitement.

Why plants produce molecules that seem perfectly designed to manipulate human biochemical circuitry is a mystery. It could be a kind of molecular coincidence. But many plants, including cannabis, might make these molecules to defend themselves from other organisms. Modern industrial agriculture employs a whole class of pesticides based on nicotine — the neonicotinoids — meant to repel insects by over-exciting their nervous systems. Cannabinoids display antibacterial, antifungal and insecticidal properties as well. Their ability to engage our native cannabinoid receptors may be a result of millions of years of biochemical warfare directed at would-be grazers: insects and other creatures that happen to share biochemical signaling pathways with humans. If plants target the cannabinoid receptors of other organisms to protect themselves, it follows that whatever signals those receptors evolved to receive have to be vital for these animals’ physiological health. Otherwise, why interfere with them?

Mechoulam concluded that our bodies must produce their own cannabinoids — endogenous molecules that, like the native opioids and nicotinelike molecules our bodies also make, engage the cannabinoid receptors throughout the human body. In 1992, he identified the first one. Mechoulam, who is often called the godfather of cannabis research — he was a senior scientist on the Brazilian CBD epilepsy trial that inspired Jacobson — and his colleagues christened it “anandamide,” after the Sanskrit word for “supreme joy.” They suspected that the molecule played a role in the formation of emotions.

The native network of cannabinoid receptors and transmitters described by Howlett and Mechoulam is now known as the endocannabinoid system. It’s central to homeostatic regulation, that is, how the body maintains, and returns to, its baseline state after being disturbed. If a person is injured, for example, native cannabinoids increase, presumably in order to resolve the inflammation and other damage signals associated with injury. They also increase after strenuous exercise, another stressor, and some scientists have argued that they, not the better-known endorphins, are really responsible for the pleasant postexercise feeling known as runner’s high.

Endocannabinoids help regulate immune activity, appetite and memory formation, among many other functions. (Heavy marijuana use is associated with memory deficits, possibly because THC short-circuits the formation of memories.) “Perhaps no other signaling system discovered during the past 15 years is raising as many expectations for the development of new therapeutic drugs,” Vincenzo Di Marzo, an endocannabinoid researcher at the National Research Council in Naples, Italy, wrote in 2008, in the journal Nature Reviews Drug Discovery. But realizing such medical benefits has proved trickier than once imagined.

When scientists at the French pharmaceutical company Sanofi-Aventis (now Sanofi) understood that THC could whet a user’s appetite, they created a weight-loss drug that blocked CB1 receptors, hoping to suppress appetite. Rimonabant was first released in Europe in 2006. Two years later, regulators pulled it from the marketplace because of its severe side effects, including depression and suicidal behavior. The episode seems to exemplify endocannabinoids’ importance to our sense of well-being and the difficulty of manipulating them therapeutically. Attempts to increase native cannabinoids with synthetic drugs have fared no better. In 2016, French scientists halted a study of a drug designed to boost endocannabinoids. For reasons that remain unclear, six patients who took the medicine, meant to treat pain, were hospitalized. One died.

And yet, for millenniums people have used cannabis itself with relatively few side effects. (These can include dry mouth, lethargy and paranoia.) THC hits CB1 and CB2 receptors, but how CBD works is less clear. It 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 S.S.R.I.s; 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.”

Cannabis has been used medicinally for thousands of years in Asia, where it was probably first domesticated before traveling to, among other places, Africa. It was almost certainly introduced multiple times to the Americas, first from Africa to South America through the slave trade — in Brazil it’s still known by an African name, diamba — but also to the Caribbean. Indian indentured laborers probably brought it to Jamaica, where it’s called by an ancient Indian name, ganja.

White Americans also had some history of using cannabis in tinctures. In the early 19th century, an Irish doctor working in India, William Brooke O’Shaughnessy, had observed that cannabis was used extensively in Indian medicine. He began experimenting and found it quite efficacious not only for infantile seizures but also rheumatism and spasms caused by tetanus. O’Shaughnessy usually gets the credit for introducing the plant to the English-speaking world, but while he popularized its use in Britain, he was not the first European to bring it back to Europe. Garcia Da Orta, a Portuguese physician, had, after living in India, written about cannabis as medicine in the 1500s.

After O’Shaughnessy published his treatises on the plant, its use spread rapidly among physicians. By the late 19th century, cannabis was an important component of British and American physicians’ pharmacopoeia. (Researchers suspect that these older cannabis cultivars, and the tinctures made from them, probably contained much less THC and much more CBD than modern varieties.) Of course, hemp, a variety of cannabis bred not for consumption but for the fiber that goes into ropes and sails, among other things, had been an important crop in Europe and the Americas for centuries. George Washington grew it. The English word “canvas” derives from the Greek kannabis.

Original Article:
https://www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.html

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