Story 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 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 studyparticularly 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.
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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.
But in the late 19th century, our ancient relationship with this plant began to fray. In 1930, Harry Anslinger, a former official at the Bureau of Prohibition, assumed a new job running the Bureau of Narcotics. The Mexican Revolution that began in 1910 had led to waves of immigrants crossing into the United States. Whereas many Americans took their cannabis orally in the form of tinctures, the new arrivals smoked it, a custom that was also moving north from New Orleans and other port cities from which African-Americans were beginning their own migration.
Anslinger disdained Mexican-Americans and African-Americans. He loathed jazz. Modern scholars argue that his demonizing cannabis both justified his position and provided a way for him to gain legal leverage over peoples he despised. The high cost paid by people of color, once he had begun what we now call “the war on drugs,” may not have been an incidental byproduct of his efforts but an unstated goal from the start. His protestations still echo today. Cannabis made people crazy, violent and prone to criminal behavior, Anslinger said.
Yet when 30 American Medical Association members were surveyed, starting in 1929, 29 disagreed with claims about the dangers posed by cannabis. One said the proposals to outlaw it were “absolute rot.” But the hysteria Anslinger helped stir up worked politically. In 1937, Congress passed the Marijuana Tax Act. High taxes made cannabis much more expensive and difficult to obtain decades before President Nixon — scientists of his era disagreed with him, too, about marijuana’s supposed dangers — signed the Controlled Substances Act of 1970. A plant that people had used medicinally for thousands of years was now driven underground.
Jacobson’s dealer in Oakland seemed to be selling harder stuff as well, which made her very nervous. But her impression was that he was having a difficult time selling this particular product — kilos of California-grown cannabis — precisely because it wouldn’t get anyone very high. With her black-market stash in hand, Jacobson entered what she calls her R.& D. phase. As suspected, the cannabis she had acquired illegally in Oakland was high in CBD and low in THC. 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. The technique she developed required heating cannabis plants in ethanol to extract the cannabinoids. Next, a machine that created a vacuum sucked the green-tinted liquid through a tube filled with carbon powder. The molecules in the extract moved through the powder at different speeds, depending on their weight and other characteristics, yielding different “fractions” that she could test for CBD and THC content. Then she heated the resulting green solution until the alcohol evaporated, leaving a green paste. It took her about six months to perfect the process. Finally, 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. But now Jacobson felt a different sort of pressure. Making the medicine was difficult. Despite all that she had learned, some batches of her extract were unusable. And who knew if the source material she was buying illegally would remain available? If this was to be their sons’ medicine, Jacobson wanted a pharmaceutical-grade product that she could always obtain.
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, a progressive autoimmune disease of the central nervous system. 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, when his condition took a turn for the worse. He rode a zip line in Hyde Park, took the subway and did other things that Nussenbaum had always avoided for fear that he would seize and hurt himself. Nussenbaum describes that week as “Twilight Zone weird,” as if she had entered a parallel dimension.
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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 — its designation as a Schedule 1 drug means it is considered to have a high potential for abuse and without any known medical application — but Sam gained access to Guy’s extract through the F.D.A.’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. In 2010, he also wrote in this magazine about using a ketogenic diet, since discontinued, to control Sam’s epilepsy.) With a petition from a U.C.S.F. epileptologist, Roberta Cilio, who was the doctor for both boys, Ben also received the medicine through the F.D.A.’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. Many parents lacked the resources and connections they had. Everyone should have access to the drug that had so helped Sam, they thought. But that meant the F.D.A. would have to approve CBD for epilepsy. For that to happen, real trials had to take place. And given the fraught political history of cannabis in the United States and the skepticism they would most likely face, Jacobson knew she would need top epilepsy experts to conduct those trials.
The D.E.A.’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 the anxiety-provoking and psychoticlike effects of THC. 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. These were small studies, and the amount of CBD involved, which was 600 milligrams in the social-phobia study, is greater than what users might consume these days in some CBD gummies, for example, but relieving anxiety is nonetheless one of the most widely reported reasons people use CBD.
CBD may also have antipsychotic properties. In susceptible individuals, its sister cannabinoid THC can, in high doses, induce psychotic symptoms, and heavy marijuana use early in life has been linked to an increased risk of developing psychotic disorders, possibly because it alters brain development. But just as Zuardi discovered that CBD can blunt anxiety, scientists at King’s College London have found evidence that CBD can lessen the psychosis-producing effects of THCand 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.
Many of those who develop schizophrenia first pass through a “prodromal” phase. They suffer from delusions, but they’re still aware that these experiences aren’t real and often seek psychiatric help. A single 600-milligram dose of CBD given to these patients, scientists at Kings College London have found, can partially normalize regions of the brain that have been shown in fMRI visualizations to become dysfunctional during schizophrenic episodes.
A follow-up study will prophylactically treat a large group of these patients thought to be teetering on the edge of psychosis. Current schizophrenia treatments merely attempt to manage the disorder once it has already emerged. A medicine that slows or prevents the disease from taking root altogether, almost like a vaccine, would address a huge unmet need. “If it works, it will be a revolution,” José Crippa, a neuroscientist at the University of São Paulo who is involved in the project, told me.
It’s reasonable to ask why the CBD naturally present in cannabis doesn’t protect recreational users from the negative effects of THC. In older varieties, where the CBD-to-THC ratio was closer to 1-to-1, maybe it did. But today’s strains typically contain about three times as much THC as the cannabis smoked recreationally even as recently as the 1990s, while CBD concentrations have fallen by about half in the same period, according to a recent University of Mississippi study on black-market marijuana. And precisely because the proportions between the two cannabinoids have become so skewed — the ratio of THC to CBD has risen to 80 to 1 from 14 to 1 in two decades — lots of modern cannabis is potentially much more toxic for the brain, says Hurd, who is the director of the Addiction Institute at Mount Sinai.
Some years ago, Hurd 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.
THC may also have therapeutic uses, particularly in treating the pain that often puts people on a path leading toward opioid addiction. Several studies have found that cancer patients need