Marijuana’s side effects, from memory-impairment to apparent addiction, have kept it on the wrong side of the law for decades. But drugs that lack those side effects, while mimicking marijuana’s favorable effects on the brain, have attracted the attention of major pharmaceutical companies and are now nearing clinical trials.
“This is a field that is exponentially developing,” says Steven Goldberg, a senior researcher at the National Institute on Drug Abuse.
The informal therapeutic use of cannabis sativa extends back to prehistory, but our knowledge of how it works is relatively recent. The main cellular receptors to which tetrahydrocannabinol (THC) and other cannabinoid compounds bind, and the “endocannabinoid” compounds our cells produce naturally, were isolated only in the 1990s. The complexities of these molecules’ interactions in the brain and body have just begun to be revealed in the past several years.
One thing is already clear: The cannabinoid system includes some of the most widely distributed and important cell-signaling pathways in humans and other vertebrate animals.
“CB1 tends to be almost everywhere,” Goldberg says, referring to the first-described and best-known cannabinoid receptor, which is found more densely on brain cells than on other cell types. The CB2 receptor also is thought to be present in some parts of the brain, although it appears mostly on immune cells throughout the body.
The chill-out receptor?
Evidence for the existence of other cannabinoid receptors, and compounds that bind to them, accumulates by the year. But so far it appears that a major function of cannabinoid receptors is to reduce the excitability of the cells on which they are found. “When a nerve is firing, these [receptors] get activated and then they slow the firing of the nerve down,” says Goldberg. “They’re sort of brakes on the system.”
This braking function seems to relate in part to learning and memory, although, as Goldberg explains, it appears also to protect the health of neurons. “Endocannabinoid levels rise after various types of neural trauma or degeneration and have protective effects against experimentally-induced epilepsy in animal models,” he says. CB1 receptors also are found widely outside of the brain, for example on heart and liver cells. CB2 receptors on immune cells are less well understood, but they appear to be involved in the regulation of inflammation and pain.
The pleasant, mood-altering effects of marijuana appear to be caused almost entirely by the activation of CB1 receptors in the brain by THC and other cannabinoids. These receptors now are targets in the development of drugs for anxiety, depression and related disorders.
Led by a team at Germany’s Max Planck Institute, European neuroscientists reported in Nature in 2002 that mice bred without CB1 receptors lose much of their ability to forget fearful associations. When a bell is rung just before they feel an electric shock, they quickly learn, like normal mice, to associate the bell with the shock, eventually showing signs of stress even when the shock is never delivered. But they take far longer than normal to unlearn the association when the accompanying shocks have ceased. The result helps to explain why THC has been found in other research to impair memory, but it also points to CB1’s role in regulating the response to fear, trauma and anxiety.
The researchers conducting the Nature study also found that an experimental drug, SR141716A, produced the same unending-fear effect in normal mice by blocking their brains’ CB1 receptors. This CB1-blocking drug, renamed rimonabant, was marketed as an appetite suppressant, because its action on CB1 is the opposite of THC’s tendency to bring on the “munchies” in cannabis users. Last June an FDA-sponsored committee of experts voted to ban rimonabant from U.S. markets over concerns that its CB1-blocking action increased the risk of suicidal thoughts, depression, seizures and other adverse psychiatric events.
By contrast, drugs such as THC that boost rather than block CB1 activity are being looked at as promising treatments for anxiety and depression. “When you give THC in the laboratory, the vast majority of patients report a calming or an anxiolytic [anxiety-relieving] feeling,” says psychiatrist Luan Phan of the University of Michigan.
In the Journal of Neuroscience on March 5, Phan and his colleagues reported a study of 16 recreational marijuana users and the effects of THC on their fear responses. When the subjects were shown standard images used in fear-induction tests, functional magnetic resonance imaging scans revealed that those given THC, compared with a group that received a placebo, had significantly lower levels of activity in the amygdala—a brain center that is loaded with CB1 receptors and known to light up during threats or anxiety.
The amygdala’s response in fear tests tends to be exaggerated in people who have anxiety disorders, says Phan. “So this result adds to the data showing that CB1 receptors would be a potential target for novel treatments in anxiety.”
THC itself is very unlikely to constitute such a treatment. Aside from its potential addictiveness, says Goldberg, “it interferes with learning and memory. It interferes with judgment. It’s not a drug that can be used as an anxiolytic [without] side effects.” That’s because THC binds to cannabinoid receptors (including CB2) throughout the body, not just in the amygdala. “So you get this real hodgepodge of effects,” he says.
One of THC’s more notorious side effects is to cause anxiety in some cases. In animal experiments, Goldberg says, this “anxiogenic” effect generally depends on the dose and the environment.
In humans, it seems also to depend on the individual brain. “If you and I are relatively normal, we’re going to react differently than someone who’s coming to that drug and is depressed,” says Richard Deyo, a cannabinoid researcher at Winona State University in Minnesota. Human studies can fail to find these paradoxical reactions “because they typically exclude people with psychiatric disorders, for liability reasons,” he says.
Deyo’s lab performs research for GW Pharmaceuticals, a U.K.-based company that specializes in the development of compounds affecting the cannabinoid system. He says he’s obliged not to discuss much of his work publicly. “What I can say is that we’re trying to see if there’s anything therapeutic in other [non-THC] cannabinoids. And we’re having some success. We’re finding some that have anxiolytic properties; we’re finding some that have antidepressant properties.”
Unexpectedly, Deyo’s animal experiments have revealed gender-related differences in how the brain responds to these compounds.
“We’re finding that some of the cannabinoids we have don’t seem to have any effects in female mice, but have very potent effects in male mice, and vice versa,” he says.
Hints of such gender-based responses can be found in the literature on cannabis abuse by humans, Deyo says: “In females, you’re more likely to get an anxiety reaction than you are in males. And in males you’re more likely to get a depression reaction.” Similar differences, he notes, are often seen in the manifestation of depression itself, with men tending to act out aggressively and women tending to become more withdrawn. “We’re working on the idea that this reflects a difference in the brain chemistry,” Deyo says.
Many pharmaceutical companies are trying to discover or invent drugs that bind to CB1. But Goldberg and others favor a different approach to CB1, developed recently by UC-Irvine pharmacologist Daniele Piomelli and colleagues.
“Rather than lighting up every CB1 receptor in the body” with a CB1-binding compound, the new approach aims to boost the activity of the body’s own “endocannabinoids,” and only where they are needed, Goldberg says.
The best known of these endocannabinoids, anandamide, is a fat-derived molecule secreted from a variety of cells as they become very active. “Whenever the body needs it released, it’s synthesized and released rapidly, so it doesn’t stay around long,” Goldberg says. “It’s broken down by a specific enzyme called fatty acid amide hydrolase [FAAH]. And there are drugs that almost all the big drug companies are developing right now that block this enzyme.”
The FAAH-inhibition concept is similar to that of Prozac and other antidepressants that inhibit the reuptake of serotonin from brain synapses. When anandamide’s breakdown is slowed, it stays active longer, but “only in those brain areas where it’s being specifically synthesized and released at that moment,” Goldberg says. In principle, then, the side effects should be minimized.
The approach is working well so far in animal tests. Goldberg says the FAAH inhibitors “seem to produce nice, anxiolytic, antidepressant and analgesic effects without producing any of the characteristic abuse-related, memory-altering effects of cannabinoids.”
Goldberg has been working with one such enzyme blocker, URB-597, which was developed by Piomelli’s lab and is now licensed to Organon, a unit of Schering-Plough. “We’ve been looking at this compound in monkeys in terms of abuse liability, and under no situation does it do anything that would be a problem,” he says.
URB-597 is about to enter initial trials in humans for analgesia, although it is expected to also be tested in people who have depression or anxiety disorders.
In general, Goldberg sees a bright future for drugs that can appropriately activate the cannabinoid system. “Cannabinoids [in marijuana] have protective effects for neurodegeneration, cardiovascular effects, they have a whole range of effects that clinically are potentially wonderful, except that you’ve got these offsetting side effects. And you may be able to get away from the side effects by enhancing the body’s own production of endocannabinoids, rather than giving a cannabinoid.”