Ladies and gentlemen and distinguished guests, welcome to this Brain Awareness Week symposium on substance abuse and mental illness. My name is William Hart. I'm the Chief Executive of Neurosciences Victoria and it is my pleasure to give a very brief introduction and welcome.

Before I commence I wonder if I could ask everyone to check that their phones are turned off or on silent for the duration of the talks. Thank you very much. This week all over the world Brain Awareness Week events, such as this one, are being held sponsored internationally by the Dana Alliance in Europe and the Society for Neuroscience in the US. And in Australia we've currently got 36 partner organisations working together, joining forces with the Australian Neuroscience Society, the National Neuroscience Facility and the Brain Foundation in celebrating Brain Awareness Week. The aims of Brain Awareness Week are basically to raise awareness of brain and mind disorders such as dementia, stroke, addiction, schizophrenia - all these devastating illnesses which place such a huge burden on society, families, individuals and the community. This week there are 22 events, such as the one that is taking place here tonight, occurring around Australia registered on our website, which you'd be welcome to visit: brainaware.org.au.

This particular event here today is a partnership between the Addiction Neuroscience Network of Australia, ANNA, and the Mental Health Research Institute. It is an event which will explore the associations between substance abuse and mental illness including some of the brain pathways that underlie these conditions.

Now, ANNA is an Australia-wide network of scientists collaborating in the field of brain research as it relates to addiction. It was founded by scientists working here at the Howard Florey Institute initially assisted by a grant from the Humanity Foundation in Western Australia thanks to the work of ANNA's Chairman, Dr Michael Cohen, and then further supported by the Ross Trust through the work of Professor David Pennington.

I'd like to thank Dr L. E. Ohman, ANNA's Executive Officer for organising this event this evening - thanks L. E. for all your good work.

And it is now my great pleasure to introduce the host for the remainder of the event this evening, Professor George Fink, the Director of the Mental Health Research Institute, which is Australia's premier research institute in the field of mental health.

Professor Fink returned to Australia in 2003 to cap off an outstanding career in neuroscience which has included 20 years of leadership of the UK Medical Research Council's Brain Metabolism unit in Edinburgh and four years as Vice President for Research at Pharmos Corporation. He is a graduate in medicine from this university with a Doctor of Philosophy degree from Oxford. His research contributions have been reported in more than 350 scientific publications. George was President of the European Neuroendocrine Association from 1991 to 1995, he was elected Fellow of the Royal Society of Edinburgh in '89, Fellow of the Royal College of Physicians of Edinburgh in '98 and was honoured with a 2000 Lifetime Achievement Award of the International Society of Psycho?Neuroendocrinology. Could you join me in welcoming Professor George Fink.

Well thanks very much indeed for those very kind and surprising remarks William. In fact, I was looking around for this George Fink until I realised you were talking about me, but it is a pleasure to be here and I'm most grateful to you all for turning up to this meeting which I'm sure is going to be exciting. I'm not going to be holding you up with any lengthy discussion. I want to get straight to the heart of the matter and let our four young lions get out here and tell you all about addiction. But I do wish to echo the remarks made by William about L. E. Ohman's sterling work in getting this meeting together and we are most grateful to her for leading us to this important junction.

Now addiction, as you all know otherwise you wouldn't be here, is a serious illness and costs Australia many billions. In fact, the figures are well over $20 billion per year. In addition to affecting people with what we might call pure addiction - there isn't such a thing as just pure addiction - but there are many concerns regarding what is called co?morbid disorder. That is, people with other psychiatric or, for that matter, non-psychiatric conditions becoming addicted to drugs. One of the questions we've got to ask ourselves is why do people get addicted? Is there a moral issue or is there a subjective issue to that? My personal view, and I think that of most of scientists is that the answer is no, that there is good evidence that there is a biological basis for addiction. That is to say the brain has what is called a reward area which was discovered about 30 years ago by studies on rats which showed very clearly that this reward area contains certain receptors and certain mechanisms which make the brain keen to return to the addictive drug or the addictive substance. Another thing that needs to be stressed is that a lot of the drugs that people become addicted to are dried from plants, and one needs to think only for a moment to realise that the plants - such as poppies, cocoa leaves, opium and Cannabis sativa which produces cannabis -are not aware of the existence of the human brain as far as we know, and the human brain actually doesn't need to be aware of those particular plants. The reason for the addiction is that the brain happens to have, for reasons probably based on statistical events purely by chance, structures called receptors which bind compounds from the outside in a lock and key fashion. And so we have an addictive phenomenon developing which is not necessarily the fault of the individual. Now it is possible to try to train people out of this habit but we do know that in certain situations, for example the benzodiazepines, that there is a proportion of the community that is probably genetically predisposed - somewhere in the order of 30 per cent in the case of the benzodiazepines - to becoming addicted to that particular drug.

Finally, does addiction have any useful role to play in the physiology and behaviour of man? The answer is we don't actually know. There are all sorts of theories about this. Some people talk about food or feeding behaviour as being equivalent to addictive behaviour, others talk about sex as being an addictive behaviour. In fact, if one looks at that carefully, it doesn't actually make a lot of physiological or pharmacological sense because one of the key features of addiction, particularly to a drug or to an exogenous substance -a substance from outside the body - is that tolerance usually develops very quickly. That is to say the person needs to take more and more, larger and larger doses of the drug. Now fortunately, except in odd people like myself, that does not apply to feeding behaviour. Most people tend to have a homeostatic system that prevents them from overeating. Whereas in the case, say, of opium addiction, heroin addiction, cannabis addiction, tolerance does develop which means that there is an ever increasing need for higher and higher doses.

Okay, that is just by way of introduction. Let me, without further ado, introduce the first speaker, Dr Dan Lubman the Senior Lecturer in Addiction Psychiatry at The University of Melbourne. He heads the Substance Use Research and Recovery Focus Program at ORYGEN Research Centre where he leads a clinical research team focused on investigating substance use and co-morbidity in youth, and drinking in adolescents and young adults. This work includes the exploration of the impact of substance use on the adolescent brain and its development. Dr Lubman has lectured widely on these topics and is distinguished both nationally and internationally for his work in this area. So we look forward, Dan, to your talk on substance use and mental illness, unravelling co-morbidity. Dan Lubman.

Thanks very much George, and thanks very much again for L. E. for organising this great event. In the next 15 to 20 minutes I'm going to talk to you about some of the issues we're trying to look at in terms of the relationship between substances and mental illness.

I suppose one of the reasons many of us are here is because for many decades now the association between substance use and mental illness has been a controversial one. One of the areas highlighted is the relationship between cannabis and psychosis, and this has been an argument that's been going on for many years. But more recently other questions are beginning to arise: the relationship with cannabis and depression, the relationship between alcohol and depression, which is something that Andy's going to be talking about. One of the things we're trying to really understand now in neuroscience is the relationship between substance use and mental health issues, because we know the two of them intertwine very closely.

What do we know clinically about different substances? Clinically, people who have alcohol-related problems often present with depression and anxiety, and in times of withdrawal they can often present with psychotic phenomena. In terms of cannabis, clinically we see people presenting with symptoms of depression, with symptoms of psychosis and also with some cognitive problems. In terms of inhalants, we know clinically that young people who inhale often present with depression, anxiety and they can present with episodes of psychosis or manic behaviour. In terms of psychostimulants such as cocaine, people who abuse cocaine regularly can present with marked depression, with psychotic disorders, and also with anxiety disorders. Similarly with amphetamine, and more recently methamphetamine, people are presenting with depression, anxiety and psychotic features. And more recently the more potent form of methamphetamine, the crystal methamphetamine, is much more associated with psychotic disturbances, aggression and violence. And finally ecstasy, which has been associated with depression and anxiety disorders, particularly panic disorder, is associated with a number of mental health conditions. What is interesting, I suppose, is we now know that ecstasy worldwide and locally contains a lot of methamphetamine, so many of the symptoms we see that are attributed to ecstasy use are actually occurring because the user is also taking methamphetamine.

Now if we are to go to the community and try to work out the relationship between people who abuse substances and mental health, we can look at what the odds are, the likelihood of having a drug-use problem and developing a mental health problem. The 1997 national survey of mental health and wellbeing looked at over 10,000 Australians who are representative across Australia in different states. It found that in an alcohol dependent population the likelihood of having a co?morbid depressive disorder was between four and five times as high as the general population. So those who abuse alcohol and have alcohol dependence are four or five times more likely to also have co?morbid depression. For those dependent on cannabis risk of developing co-morbid depression was two or three times greater, and cigarette smokers have up to two times increased risk of highly depressive disorder.

In terms of anxiety disorders, someone with alcohol dependence is four to five times more likely to have an anxiety disorder, and similarly, an anxiety disorder is four times more likely to occur in a person with cannabis dependence than in the general population. A smoker has between two and three times the risk of having a co?morbid anxiety disorder.

And finally for psychosis; this study wasn't able to look at a strict criteria for psychotic disorders per se and they used people who screened positively to some symptoms of psychosis. What is really interesting here is that in terms of alcohol dependence, the likelihood of reporting psychotic symptoms is in the order of six times as high. For cannabis, up in the order of 10 to 11 times as high and for smoking, between four and five times as high. We are most likely seeing this in smoking because people with psychotic disorders have incredibly high rates of smoking behaviour. Between 90 per cent and 95 per cent of people with a chronic psychotic disorder smoke and they smoke really heavily and so, because smoking is actually decreasing in the community a high rate of smoking is often associated with psychosis. But what these figures indicate is that being dependent on alcohol, cannabis or smoking is associated with high degrees of likelihood of having a co?morbid mental disorder.

The question at ANNA is, why do people with co?morbid mental health and substance use disorder use drugs? Studies that have looked subjectively at why people report that they use drugs come up with a whole list of reasons. One of the most common reasons is, just like the general community, people use to feel good. Using drugs makes you feel good, it makes you relax, it makes you have euphoric feelings. People with mental health problems, co?morbid problems, use substances for generally the same reasons as the general population. People often use them to cope, and when they say to cope it is mainly to cope with dysphoric feelings - feeling pretty crappy, feeling quite negative, feeling distressed, feeling anxious - that is why people use substances.

Often people with mental health problems have difficulty interacting socially and they use substances to help overcome that anxiety. They use the substance as an anxiolytic to calm anxiety and to help engage in peer relationships. Another reason for using is that it can help a person be accepted into a peer group, especially in young people where experimental substance use is pretty common. So it can help gain acceptance into a peer group.

One big factor, especially for young people with mental health problems and substance use problems, it is better to be a young drug user with mental health problems than a patient with mental illness and substance use problems because if you're a drug user with mental health problems it means that if you actually stop using drugs the mental health symptoms go away. So often people can get caught up in this trap saying that the mental health symptoms are mainly related to using substances and sort of denying what is actually going on for them.

Some groups of people use drugs to actually cause damage to themselves, to harm themselves.

The last category is time management. Often if a young person is disenfranchised, has got mental health problems and there are no vocational activities or work for them, there is not much to do. Using drugs and using drugs with friends takes up the day and fills that gap. So when we think about the treatments that are going to be effective for people with co?morbid mental health and substance abuse problems, we need to think about what we're going to replace when we ask people to stop using drugs.

Those are the subjective reasons people give for using drugs. But what are the objective consequences for people with co?morbid mental health and substance use problems? We know that mental health symptoms get worse with substance abuse in people who have psychiatric symptoms. Substance use in patients with mental health disorders is associated with problems in cognition, and problems with thinking, planning, and judgment make their cognitive function worse. Obviously, using a lot of drugs, especially if you're not working, causes financial difficulties, unemployment and homelessness. It obviously causes increased conflict in families when people are already coping with difficulties in that setting. People are less likely to be treatment compliant, they are less likely to take medication and less likely to turn up for appointments, and less likely to engage in therapy. That leads to increased rates of relapse, hospitalisation and use of emergency services. People with co?morbid disorders tend to not come to the nine-to-five services that we offer but tend to present in crisis to either community crisis assessment teams or to emergency departments. People who have mental health problems and use a lot of substances are more likely to be violent, engage in criminal behaviour and end up in the prison system. Using drugs when you also have a number of other problems leads to increase risk behaviour. Risky behaviour, risky injecting practice and risky sexual behaviour can lead to increased rates of Hep B, C and HIV. And overall that leads to early mortality amongst this group and increased rates of suicide. In fact, co?morbid patients as a whole do very poorly in standard treatment settings and have a much worse prognosis than people just with one mental health disorder or a substance use problem.

To see what is happening from a youth perspective, we can look at some of the patients we are seeing at ORYGEN. For people who don't know, ORYGEN Youth Health is a public mental health service that treats people aged 15 to 25 in the North and Western suburbs of Melbourne. We have a catchment area of about one million people and we get about 2,000 referrals each year.

A study conducted by Alison Young and colleagues at ORYGEN looked at young people presenting with non-psychotic disorders. Which means people presenting with depression, anxiety or eating disorders. They were interested in looking at how that impacts on functioning. What I'm going to present to you here is the rates of substance use in young people, average age 17 presenting to ORYGEN for treatment of distress, for depressive and anxiety symptoms. I've compared it against stats from the National Household Drug Survey which looks at Australians aged 14 and over within the wider community. People presenting to our service have higher rates of smoking daily, up to 50 per cent, increased rates of cannabis use, amphetamine use, ecstasy use, inhalant use, heroin use and IV drug use. So over the whole range of drugs and the whole range of administration of drugs, we are seeing much higher rates in the population presenting with distress than seen in the general population. It is also interesting that the young people presenting to ORYGEN use drugs at a much earlier age. So across the whole range of drugs, they are using a whole variety of drugs and they are using them well before they present for services. For us at ORYGEN that raises the question of what is the relationship between early substance use and later mental health symptoms, and what is the nature of that relationship.

If we then go to the psychotic population, between 1998 and 2000 ORYGEN saw about 780 young people with first episode psychosis. Philippe Conus and Martin Lambert at ORYGEN went back to the case records and looked at how the prevalence of substance use in that population related to outcomes. They were able to examine 668 medical files and found that only 39 per cent had no substance use disorder. So less than 40 per cent of people presenting with psychosis to ORYGEN didn't have a co-morbid substance use problem. In fact, the majority at 61 per cent had a co-morbid substance use problem. So when people present to a service with psychosis, it is actually the norm to have a co?morbid drug and alcohol problem compared to not having a drug and alcohol problem. Within that 60 per cent, the majority were using cannabis, about 11 per cent were using a range of substances and didn't really have a predilection for one, three per cent using opium, three per cent using alcohol and three per cent using amphetamine. The other thing to say is that about a third of this population were abusing or dependent on another drug, so it wasn't that they were just solely using cannabis, often the most common interaction was cannabis plus alcohol.

To reiterate, there were high rates of substance use in this population, and the records showed that people didn't start using drugs once they became psychotic they were using drugs four to six years prior to the onset of psychotic symptoms. So, again, early use of substances is related to later psychotic symptoms and we're still trying to understand what the nature of that relationship is.

Now, I want to touch on the brain because that is what we're here to talk about. Until very recently we thought that the brain was a pretty static organ. We used to think that between the ages of five and 10 the brain reached its maximal size and didn't grown anymore and that was it, that is all you had for life. We now know that the brain is constantly being remodelled throughout adolescence. When you're born you have a series of nerve cells in the brain and a number of connections. All the stimulation that is going on around you in the first five to six years of life leads to a proliferation of nerve cells and neurons within the brain and a proliferation of connections. We now think that the brain is completely remodelled in adolescence to get rid of all the useless connections and reinforce the really strong connections. The adolescent period is about making sure that the most important neurones, the optimal nerve cells, are connecting with each other and talking to each other. That means that adolescence is a time of incredible opportunity where we can learn a lot of new things, but because of these changes within the brain, adolescence is also a time of vulnerability. Only now are we beginning to tease out the effects of adolescent substance use on the brain during this period of marked changes within the brain.

What we know about alcohol, for example - which is again incredibly recent data - is that adolescents and adults have a very differential response to alcohol. For example, young people can drink a lot of alcohol and can stay awake and dance all night long. When older people drink alcohol they fall over and fall asleep. I used to think that was just because I was getting older and I couldn't take it anymore, but it is because alcohol has a very different affect in adults and adolescents. This has been shown rigorously in animal experiments. If you give adolescent an adult animals a lot of alcohol, you find that the adolescent animal is not as affected by the motor incoordination and that set of properties of alcohol. That means young people can actually drink a hell of a lot more without having the negative consequences. We are now beginning to understand that there are negative consequences, but they are really subtle and hard to see. We know that adolescents are much more vulnerable to the neurotoxic properties of alcohol. Alcohol significantly affects areas of the brain that are involved in mental health disorders in adolescent animals, whereas the same amount of alcohol doesn't produce those changes in an adult.

Debellis and colleagues from the States looked at adolescents who had only experimented with alcohol, never used it heavily, compared to a group of adolescents who had alcohol-related disorders and used it problematically. They found that an area of the brain called the hippocampus is much smaller in the adolescents who abused alcohol than in those who didn't. That is important because the hippocampus has been implicated in a number of mental health conditions such as depression and psychosis. This indicates that alcohol has some affects on the brain that may relate to why we are seeing increased rates of psychopathology in that population, although the nature of that relationship really needs a lot more work.

If we look at smoking, we know that it is much harder for people who started smoking as an adolescent to give it up than it is for those who started as an adult. So smoking at a younger age is associated with much longer and more intense levels of use. If we then go the animal literature, we find that it is really hard to make adult animals take nicotine. Adult animals don't like taking nicotine. Unlike other drugs, they won't work to get a dose of nicotine, and the only way we can get adult animals to work for it is to make them dependent first. However, adolescent rodents find nicotine incredibly rewarding and reinforcing and they work very hard to get nicotine, which seems to map a bit with the human experience. Whereas if you don't start smoking by the time you've finished adolescence, you're unlikely to pick up smoking as an adult. If we give high doses of nicotine to adult animals, we don't really see any brain changes. In an elegant set of experiments, Slotkin and colleagues in the States, have been able to show that regular doses of nicotine in adolescent animals causes damage to brain regions implicated in mental illness, the frontal part of the brain that Murat is going to talk about, and the hippocampal regions.

To summarise, there seem to be high rates of substance use in people with mental health problems and we now know that substance abuse during adolescence may affect the development of brain areas implicated in those disorders.

To finish, I'd like to tie this up and give you a model for thinking about the relationship, or the interaction, between substance use and mental health symptoms. Mental health symptoms can cause substance use for self medication. People self medicate with drugs to try to manage mental health symptoms, and there has been a lot of people talking about how different populations of psychiatric patients use different substances to try to manage their mental health symptoms. And that seems to be largely untrue. The people with mental health problems tend to use substances for the same reasons and in the same amounts as people in the community. They tend to use substances that are widely available in the community just as anybody else would, and they don't seem to select specific substances per se although, again, more work is needed in that area. Generally, it doesn't matter if someone has psychosis, or depression, or anxiety, people tend to use substances to manage difficult, unpleasant feelings. If you're full of anxiety or feeling dysphoric or feeling that you've got a bad mood - people tend to use substances to manage that and they are not trying to manage the psychotic symptoms or the other symptoms that might go along with mental health conditions.

Substance use might cause mental health symptoms because it either precipitates or exacerbates symptoms in people who have vulnerability. We are now thinking that cannabis - in terms of its relationship to psychosis - might amass psychosis in people who are vulnerable. At least that is where the literature is pointing at the moment. We also know that in people with established psychotic disorders, cannabis actually makes the symptoms worse. In terms of secondary neurochemical changes - and again, this is something Murat is going to touch on - substance use might cause mental health symptoms because we know that intoxication, withdrawal and chronic use leads to changes within the brain, and it is not surprising that those changes can lead to psychological difficulties associated with mental health problems. So chronic use might cause changes in the brain that lead to mental health symptoms.

And finally, using substances causes a lot of social problems - unemployment, conflict and financial difficulties. Those social difficulties place people at risk of developing mental health problems. Social adversity puts one at risk of developing depression, and by virtue of the substance use problem, puts one at risk of developing mental health symptoms. However, both might be a component of an underlying disorder. So, for example, antisocial personality disorder puts you at risk of both developing a depressive disorder and other mental health disorders and also of developing a substance use disorder. Both may have similar risk factors that predispose to both disorders, so things like social adversity, trauma, abuse in childhood increases the risk of developing adolescent problems with substances and also increases the risk of developing later anxiety and depressive disorders. And finally, both are really common. They both might have independent aetiologies and just be coincident in the same person just because they are so common in the community.

The take home message is that any interaction is likely to be pretty complex and that is why it is really important to think about co-morbidity using complimentary methodologies and a number of viewpoints. And this evening we're going to be focusing more on what we know from brain research and how that informs us about the relationship between mental health and substance use.I'm going to finish there. Thank you.

Thanks George and thanks L. E. for organising all of this.

I'm going to talk about quite a controversial area of addiction in the next 15 or 20 minutes, that is, do people become addicted because they choose to, because of some kind of moral weakness or is it actually a disorder of the brain? I probably won't answer that question - but I will try to shed some light on it from the brain researcher's point of view and I'm going to do that by initially presenting a case scenario of somebody who starts experimenting with drugs and then ends up being addicted and highlight the stages that people can go through. Then I'm going to present some evidence to show that there are actually brain changes occurring toward the later stages of this process and show how that makes it very difficult for this person to disengage from addictive behaviour to the point that it may become compulsive for some.

The scenario starts off like this: it is about a young male who decides that he wants to experiment with an addictive drug like heroin and he says to himself, "I'll just try this once" or "I'll just try it again", and "it is just to get the experience of it, see what it is like". What ends up happening is that he likes the euphoric effects so much that over the next weeks and months he ends up using again and again and again, and it ends up becoming a habit. So now he find himself saying "I like to get a hit when I can, but it is okay if I can't too". Time goes by and the young man finds that he is using with increasing frequency and he also begins to realise that there are actually some negative consequences associated with drug use. Dan highlighted many of them and, just to reiterate, people abusing substances might find that they are spending lots of time and lots of money, that they are losing contact with their friends, there is family conflict, not to mention legal problems, and health problems, so on, so he decides that he really should stop. But by this stage, and the person is usually unaware of it, the exposure that the brain has had to these drugs has actually caused changes so that it now demands the drug, and the person is dependent. And our young man now finds himself saying "I know I should stop this but the urge is overwhelming, I need it". Again, more time goes by and the process continues - he has it again and again and the negative consequences escalate and despite his best intentions to quit because of the negative consequences, he continues to use. He is losing control of his behaviour, he is becoming compulsive. Now he finds himself saying "I feel compelled to use, I'm losing control" and he is now addicted.

This highlights how addiction is a chronic and relapsing disorder. It also shows how toward the end stages of this addictive process there are some brain changes going on that make it very difficult for the person to disengage from this behaviour.

But what is the evidence for this? What is the evidence that there are actual brain changes going on and that these changes actually promote or underpin this sense of an overwhelming desire to continue drug use or that they feel compelled or losing control of their behaviour?

There are core features of addiction at the later stages. The first core feature is the overwhelming urge or desire. What is happening at the level of the brain? Well we've known, as George said before, since the 1940s or 50s from animal studies that the brain has a very specialised circuitry called the reward circuit or the reward system. This system releases a chemical called dopamine, and dopamine is what gives us a sense of pleasure or happiness. Typically this system is designed to release dopamine when we engage in behaviours that promote the species survival or reproduction, things like eating, drinking, nurturing behaviour and having sex. All of these are natural rewards that stimulate the release of dopamine to give you a pat on the back to continue engaging in that behaviour. Drugs of abuse, addictive drugs, can powerfully capture this system so much so that the system then becomes selectively responsive to drugs and drug cues in the environment. This is what we think makes drug taking an intensely pleasurable experience. The euphoric effects are produced when dopamine floods the brain and it is coming from an external source. To cope with this flood of dopamine, the brain produces changes - chemical changes, physiological changes, genetic changes -to try to adapt and bring some sense of normality back into the system. And when the drug is taken away, the brain doesn't like that either, because now the system is changed and it is reliant on that external source of dopamine. We think that those two aspects of this euphoric experience together with the brain changes that occur underlie the overwhelming urge/drive that people report feeling.

These are changes in the reward system, but what else is occurring in the brain? What other changes are occurring? There are now probably over 1,000 papers in the scientific literature suggesting that exposure to drugs causes change at some level of brain functioning, so it is pretty strong. I'm going to very briefly review some of these studies from humans and, in order to make this easier, I've broken the brain and its properties into a few different areas and I'm going to review it with respect to these areas.

A couple of years ago a group looked at how MDMA, or ecstasy, abuse affected the grey matter of the brain. Now the grey matter is where all the nerve cells are; it is where processing and thinking actually occurs - it is the outer cortex. This group looked at the amount of grey matter in the brain in people who'd been abusing MDMA compared to people who had never used MDMA. They found that a number of key areas had reduced grey matter volume, suggesting that MDMA may affect this grey matter of the brain.

What about white matter? Now, white matter is the actual bits that connect those nerve fibres, it connects the grey matter where the processing occurs. It is the wiring in the system. And this is a process that, as Dan showed, continues throughout development into adolescence. In a study by Rosenberg, they looked at the affects of inhalants on the brain. Inhalants are one of the most toxic substances around. They are lipophilic so they get into the fat very quickly and there is a lot of fat in the brain. In fact, 50 per cent of the body weight is made of fat. Rosenberg and colleagues showed that inhalants actually get into the system and cause toxic affects in the brain. To illustrate this, this MRI scan shows one of the more dramatic cases. This is a top down bird's eye view of the brain and the skull would be around here and the black stuff that you see is the actual brain matter, the darker stuff is the white matter. The white is actually fluid in the brain. And what you see there is a normal looking adolescent brain. Now this is a case of a 25 year old who's been abusing inhalants for a while and immediately you can see this really big white, bright spot and that is fluid. The white matter that we would expect to see around these areas has been wasted or atrophied away and replaced by fluid, and that is likely to have a significant impact on this person's functioning. Remember that this person's 25 years old and in the prime of his life.

What about blood flow? We need blood flow to all parts of our body and brain to supply oxygen and nutrients. A study done in 2002, compared blood flow in methamphetamine users and people who never used methamphetamine. They found that methamphetamine users had both increases and decreases in blood flow in certain parts of the brain. The authors suggested this meant that those areas that showed increased blood flow are at risk of injury. That is, there is increased blood flow to these parts in order to try to protect or recover some injury that is occurred. Whereas the parts that showed decreased blood flow may be areas that have already gone through that process and have been injured.

And what about glucose metabolism? Glucose is the fuel source of the brain and we need it for all the processes that the brain is engaged in, and while the brain only weighs two to three per cent of our total body weight, it uses up almost 20 per cent of its total fuel. So it is very important that the brain gets this glucose and fuel. We can use brain imaging to measure glucose metabolism, as is shown in this PET scan. The red bits show where lots of energy is being utilised by this brain. The bits in the middle are where the fluid is - we don't expect to see red there. That is what a normal scan looks like. This is somebody who's been using cocaine and you can see that there is much less red and much more yellow indicating that this brain is not utilising energy nearly as efficiently. And it is thought that if destruction to glucose metabolism continues, and blood flow becomes inefficient, over the long term it can cause injury.

There are a lot of changes potentially going on in the brain, but what does all this have to do with compulsion, you may be wondering? We know that a lot of the changes that are occurring promote addictive behaviour, and I say that because there are studies that show this. In one example - the study by Garavan and colleagues in which they used a fMRI scanner to measures the amount of activity going on in the brain. Cocaine users and non-users were shown three video clips while brain activity was measured. In one they were shown a clip portraying cocaine use, in another just natural outdoor nature scenes and in the third, something that portrayed things of an explicit sexual nature. They found that in the cocaine-using group the brain was working just as hard, if not harder, when the cocaine video was being played as when the sexually explicit video was played. This suggested that in cocaine users the natural reward system is activated by cocaine to a high level, perhaps even more so than by natural rewards. This was interpreted to mean that cocaine users become more sensitised, or tuned in, to environments that are drug related. What is happening is that as a user takes drugs and is exposed to cues, their natural system responds and the reward system starts to release a little bit of dopamine into the brain giving them the beginnings of a sense of pleasure, it is a bit of a tease, an appetizer of what could really happen if they were to engage in that behaviour, and it motivates them toward the behaviour even more so.

There are other brain changes that occur as a consequence of exposure to various drugs. Drugs can impair those bits of the brain in the frontal lobe that Dan talked about, the ones that are very much involved in exercising control over behaviour. They act as your brakes, your mental brakes. This slide shows healthy controls during a task where they have to use their mental brakes, and you see red blobs that highlight which bits of the brain we know are activated in that task. They compared the scans of these healthy people to people who have been using cocaine. Cocaine users also show the red blobs - they are not completely absent - but they are less efficient at it. This suggests that cocaine users need to work harder to enforce the same level of braking as people who have never engaged in that activity.

When we put it all together, the evidence suggests that there are indeed brain changes that affect thinking and attention making users more sensitive and tuned in to drug cues in the environment. Studies of how intense these thoughts are have found that their obsessional nature is just as intense, if not more intense, than people who experience obsessive compulsive disorder. The changes also influence our motivations and emotions, as we saw with the changes in the reward system, and they underlie these feelings of an extreme urge/drive, to continue drug use. And finally, once you've been sensitised and tuned in to these cues and are motivated to take that path, control over your behaviour is impaired. And all of this is consistent with notions of compulsion.

But this doesn't occur for everybody who uses drugs. In fact, most people experiment with drugs and move on without any consequences. A lot of people become regular users and are able to control it. But a small but significant number do end up at those later stages of addiction characterised by compulsive behaviours. However, this doesn't mean that they are just victims to the changes in their brains, they are still accountable for their behaviours and need to engage in treatment and recovery processes willingly.

Clearly, there are a number of things that are involved in the addiction process that I haven't touched on, such as social factors, cultural, environmental, and genetic factors. But the point is that biological factors are also important and they may help explain why some people find it very difficult to simply quit using only their own willpower without any support. Another thing to say is that if people do engage in treatment, there is a lot of evidence coming out now that some of the changes are indeed reversible with periods of abstinence and, as Dan showed, the brain is actually much more flexible and malleable than we once thought and that provides an opportunity to recover some that lost function.

Finally, let's come back to the original question that was proposed - is drug addiction compulsive? Another way to think of it is, is it voluntary? It certainly starts off being voluntary when you first experiment with the drug. But continued use affects the structure and function of your brain which then affects your thinking, motivations, emotion and behaviour. As you work your way down these stages of addiction, it becomes less and less voluntary. How much depends, it is a complex disorder and depends on a number of other factors that suggest that it is not all completely voluntary.

Thank you.

Well thanks very much indeed Murat for a superb talk.

Our next speaker is Dr Andrew Lawrence who is Senior Research Fellow at the Howard Florey Institute where he runs the Addiction Neuroscience laboratory. He is Chief Investigator on a NHMRC funded program grant and also holds an NRC discovery project. In the last five years he's published over 50 scientific papers in very distinguished high impact journals. He was recently appointed Fellow of the British Pharmacological Society. He sits on numerous editorial boards and we look forward to hearing his lecture on co?morbid depression and alcoholism lessons from animal models. Andy.

Thanks George and thanks again L. E. for putting all the hard work in to get this thing to happen again - two years in a row, it is a great effort.

I'm a basic neuroscientist, not a practising clinician, and my favourite patients have four legs and a tail rather than two legs and stand upright. So I'm going to talk to you a bit about the problem of human alcoholism, but then I will talk about how we go back to the laboratory and model alcoholism in animals to get some forward thoughts and some advances in the potential development of new therapeutic strategies to help those patients.

This is a slide that I often use [of a dejected, perhaps homeless, man sitting on the side of the road holding a sign that says 'Need cash for alcohol research']. That is me there-need cash for alcohol research. I try to use this slide whenever I can because if you look at this guy, he puts the public face on alcoholism and so it is worth looking at that picture and having a think about it and what the human costs of addiction really are.

And just to get on to the social, financial and healthcare reasons for studying alcoholism - in the US the NIAAA which is the government organisation responsible for alcoholism alone - not all drug addiction, just alcoholism - they've estimated that alcoholism costs the US economy about US$170 billion per year and the World Health Organisation have indicated that it costs as much, if not more, death and disability as measles, malaria, tobacco or all other illegal drugs. But to me the most telling statement is the fact that the human costs are incalculable - you cannot put a dollar value on the human costs. However, when we write our grants to the NHMRC we have to make it economically as well as healthcare related, and even in a small country like Australia that is only got 20 million, just alcoholism - not all drug abuse, simply alcoholism - costs in excess of $6 or $7 billion dollars to our economy every year.

These are some pictures out of a recent article on binge drinking in Europe and specifically binge drinking in the UK. Adolescents, particularly young girls, drinking these premixed alcohol drinks at a party may be a familiar sight to many of you. That is when the youth start the evening, and for some people that is how they end up the evening. As Dan said before, young people can drink a lot without having too much of a hang over the next morning, but that doesn't mean to say it is not causing a lot of long-term damage.

As scientists trying to model alcoholism in animals, we have to first ask ourselves - what is alcoholism? Well, it is a polymodal disorder. Now what does that mean? It simply means that not all alcoholics are alcoholics for the same reason but what is known is that a significant number of alcoholics -human alcoholics, not my rats - present with some type of psychiatric co-morbidity. A while ago there was a big fanfare over a genetic linkage study that suggested that a dysfunction of one of the receptors for dopamine was implicated in human alcoholism. you've heard about dopamine as being an important brain chemical in giving feelings of pleasure. However this has been particularly controversial issue. It hasn't been replicated across different population groups, and we are left with the fact that while there is undoubtedly genetic reasons that predispose people to alcoholism, the identification of those genes still awaits. It is also clear that there are likely to be environmental factors. We just saw the picture a moment ago of the young girls in a nightclub, peer pressure that Dan mentioned before is one, and self medication that Dan mentioned is another.

People aren't alcoholics all for the same reasons. There are likely to be both genetic and environmental components. But the bottom line is that diagnosis is still the most critical factor for the most successful treatment outcome. So that puts a lot of pressure on the general practitioners and psychiatrists or clinic operators alcoholics are referred on to.

If we think about the therapeutics of alcoholism - recently a survey of 1,000 clinicians in the US who have alcoholism-related clinics was published in the journal Addiction. Only 13 per cent prescribe their patients the opioid receptor antagonist, Naltrexone which is used widely in this country and around the world, mainly because they only reported a very small to medium effect in that patient group. Disulfiram, brand name Antabuse - again only about 10 per cent prescribed. In theory, this is the best drug to stop people drinking alcohol because it blocks your liver's ability to metabolise alcohol. So if you drink alcohol while you're taking this drug, it makes you violently ill because basically you get a build up of highly toxic chemicals within your liver. While in theory it is a perfect drug, in practice it has almost a zero compliance rate because people will just stop taking it so they can go and have a drink. That is a very good example of how a perfect drug in theory just doesn't work in practice because you can prescribe a person a drug and they can go to the chemist and get a jar of pills, but you can't make them take the pill every day.

About 10 per cent of the patients were prescribed benzodiazepines. But by far the largest group of prescriptions were the antidepressants -about half of all of the alcoholics in the US are primarily treated with antidepressants to try to cure their alcoholism. So, as a scientist what do I think is needed? I think we need to improve the education of the prescribing physician, but I also think as scientists we need to develop better therapeutics, whether that is developing new compounds or whether that is developing new strategies.

I'm going to talk to you now about some data pertaining to an animal model that we have in our laboratories in the Florey Institute called the Fawn-hooded, or the FH rat. Basically, it is a white rat with a brown head and that is where the name Fawn hooded comes from, and it is thought to be the best rodent animal model of co?morbid depression and alcoholism. It is an inbred rat. It has a genetic serotonin dysfunction, as I'll talk about in a short while. The neurotransmitter serotonin is strongly implicated in depression, and a lot of the most commonly prescribed antidepressants act by modulating serotonin. These animals show a marked depressive phenotype in both the behaviours that we can measure and in the hormones in their blood. So from both endocrine and behavioural measures we can see that these animals are depressed and they respond favourably to antidepressant medication with improvements in behaviour and improvement in neuroendocrine status. Not only that, in a two-bottle free choice situation with zero coercion, it is totally voluntary - they will consume large amounts of alcohol with a very high preference, and they show the hallmark components of human alcoholism. They show tolerance, which was mentioned earlier, they show an alcohol deprivation effect, which is what Murat was talking about with the development of compulsive behaviour and the desire to go back and re?seek drug when you can't access it. They also show a quantifiable withdrawal syndrome following a period of self-administration of ethanol.

Using this animal model, we set out to discover if affective behavioural states were related to the propensity of these animals to self-administer alcohol. And I'll show you in a moment an experiment we did that demonstrated that anxiety is associated with the acquisition of alcohol-seeking behaviour, but once that behaviour has been acquired, anxiety levels really have no bearing on the maintenance or the establishment of that behaviour. To do this, we took Fawn-hooded rats that are already depressed rats, and when they were three weeks old, old enough to take away from their mothers, we brought them up in isolation. They were singly housed with no social contact whatsoever. So, on top of the depressive phenotype we are adding an anxiety phenotype with social isolation. A simple environmental manipulation can make them not only depressed but also highly anxious. We can confirm that with behavioural studies.

After developing this anxiety pattern on top of the depression, we chose to treat them with saline - a vehicle control, with diazepam, which is a benzodiazepine - Valium, or with a test drug called antalarmin. We treated them for three days with these compounds and looked at whether that treatment affected the development of a preference for alcohol, measured by a high level of self-administration of alcohol. We then withdrew this drug treatment and allowed all of the animals to acquire a high alcohol-preferring nature, then treated them again with these drugs to see what would happen once this pattern of behaviour had been allowed to establish. This figure shows you that the doses of these drugs were titrated to give us an equivalent anxiolytic dose; that means that each drug produces a similar reduction in the anxiety symptoms we induced in these animals.

This slide shows the percentage of animals that readily acquired a preference for alcohol after the first presentation of alcohol for three days. By that I mean, the majority of what they drank in a day was alcohol rather than water. Around 70 to 75 per cent of the control animals develop a high alcohol preference within two or three days of being presented with ethanol. However, if we treat these animals with diazepam or Valium, or the test drug, antalarmin, we can reduce that to about 15 per cent. To reiterate, treatment with anxiety-reducing compounds reduce the number of rats acquiring a preference for ethanol. Not only that, we can also demonstrate that adding anxiety by isolation rearing actually increases the number of rats that very rapidly acquire this alcohol-preferring nature. Therefore, we can quite comfortably conclude that behavioural state appears to play a crucial role in the acquisition of alcohol preference. The antalarmin reduced anxiety levels to the same extent that Valium did.

If we now turn the coin and ask if that behavioural pattern is already acquired, then how significant are anxiety levels? On this slide the red symbols refer to the control animals, those injected with saline, and the blue symbols refer to the animals that were treated with the test drug, antalarmin. Both groups of animals are drinking the same quantity of alcohol every day with the same preference. As you can see, their preference is about 80-85 per cent. What that means is 85 per cent of the total amount of fluid they consume in a day is alcohol, and only 15 per cent is water. This is voluntary, there is no coercion. When we start to treat them with this test drug antalarmin nothing much really happens in the first couple of days. But as we continued, we saw a very dramatic reduction in the amount of alcohol they consumed and an increase the amount of water they consumed. So, there was a dramatic reduction in preference and only about half of what they were drinking every day was alcohol compared to 85 per cent.

On the other hand, if we do the same experiment with diazepam, there is absolutely no effect on established drinking behaviour patterns, even though it was very effective, as effective as antalarmin, at stopping the acquisition of this behaviour in the first place. But once that behaviour pattern has been established, diazepam does absolutely nothing to it.

So while both drugs can block the development of alcohol-seeking behaviour, if we allow the behaviour to establish, only one of the drugs has an impact on it and the other has absolutely no effect. That tells us that specific blockade of the receptors that antalarmin acts on not only reduces the acquisition of alcohol-seeking behaviour, but once that behaviour has been established, it can also reduce it. Because diazepam didn't do that, we know that just reducing anxiety levels is not enough to reduced established alcohol preference. We did other experiments to demonstrate that this drug wasn't reducing the amount of fluid animals consume in a day and wasn't reducing the amount of food they eat in a day.

Hopefully, that demonstrated to you that affective state is important, particularly anxiety levels are important in the development of addictive behaviours, but once that addiction or that desire to consume the substance has been established, alleviation of those anxiety levels doesn't reduce the use of the substance.

Subsequently, we asked another question. As you know from what Dan said and what I mentioned to you in my introduction, we know that a significant portion of human alcoholics have co-morbid depression. It is debatable whether that is primary or secondary depression, as both patient categories exist. But, as I showed you before, it is clear that antidepressants remain highly prescribed for human alcoholics. So we have a perfect model for a very simple question. And that is, will alleviation of depressive symptoms also reduce alcohol consumption in this animal model of depression with alcoholism? In other words, is there a clear link between depression in these animals and their desire to consume alcohol? Can we dissociate the two? Which gets to one of the questions that Dan asked toward the end of his talk - does depression cause substance abuse, or does the substance abuse cause the depression, or do the two things happen just by chance in the same person? As I will show you in a moment some, but certainly not all drugs, with antidepressant-like activity can reduce established alcohol-seeking behaviour in Fawn-hooded rats.

This first data slide compares the effect of the two most commonly prescribed antidepressants on the market today on ethanol consumption. They are sertraline, trade name Zoloft, which is a selective serotonin reuptake inhibitor, or SSRI. It is the number one SSRI prescribed in humans worldwide for depression. The other is imipramine. Imipramine is an older drug, it is a tricyclic antidepressant, and still remains highly prescribed for depressive disorders in humans. In this slide, the red symbols are animals treated with saline - the controls, the blue are animals treated with sertraline, and the green symbols are animals treated with imipramine, the tricyclic antidepressant. As you can see, even on the very first day of medication, these antidepressants dramatically reduce alcohol consumption and the reduction in alcohol consumption remains stable for an extended period of time.

On the other hand, if we take a non-prescription antidepressant, such as St John's Wort, you can go into the supermarket and buy it off the shelf, lots of people do. It is debatable as to whether or not one jar to the next contains the same components. The St. John's Wort we got was from a German pharmaceutical manufacturer. It is very highly prescribed in Europe, particularly in Germany. We treated these same rats that are depressed and like to drink alcohol with St John's Wort, at a dose we know alleviates depressive symptoms and increases the amount of serotonin in the brain. It had absolutely no effect on alcohol consumption. We can relieve depression in the rats with this drug, we can increase the amount of 5HT in the brain of these rats with this drug, just as the Zoloft and tricyclic antidepressant did, but we didn't change the alcohol-seeking behaviour.

How can I summarise these studies? Well, I've just shown you the tricyclic antidepressant imipramine, the SSRI, sertaline and that test compound I spoke about at the beginning, antalarmin, all reduced voluntary ethanol consumption. On the other hand, St. John's Wort and this drug that looks like a telephone number, which is an experimental antidepressant, both behaviourally reduce the depression in these animals, increase the amount of serotonin in their brains, but we don't touch their alcohol consumption. So, the question to me, the scientist, is why? Well, we know that these prescribed drugs are intrinsically reinforcing, so we may just be substituting the reinforcement these animals are getting with the alcohol with the reinforcement they are getting from the antidepressants. St. John's Wort and the experimental antidepressant are not intrinsically reinforcing.

What is the take home message? Well, hopefully, I've shown you that the depressive part of the make up of these rats can be dissociated from their propensity to consume alcohol. Therefore, the ability of antidepressants to reduce alcohol consumption is not simply due to improving their affective behaviour. We can improve their depression with some drugs and not change their alcohol consumption, and yet with other drugs we can do both things, we can improve their behaviour and reduce their alcohol consumption. Therefore, what do we need to do? We need to develop new approaches and/or polypharmacy, which is just using a cocktail of therapeutic strategies rather than a single compound.

The most important take home message is that antidepressants are not, and should not be regarded as a panacea for the treatment of alcoholism. We can do better for these patients, and we should do better for these patients. However, I don't want you to think that I am suggesting that no one who is an alcoholic should be prescribed antidepressants. As I told you earlier, alcoholism is a polymodal disorder, not all people are alcoholics for the same reason. So it stands to reason that certain populations of human alcoholics will actually do very well on antidepressants. It simply means that some will and some won't. It gets back to that diagnosis and understanding how these behaviour patterns are established in the first place. And a bit of black magic on the side of the psychiatrists, too.

Thank you.

Thanks for those kind words George and L.E. for organising today.

I want to talk to you today about this whole issue of madness and marijuana and in particular, the link between psychosis and cannabis use. Now, you've heard a lot about drugs of abuse generally and about addiction as a problem and about using animal models in the understanding of addiction, especially depression and alcoholism. What I want to talk to you about today is a slightly different slant on this, looking at how drug use, in terms of cannabis, might be implicated in disorders such as psychosis where addiction isn't the central core issue, but rather harmful drug use resulting in, or in some way contributing to, an exacerbation of a pre?existing problem, in particular schizophrenia or psychosis.

Now, for me to be able to do this I need to first take you through what we understand about how cannabis works in the brain and then I'm going to talk to you a little bit about what we know is wrong with this system in people with schizophrenia and then finally, try to bring together some of these elements.

So the first bit I'm going to talk to you about today is this whole issue of how cannabis works in the brain. George and others have already talked to you a little bit about this but Cannabis sativa is one of the oldest known drugs that humans have experienced. There is certainly evidence maybe going back as far as 10,000 years in eastern China and Taiwan showing that people used cannabis, and certainly there is well documented evidence that goes back 4,000 years to India and related countries. Very quickly it spread throughout most of the civilised world and the uncivilised world and it is certainly rivalled in its use only by opium and by alcohol.

From a psychiatric perspective, cannabis has a number of very important effects, and Dan has already alluded to some of these but I'll just go through them briefly. Firstly, it has quite profound effects on mood. As people who've smoked cannabis - excluding Bill Clinton - will know, it can cause euphoria if it is inhaled and what people will notice is a very quick rush of a positive feeling, but some of the work that is come out from the Royal Children's Hospital and New Zealand also suggests that cannabis might actually predispose or contribute towards major depressive disorders and other affective disturbances which are much less pleasant than the euphoria that we commonly associate with it. The second effect, of course, is the anxiety producing effect, and Dan has already shown you a very strong association between anxiety disorders and cannabis use. I'm going to spend a lot of time talking about psychosis towards the end of the talk so I won't mention it again. Clearly, it is a drug which is involved in reward and addiction pathways, and finally there is a lot of work, in particular including work by Nadia Solowij up at the University of Wollongong, which shows that cannabis has two quite profound and distinctive effects on human cognition. It has a very severe effect on initial short-term cognitive effects, such as memory, but also with chronic use, It leads to some discreet, distinct and quite profound impairments in human cognitive function which appear to be long lasting.

Now, as George has mentioned the cannabis plant didn't evolve purely for our benefit, and similarly, our brain didn't evolve for the benefit of consuming cannabis, although some of us may think it did. What in fact this is suggesting is that there is some special connection between cannabis and our brain, otherwise why wouldn't we just sit outside and smoke the cooch grass that is growing on South Lawn? The reason is because it doesn't do anything for us presumably, but cannabis does. Now, the reason that cannabis does is because there are particular systems within the brain which are highly responsive to the active elements of cannabis in exactly the same way as that there are specific systems within the brain which are responsive to the active elements of the poppy plant or poppy flower, namely the opium and opioids.

So in the same way that scientists began to look at what that system might be for opioids and for heroin and morphine and pethidine, people also began to search for that system in the brain for cannabis. And this is the so-called endogenous cannabinoid system. The hypothesis was that the active ingredient of cannabis, which is Delta 9 THC - but in fact there is lots of active ingredients in cannabis, that is probably the major one - has a very specific effect. In other words, I could give 100 people a smoke of cannabis and I can get some very reproducible effects in terms of what people will experience. They might experience a range of effects but in terms of the actual number of effects, it will be very similar and what that indicates is that there is quite a high degree of specificity as to how cannabis is working in the brain. So the big search was on right throughout the 60s, 70s, 80s and into the 90s for this endogenous system through which cannabis operated, and it wasn't really until the late 80s and early 90s that it was finally cracked.

This is just to take you back through neuroscience 101. What you see up here is a brain cell, what you see down here is another brain cell and this shows you how the majority of neurotransmitters, such as serotonin, which Andy has just mentioned, and dopamine, which Murat mentioned, work. They work in a very simple way. An electrical signal comes down the neuron and into this final bit of the neuron and it triggers a process by which the neurotransmitter or neurochemical that is stored in little vesicles is released into the synaptic cleft. Then the neurotransmitter, for example dopamine or serotonin, diffuses across the synaptic cleft and works on the post-synaptic cell or the brain cell to which it is sending the signal. So that is what we've got here - a little receptor, which might be a dopamine receptor or a serotonin receptor, receiving the chemical signal and it then does things on this particular cell. In addition, we know that there are receptors on the cell that released the neurochemical, and we also know that there are enzymes and other things that produce the neurochemical or neurotransmitter.

Now, we assumed that that would be the case for cannabis. The problem was that it was nothing like it. Firstly, we all thought that, as it is with serotonin and dopamine, there are particular neurons or particular brain cells that produced that particular neurotransmitter. So there are dopamine neurons, serotonin neurons and a particular neuron for every type of neurotransmitter for the most part. That is not the case at all with cannabis, or the cannabinoid system. In fact, the cannabinoid system only exists with other neurotransmitters. It doesn't exist by itself- it is co-localised with other neurotransmitters.

We've discovered a couple of receptors - the CB1 which is the main one, and I'll talk a lot about that, there is also CB2 and there is potentially other receptors. And we've discovered a number of neurotransmitters that are specific for the cannabinoid system: anandomide and this long one 2?arachidonylglycerol or 2?AG for short, and there probably are others as well. And we've also discovered the enzymes that produce and get rid of these neurotransmitters and this is a transport process that I won't talk about today.

Now, the receptors. Firstly, two receptors of major note - the CB1 and CB2 receptor. The CB1 is the major one because that is the one that is predominately in the brain and it is the one that is thought to mediate most of the actions of cannabis within the central nervous system. Interestingly, it is very highly conserved across species, and I'm talking about mammalian species, but even orders lower than the mammalian species. This indicates that it is something of relatively recent evolutionary origin. In other words, there hasn't been enough time for this system to evolutionary diversify across species which means it is fairly new. The CB2 receptor is found predominantly in immune cells and immune organs and I won't talk any more about this.

Now, this is some work that we did a couple of years ago with Brian Dean at the Mental Health Research Institute, these are sections from a post mortem human brain. The sections come from people who have donated their brain to the Mental Health Research Institute. This is the prefrontal cortex, which is very important in terms of organising behaviour, and this is the hippocampus - very important for memory and things like that - and the caudate putamen which is very important in controlling movement amongst other things. The dark regions on this slide are where there is high levels of CB1 receptor, the lighter regions are where there is not very much CB1 receptor. And what you can immediately see is that there are high concentrations of the CB1 receptor throughout large parts of the brain. What does this mean? Well if we have a look here - and this is a diagrammatic representation of what I've just shown - the dark green shows very high densities of receptor and the paler it gets the less receptor there is. You can see there are huge amounts of CB1 receptor throughout the whole of the human brain and that is the same for most mammalian species examined.

The importance of this is that we don't quite know what the CB1 receptor is doing in such great quantities. We've only just discovered it in the last 10, 15 years or so, and it is clearly playing a very important role because otherwise there wouldn't be so much of it around. The CB1 receptors are very dense in all the brain regions that are important in terms of mental disorders and psychiatric illness, such as the basal ganglia, the cortex, the hippocampus, which makes it very interesting from a psychiatric, or mental health perspective. And when you smoke cannabis we can predict most of the effects that you're going to experience from where the CB1 receptor is localised.

This is to show you what the receptor does inside the brain cell, and I can summarise it very quickly for you. The receptor inhibits neurotransmitter release. The important point about this is that the CB1 receptor does not inhibit anandomide or 2?AG release, the neurotransmitters that activate it, it inhibits release of the neurotransmitter that is co?localised with the cannabinoid receptor. So if the cannabinoid receptor is co?localised with, say, serotonin or dopamine, stimulation of the cannabinoid receptor turns off the release of dopamine or turns off the release of serotonin. That is a very important point.

Anandomide and 2?AG, the two major neurotransmitters that work on the CB1 receptor, are also quite different than the typical neurotransmitters that we've been talking about. Firstly, they are not stored in those little round vesicles that I talked about before, they are actually stored in the membrane layer of the neuron. When there is a stimulus for anandomide to be produced, the enzymes are activated and the anandomide is released straight from that membrane layer. It doesn't need to go through that whole complex process of being released from those little round vesicles that I talked about before. We think that may mean that it can very quickly respond with very quick stimulation of the receptor.

This is what we think is actually happening at a cellular level in the brain. We have two brain cells; this one uses anandomide, which is AEA, and this one is 2?AG or 2? arachidonylglycerol - essentially the same function but with the two different neurotransmitters. This illustrates a normal brain cell from the front part of the brain, the cortex, projecting to an important part of the brain which controls movement but lots of other things as well - the striatum - and this is one of the brain cells which is receiving that signal. Now, normally what happens is glutamate excites brain cells - it is an excitatory and neurotransmitter - and so if glutamate is released and stimulates this cell, then this cell will fire, it will become active and respond. Now what we think happens is that glutamate gets released from this brain cell and activates a second brain cell. In the process anandomide is produced. Anandomide diffuses backwards across the synaptic cleft, stimulates a cannabinoid receptor on what is called the presynaptic neuron, and by stimulating this receptor it turns off glutemate production so that the signal to stimulate this cell, is actually being turned off and is no longer active.

The same thing again, but this time with an inhibitory neurotransmitter called GABA. When GABA gets released it turns off this brain cell and this brain cell no longer works. So, now what happens is GABA gets released, signals to this brain cell to be quiet or not work anymore. But in that process 2-AG is produced and it diffuses backwards across the synaptic cleft, stimulates the CB1 receptor and in stimulating the CB1 receptor, turns off GABA release. If you turn off GABA release this brain cell can work again. So in other words, the production of anandomide or 2?AG actually relieves the brain cell that is producing that neurotransmitter from whatever influence was coming from the other cell. In other words, it is a way for a brain cell to regulate what inputs it is going to receive.

So, how does this all relate to cannabis and psychosis? I'll cover this quickly because Dan's already talked a little bit about this. Firstly, we know from clinical studies that if you give enough Delta 9 THC to anybody you can get psychotic symptoms, and there have been studies that have done exactly that. In fact, a couple of years ago there was a paper published where they gave increasing amounts of Delta 9 THC to university students - who would be about the only people who would take it - and they showed psychotic symptoms. As soon as the THC infusion was stopped - they gave it intravenously - the psychotic symptoms disappeared very quickly. When people with schizophrenia are given Delta 9 THC, their psychotic symptoms become worse. So we know that Delta 9 THC causes psychosis or makes psychotic symptoms. As Dan has already shown you, there are very high rates of cannabis use in patients with schizophrenia, very high rates.

Now, very interesting data which has come out of a couple of large scale meta-analyses or, if you like, collections of studies which have looked at the relationship between cannabis use and schizophrenia show quite clearly that cannabis use is associated with an increased risk of schizophrenia and these are epidemiological or population surveys. A very important paper that came out a couple of years ago from the Institute of Psychiatry in London shows that the attributable risk - in other words, how much schizophrenia you could attribute to cannabis use - is about 8 per cent. So if all cannabis use was stopped right now, the incidence of schizophrenia would be reduced by about 8 per cent. Another study which came out from New Zealand a few weeks ago showed that there was an increased risk of cannabis use in people who had psychotic symptoms. So clearly there seems to be a relationship, although it is certainly not as clear cut as some people would like to make it out to be. Dan has already talked about this -for people who have schizophrenia, cannabis use makes their symptoms much worse. They have more hospitalisations and longer hospital stays, it causes relapse and it stops people from taking their normal medication.

We've looked at what might be wrong in people with schizophrenia with regard to their cannabinoid system, and this again is work that we've done at the Mental Health Research Institute, and I'll summarise it very quickly. There are changes in the cannabinoid 1 receptor in people with schizophrenia, but only in specific brain regions, and those brain regions are the prefrontal cortex or the very front part of your brain. It doesn't matter if the person with schizophrenia smokes cannabis or doesn't smoke cannabis. People who smoke cannabis have changes in the CB1 receptor but it is in a different part of the brain, part of the brain called a striatum. So there is a very specific change in the cannabinoid receptor in a particular part of the brain in people with schizophrenia.

A group in Germany has shown that in the cerebrospinal fluid, or the fluid around the brain, there is an increase in this neurotransmitter, anandomide which is very high in people with schizophrenia before they've received any treatment with antipsychotic drugs. Anandomide levels decrease with treatment. There are also changes in the gene for the CB1 receptor but it seems to be very specific to Japanese populations. It certainly wasn't found in a European population, which says something about the Japanese I think.

And a very interesting case report using an imaging technique called SPECT - and you don't need to know what this is - but this was a study looking at dopamine, which you've heard a lot about, in people with schizophrenia. We think that dopamine's abnormal in people with schizophrenia. Now there is a patient who got very anxious during the SPECT scan. He said that he needed to go to the toilet, he went to the toilet and came back 10 minutes later looking very relaxed and quite happy and wanted to do the scan. He did the scan. The next day he was quite psychotic and quite unwell and they noticed that in the scan there was an increase in dopamine whilst he was having the scan. They asked him what he'd done, and he'd said he'd had a joint. So in fact smoking a joint increases the amount of dopamine in a very acute way and made this chap's psychotic symptoms much worse.

In conclusion, firstly about the endocannabinoid system itself - it is densely distributed throughout the central nervous system and coexists with other neurotransmitters where it works by moving endocannabinoids, like anandomide and 2?AG, backwards across the synaptic cleft or across that gap between the two brain cells to work on what are called presynaptic receptors to stop the neurotransmitter from being released. They are working in a way which is quite counterintuitive to the way that we usually understood neurotransmitter systems to work, and they are working as a brake on the brain system. And we know from the data that I've just shown you, the system is clearly abnormal in schizophrenia.

We're not clear what it is doing, we're not clear why it is different, but we know that it is different, and it certainly seems to be different irrespective of whether people are smoking cannabis or not smoking cannabis. I think the big challenge for us is to work out what its actual role is in this disorder. So I'll stop there. Thanks.