Neurology Center

Two recent papers have provided strong evidence that the brain's endocannabinoid system is dysfunctional in Huntington's Disease, paving the way to possible new treatments.

Huntington's Disease is a genetic neurological disorder. Symptoms generally appear around age 40, and progress gradually from subtle movement abnormalities to dementia and complete loss of motor control. It's incurable, although medication can mask some of the symptoms. Singer Woodie Guthrie is perhaps the disease's best known victim: he ended his days in a mental institution.

The biology of Huntington's is only partially understood. It's caused by mutations in the huntingtin gene, which lead to the build-up of damaging proteins in brain cells, especially in the striatum. But exactly how this produces symptoms is unclear.

The two new papers show that cannabinoids play an important role. First off, Van Laere et al used PET imaging to measure levels of CB1 receptors in the brain of patients in various stages of Huntington's. CB1 is the main cannabinoid receptor in the brain; it responds to natural endocannabinoid neurotransmitters, and also to THC, the active ingredient in marijuana.

They found serious reductions in all areas of the brain compared to healthy people, and interestingly, the loss of CB1 receptors occurred early in the course of the disease:

That was an important finding, but it didn't prove that CB1 loss was causing any problems: it might have just been a side-effect of the disease. Now another study using animals has shown that it's not: Blazquez et al. They studied mice with the same mutation that causes Huntington's in humans. These unfortunate rodents develop Huntington's, unsurprisingly.

They found that Huntington's mice who also had a mutation eliminating the CB1 receptor suffered more severe symptoms, which appeared earlier, and progressed faster. This suggests that CB1 plays a neuroprotective role, which is consistent with lots of earlier studies in other disorders.

If so, drugs that activate CB1 - like THC - might be able to slow down the progression of the disease, and indeed it did: Huntington's mice given THC injections stayed healthier for longer, although they eventually succumbed to the disease. Further experiments showed that mutant huntingtin switches off expression of the CB1 receptor gene, explaining the loss of CB1.

This graph shows performance on the RotaRod test of co-ordination: mice with Huntington's (R6/2) got worse and worse starting at 6 weeks of age (white bars), but THC slowed down the decline (black bars). The story was similar for other symptoms, and for the neural damage seen in the disease.

They conclude that:

Altogether, these results support the notion that downregulation of type 1 cannabinoid receptors is a key pathogenic event in Huntington’s disease, and suggest that activation of these receptors in patients with Huntington’s disease may attenuate disease progression.

Cannabinoid Receptor, Type 1 (CB1) antagonists were supposed to be the next big thing.

They're weight loss drugs, and with obesity rates rising and the diet craze showing no signs of abating, that's a large and growing market (...sorry). They worked, at least in the short term, and they were at least as effective as existing pills. They may even have had health benefits over and above promoting weight loss, such as improving blood fat and sugar levels through metabolic effects.

It all started off well. Rimonabant, manufactured by Sanofi, was the first CB1 antagonist to become available for human use: it hit the European market in 2006, as Acomplia. Four large clinical trials showed convincingly that it helped people lose weight. Rival drug companies were hard at work developing other CB1 antagonists, and inverse agonists (similar, but even more potent). The "bants" included Merck's taranabant, Pfizer's otenabant, and more.

Even more excitingly, there were indications that CB1 antagonists could do more than help people lose weight: they might also be useful in helping people quit smoking, alcohol or drugs. The animal evidence that CB1 antagonists did this was strong. Human trials were underway. Optimists saw rimonabant and related drugs as offering something unprecedented: self-control in a pill, abstinence on demand.

When you smoke pot, you get stoned.
Simple. But it's not really, because stoned can involve many different effects, depending upon the user's mental state, the situation, the variety and strength of the marijuana, and so forth. It can be pleasurable, or unpleasant. It can lead to relaxed contentment, or anxiety and panic. And it can feature hallucinations and alterations of thinking, some of which resemble psychotic symptoms.

In Central nervous system effects of haloperidol on THC in healthy male volunteers, Liem-Moolenaar et al tested whether an antipsychotic drug would modify the psychoactive effects of Δ9-THC, the main active ingredient in marijuana. They took healthy male volunteers, who had moderate experience of smoking marijuana, and gave them inhaled THC. They were pretreated with 3 mg haloperidol, or placebo.

They found that haloperidol reduced the "psychosis-like" aspects of the marijuana intoxication. However, it didn't reverse the effects of THC of cognitive performance, the sedative effects, or the user's feelings of "being high".

This makes sense, if you agree with the theory that the psychosis-like effects of THC are related to dopamine. Like all antipsychotics, haloperidol blocks dopamine D2 receptors, and increased dopamine transmission has long been implicated in psychosis; some studies have found that THC causes increased dopamine release in humans (although others have not.)

Heavy marijuana use probably raises the risk of psychotic illnesses, like schizophrenia, although this is still a bit controversial, but it's accepted that some people do experience psychotic-type symptoms while stoned. So Liem-Moolenaar et al's conclusion that "psychotic-like effects induced by THC are mediated by dopaminergic systems" while the other aspects of being stoned are mediated by other brain systems, is not unreasonable, and this study is a nice example of the 'pharmacological dissection' of drug effects.

Still, like most papers of this kind, this leaves me wanting to know more about the subjective effects experienced by the volunteers. What did it feel like to get stoned on haloperidol? The paper tells us that

THC caused a significant increase of 2.5 points in positive PANSS, which was significantly reduced by 1.1 points after pre-treatment with haloperidol... Haloperidol completely reversed THC-induced increases in ‘delusions’ and ‘conceptual disorganization’ and almost halved the increase in ‘hallucinatory behaviour’. Although not statistically significant, haloperidol seemed to increase the items ‘conceptual disorganization’, ‘suspiciousness/persecution’ and ‘hostility’ compared with placebo.

Every stoner knows about the munchies, the fondness for junk food that comes with smoking marijuana. Movies have been made about it.

It's not just that being on drugs makes you like eating: stimulants, like cocaine and amphetamine, decrease appetite. The munchies are something specific to marijuana. But why?

New research from a Japanese team reveals that marijuana directly affects the cells in the taste buds which detect sweet flavours - Endocannabinoids selectively enhance sweet taste.

Yoshida et al studied mice, and recorded the electrical signals from the chorda tympani (CT), which carries taste information from the tongue to the brain.

They found that injecting the mice with two chemicals, 2AG and AEA, markedly increased the strength of the signals produced in response to sweet tastes - such as sugar, or the sweetener saccharine. However, neither had any effect on the strength of the response to other flavours, like salty, bitter, or sour. Mice given endocannabinoids were also more eager to eat and drink sweet things, which confirms previous findings.

2-AG and AEA are both endocannabinoids, an important class of neurotransmitters. Marijuana's main active ingredient, Δ9-THC, works by mimicking the action of endocannabinoids. Although Δ9-THC wasn't tested in this study, it's extremely likely that it has the same effects as 2-AG and AEA.

In follow-up experiments, Yoshida et al found that endocannabinoids enhance sweet taste responses by acting on cannabinoid type 1 (CB1) receptors on the tongue's sweet taste cells themselves. In fact, over half of the sweet receptor cells expressed CB1 receptors!

This is an important finding, because CB1 receptors are already known to regulate the pleasurable response to sweet foods (amongst other things) in the brain. These new data don't challenge this, but suggest that CB1 also modulates the most basic aspects of sweet taste perception. The munchies are probably caused by Δ9-THC acting at multiple levels of nervous system.

This paper also sheds light on CB1 antagonists. Given that drugs which activate CB1 make people eat more, it would make sense if CB1 blockers made people eat less, and therefore lose weight, a kind of anti-munchies effect. And indeed they do. Which is why rimonabant, a CB1 antagonist, was released onto the market in 2006 as a weight loss drug. It worked pretty well, although unfortunately it also it caused clinical depression in some people, so it was banned in Europe in 2008 and was never approved in the USA for the same reason.

The depression was almost certainly caused by antagonism at CB1 receptors in the brain, but Yoshida et al's findings suggest that a CB1 antagonist which didn't enter the brain, and only affected peripheral sites such as the taste buds, might be able to make people less fond of sweet foods without causing the same side-effects. Who knows - in a few years you might even be able to buy CB1 antagonist chewing gum to help you stick to your diet...

Yoshida, R., Ohkuri, T., Jyotaki, M., Yasuo, T., Horio, N., Yasumatsu, K., Sanematsu, K., Shigemura, N., Yamamoto, T., Margolskee, R., & Ninomiya, Y. (2009). Endocannabinoids selectively enhance sweet taste Proceedings of the National Academy of Sciences, 107 (2), 935-939 DOI: 10.1073/pnas.0912048107

Why do some people get addicted to things? As with most things in life, there are lots of causes, most of which have little, if anything, to do with genes or the brain. Getting high or drunk all day may be an appealing and even reasonable life choice if you're poor, bored and unemployed. It's less so if you've got a steady job, a mortgage and a family to look after.

On the other hand, substance addiction is a biological process, and it would be surprising if genetics did not play a part. There could be many routes from DNA to dependence. Last year a study reported that two genes, TAS2R38 and TAS2R16, were associated with problem drinking. These genes code for some of the tongue's bitterness taste receptor proteins - presumably, carriers of some variants of these genes find alcoholic drinks less bitter, more drinkable and more appealing. Yet most people are more excited by the idea of genes which somehow "directly" affect the brain and predispose to addiction. Are there any? The answer is yes, probably, but they do lots of other things beside cause addiction.

A report just published in the American Journal of Medical Genetics by Argawal et. al. (2008), found an association between a certain variant in the CNR1 gene, rs806380, and the risk of cannabis dependence. They looked at a sample of 1923 white European American adults from six cities across the U.S, and found that the rs806380 "A" allele (variant) was more common in people with self-reported cannabis dependence than in those who denied having such a problem. A couple of other variants in the same gene were also associated, but less strongly.

As with all behavioural genetics, there are caveats. (I've warned about this before.) The people in this study were originally recruited as part of an alcoholism project,COGA. In fact, all of the participants were either alcohol dependent or had relatives who were. Most of the cannabis-dependent people were also dependent on alcohol. However, this is true of the real world as well, where dependence on more than one substance is common.

The sample size of nearly 2000 people is pretty good, but the authors investigated a total of eleven different variants of the CNR1 gene. This raises the problem of multiple comparisons, and they don't mention how they corrected for this, so we have to assume that they didn't. The main finding does corroborate earlier studies, however. So, assuming that this result is robust, and it's at least as robust as most work in this field, does this mean that a true "addiction gene" has been discovered?

Well, the gene CNR1 codes for the cannabinoid type 1 (CB1) receptor protein, the most common cannabinoid receptor in the brain. Endocannabinoids, and the chemicals in smoked cannabis, activate it. Your brain is full of endocannabinoids, molecules similiar to the active compounds found in cannabis. Although they were discovered just 20 short years ago, they've already been found to be involved in just about everything that goes on in the brain, acting as a feedback system which keeps other neurotransmitters under control.

So, what Argawal et. al. found is that the cannabinoid receptor gene is associated with cannabis dependence. Is this a common-sense result - doesn't it just mean that people whose receptors are less affected by cannabis are less likely to want to use it? Probably not, because what's interesting is that the same variant in the CNR1 gene, rs806380, has been found to be associated with obesity and dependence on cocaine and opioids. Other variants in the same gene have shown similar associations, although there have been several studies finding no effect, as always.

What makes me believe that CNR1 probably is associated with addiction is that a drug which blocks the CB1 receptor, rimonabant, causes people to lose weight, and is also probably effective in helping people stop smoking and quit drinking (weaker evidence). Give it to mice and they become little rodent Puritans - they lose interest in sweet foods, and recreational drugs including alcohol, nicotine, cocaine and heroin. Only the simple things in life for mice on rimonabant. (No-one's yet checked whether rimonabant makes mice lose interest in sex, but I'd bet money that it does.)

So it looks as though the CB1 receptor is necessary for pleasurable or motivational responses to a whole range of things - maybe everything. If so, it's not surprising that variants in the gene coding for CB1 are associated with substance dependence, and with body weight - maybe these variants determine how susceptible people are to the lures of life's pleasures, whether it be a chocolate muffin or a straight vodka. (This is speculation, although it's informed speculation, and I know that many experts are thinking along these lines.)

What if we all took rimonabant to make us less prone to such vices? Wouldn't that be a good thing? It depends on whether you think people enjoying themselves is evidence of a public health problem, but it's worth noting that rimonabant was recently taken of the European market, despite being really pretty good at causing weight loss, because it causes depression in a significant minority of users. Does rimonabant just rob the world of joy, making everything else less fun? That would make anyone miserable. Except for neuroscientists, who would look forward to being able to learn more about the biology of mood and motivation by studying such side effects.

Arpana Agrawal, Leah Wetherill, Danielle M. Dick, Xiaoling Xuei, Anthony Hinrichs, Victor Hesselbrock, John Kramer, John I. Nurnberger, Marc Schuckit, Laura J. Bierut, Howard J. Edenberg, Tatiana Foroud (2008). Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 9999B DOI: 10.1002/ajmg.b.30881