What's your anti-drug? Well, it might well be hemopressin. At least, that's probably your anti-marijuana.

Hemopressin is a small protein that was discovered in the brains of rodents in 2003: its name comes from the fact that it's a breakdown product of hemoglobin and that it can lower blood pressure.

No-one seems to have looked to see whether hemopressin is found in humans, yet, but it seems very likely. Almost everything that's in your brain is in a mouse's brain, and vice versa.

Pharmacologically, hemopressin's literally an anti-marijuana molecule: it's an inverse agonist at CB1 receptors, which are the ones targeted by the psychoactive compounds in marijuana, and also by the neurotransmitters known as endocannabinoids. Cannabinoids turn CB1 receptors on, hemopressin turns them off.

Artificial CB1 blockers were developed as weight loss drugs, and one of them, rimonabant, made it onto the market - but it was banned after it turned out that it caused depression and anxiety in many people.

So hemopressin is Nature's rimonabant: in which case, it ought to do what rimonabant does, which is to reduce appetite. And indeed a Journal of Neuroscience paper just out from Godd et al shows that it does just that, in rats and mice: injections of hemopressin reduced feeding.

Interestingly, this worked even when it was injected by the standard route under the skin - many proteins can't enter the brain if they're given this way, because they can't cross the blood-brain barrier, meaning that they have to be injected directly into the brain, which makes researching them much harder. So hemopressin, with any luck, will be pretty easy to study. Any volunteers for the first human trial...?

Dodd, G., Mancini, G., Lutz, B., & Luckman, S. (2010). The Peptide Hemopressin Acts through CB1 Cannabinoid Receptors to Reduce Food Intake in Rats and Mice Journal of Neuroscience, 30 (21), 7369-7376 DOI: 10.1523/JNEUROSCI.5455-09.2010

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

Previously I wrote about a small study finding that smoked marijuana helps with HIV-related pain. In the last month, two more clinical trials of medical marijuana - or rather, marijuana-based drugs - for pain have come out.

First, the good news. Johnson et al tested a mouth spray containing the two major psychoactive chemicals in marijuana, THC and CBD. Their patients were all suffering from terminal cancer, which believe it or not, is quite painful. Almost all of the subjects were already taking high doses of strong opiate painkillers: a mean of 270 mg morphine or equivalent each day, which is enough to kill someone without a tolerance. (A couple of them were on an eye-watering 6 grams daily). Yet they were still in pain.

Patients were allowed to use the cannabinoid spray as often as they wanted for 2 weeks. Lo and behold, the THC/CBD spray was more effective than an inactive placebo spray at relieving pain. The effect was modest, but statistically significant, and given what these people were going through I'm sure they were glad of even "modest" effects. A third group got a spray containing only THC, and this was less effective than the combined THC/CBD - on most measures, it was no better than placebo. THC is often thought of as the single "active ingredient" in marijuana, but this suggests that there's more to it than that. This was a relatively large study - 177 patients in total - so the results are pretty convincing, although you should know that it was funded and sponsored by GW Pharma, whose "vision is to the global leader in prescription cannabinoid medicines". Hmm.

It's always nice when a local boy makes good in the big wide world. Many British neuroscientists and psychiatrists have been feeling rather proud this week following the enormous amount of attention given to Professor David Nutt, formerly the British government's chief adviser on illegal drugs.

Formerly being the key word. Nutt was sacked (...write your own "nutsack" pun if you must) last Friday, prompting a remarkable amount of condemnation. Critics included the rest of his former organisation, the Advisory Council on the Misuse of Drugs (ACMD), and the Government's Science Minister. The UK's Chief Scientist also spoke in favour of Nutt's views. Journalists joined in the fun with headlines like "politicians are intoxicated by cowardice".

"The sacking of a government adviser on drugs shows Britain's politicians can't cope with intelligent debate... the position of the Labour government and of the leading opposition party, the Conservatives, which vigorously supported Nutt's sacking, has no merit at all. It deals a significant blow both to the chances of an informed and reasoned debate over illegal drugs, and to the parties' own scientific credibility."

"Where there is a clear and serious problem [i.e. cannabis health problems], but doubt about the potential harm that will be caused, we must err on the side of caution and protect the public. I make no apology for that. I am not prepared to wait and see."

"the precautionary principle - if you’re not sure about a drug harm, rank it high... at first sight it might seem the obvious decision – why wouldn’t you take the precautionary principle? We know that drugs are harmful and that you can never evaluate a drug over the lifetime of a whole population, so we can never know whether, at some point in the future, a drug might lead to or cause more harm than it did early in its use."