Antonio Cepeda-Benito, Ph.D.: Our first speaker is Fernando Rodriguez de Fonseca. Dr. Rodriguez de Fonseca, I've known him for several years now. I met him in Madrid, Spain, 2001, 2002, around then, and he's very well known in Spain. He's a very prestigious, renowned scientist, and on very short notice he accepted to come to the conference, for which I'm very grateful.

And he's also the person who organizes a network in Spain called Red de Trastornos Adictivos. It's a network; it's a little bit different than our network in the sense that it is composed of groups of investigators or investigating teams. And it has been very successful in increasing the productivity of the research there.

He's a senior researcher at IMABIS Fundacion in MÃ?laga, which is a system that they have created to manage funding to conduct research. And he also is a full Professor at the Department of Psychobiology at the University, Universidad Complutense de Madrid, which is a very good university in Spain.

So he's going to talk to us about the neuropharmacology of the endogenous cannabinoid system.

Please welcome Fernando.

Fernando de Fonseca, M.D., Ph.D.: Good afternoon. First, let me say that I'm very honored to be here with this hispanics network society that you have. It's more or less the same that we have in Spain. In a way, we're discussing all of the possibilities that in the future we can merge our interests.

The title of my talk is based on the idea that all of you know already, that marijuana is associated with alcohol. This morning in the Northwestern study you'll see 20% of the youth recruited in that study were using marijuana and alcohol.

The question is, what is the neural basis for this interaction? Why they are associated? And I will try to convince you that there is a clear neurobiological basis for that interaction, though your social and epidemiological variables can be contributing towards that association, and also to provide a framework on which we can develop future strategies for prevention and for treatment. This is more or less the idea of what we want to do.

Fernando de Fonseca: Let us go back to the '60s when Raphael Mechoulam discovered the structure of the active principles of marijuana, namely tetrohydrocannabinol, and more or less 25 years we were searching for the target of these cannabinoids.

These are structures that were present in the plant, and they apparently were these EPCRs, receptors that are present in the membrane of cells that are the target of the main drugs of abuse. While directly, like the opiates that are targeting EPCRs that are the opioid receptors, or indirect, like all the psychostimulants that, by increasing dopamine, are targeting the EPCRs called dopamine receptors.

Then we got our target one, which is the cannabinoid receptor. This cannabinoid receptor is located in the same cells in the reward system that express all dopamine receptors or glutamate receptors or acetylcholine receptors or opioid receptors. And they're interacting then with the reward system in a way that were very well described around the '80s.

Fernando de Fonseca: But the surprise came when we went to the anatomy of the cannabinoid receptor and we found that in the brain, the most abandoned EPCR receptor expressed is the cannabinoid CB1 receptor, something that still strikes all the scientific community, because if you consider that the cannabinoid receptor is overexpressed at much more than the glutamate receptor, one start wondering why they are there.

And even more, 400 million years after the first ____________ were expressing cannabinoid receptors for regulating-motivated behaviors, like feeding, we still see that vertebrates, including humans, express enormous and abundant receptors in the hippocampus in all of the motor system, including the reward system, the cerebellum, and the cortical areas.

We do know now that this is because the cannabinoid receptor is part of a machinery that controls exactly the synaptic weight of neural transmission. I mean, how strong are certain synapses communicating, which are the dynamics by which communication flows through circuits that use glutamate, acetylcholine, and GABA, mainly.

Fernando de Fonseca: But this is just only the tip of the iceberg, because we know now that the cannabinoid system is not only the endogenous ligands for this CB1 receptor that was, most of you probably know that there are endocannabinoid compounds that are present in the brain that target the CB1 receptor, but a very complex machinery that is almost doubling every two years.

Fernando de Fonseca: I'm just placing here [for] you, one half of the machinery that is now related to the cannabinoid system because we are talking about the synthesis of anandamide or the synthesis of 2-arachidonoylglycerol to endocannabinoids, the main one.

But look, for instance, the number of receptor is increasing. The GBR 55, we can call it now the CB2 receptor. We have also nuclear receptors. We have plenty of lipids that are transmitters. And then we have much more enzymatic pathways that are intermingled for creating this wide family of transmitters, what we call endocannabinoids.

But for alcohol and cannabis addiction, we have something we'd like to focus for this talk, and I mean that you need to keep in mind that all this family's going to give us a lot of news concerning how a reward is processed, how motivational behavior is processed, and how the introduction with drug abuse are intermingled with the use of cannabis.

But we're going to focus only on the CB1 receptor and mainly in the enzyme that degrades one of the endocannabinoids, the anandamide, and this enzyme is the fatty acid amide hydrolase. It's an enzyme that degrades, or clips, anandamide in arachidonic acid and ethanolamine. Let's think about only these two, but this is like the tip of the iceberg, okay?

Fernando de Fonseca: What is important to consider is that anandamide, like the main endocannabinoid, is not a typical transmitter that this is stored in the brain. It's produced by the cleavage of phospholipid that is in the membrane, so it's a demand transmitter. It's only activated when something is pushing to its release.

We can't control the synthesis of this precursor through this enzyme, but the important thing is that some particular stimuli, mainly calcium influx and other excitation of the cells, would activate this phospholipase D. That will release anandamide, and this anandamide also lives in the membrane, the phosphodiesterase.

Fernando de Fonseca: This is a state-dependent transmission. It's very completely different to other transmitters like dopamine or like opioid that are stored in vesicles. It appears when it's demanded, and it's degraded immediately by a complex system that is accepting more or less the same that's used for the transmitters.

An uptake system, the anandamide transporter that place anandamide inside the cells, and the fatty acid amide hydrolase cleaves it in the two main components that enter again in the cycle of resynthesis.

This is the way that the endocannabinoids work, and then we know that if we want to relate this to alcohol, we need to remember that the association of cannabis and ethanol for abuse, that it's very frequent.

Fernando de Fonseca: But also the cannabinoids, and everybody knows that it, promotes motivated behavior, intake behavior. So the use for instance of cannabis as a therapeutic source of ameliorating cachexia in AIDS or in terminal cancer has been promoted in this country [even] with this strong collaboration against the use of drugs as therapeutic medicines. That has been authorized within certain states because it's clear, and there is a neural basis for that.

And we know that this promotion of intake of food is also seen when, instead of food, we use ethanol as the sort of caloric intake. That cannabinoid antagonist - so we give a compound that antagonizes marijuana effects or anandamide effects -- does the opposite work. If cannabis promote, antagonist blocks the self-administration. And that clinical core increases these compounds in the brain in a way that was not very well understood.

And finally some work done at the Laboratory of Dr. Kunos at the NIH/NIAAA, they demonstrated that the cannabinoid knockout like alcohol. And the most exciting thing is that there is a clear linkage between certain polymorphisms and mutations of the fatty acid amide hydrolase and alcoholism, mostly very severe forms of alcoholism.

This is what we already know, but what I want you to show is, how can we explain this on the basis of the neurobiology of endocannabinoids?

Fernando de Fonseca: We also did some expression profiling studies under the TARGALC, which is a consortium that we have in Europe, financed by European Community and directed by Markus Heilig, all of you probably know him, which is actually at the NIAAA, and doing all the clinical research and coordinating the clinical research on alcoholism.

And we would do expression profile in Wistar rats in two strains of rats with preference for alcohol. And one of the main candidates was the CB1 receptor and related chains, including the fatty acid amide hydrolase, with all these other potential candidates. So the CB1 receptor is clear associated with the genetics of alcoholism.

Fernando de Fonseca: So, first, what we want to know, I mean, how alcohol can change the production of the endogenous cannabinoids. How these changes can be produced in allostatic mechanism of a chronic stimulation of the cannabinoid system so we can have adaptations, neuroadaptations, that can produce the alcoholic phenotype, and if these chronic changes persist after abstinence and could be related to permanent phenotypes or even genetic alterations.

Fernando de Fonseca: Well, simple study: is alcohol affecting the production of anandamide? So we did a simple study with rodents that were given acute ethanol IV. And we studied several time points in plasma, hippocampus, cerebellum, and nucleus accumbens, and we measured anandamide and also we measured plasma, the activity of the enzyme of synthesis and the enzyme of degradation.

Fernando de Fonseca: Well, this is more or less, in this experimental study, how are the levels of ethanol...

Fernando de Fonseca: ...and then in plasma, immediately anandamide drops...

Fernando de Fonseca:...in the accumbens also drops...

Fernando de Fonseca:...in the cerebellum also drops...

Fernando de Fonseca:...and the hippocampus was the most permanent drop. In all the areas that we were studying, and even in peripheral blood, alcohol is associated with an acute depression of anandamide.

Fernando de Fonseca: And this is not associated with changes in the enzyme that produces the precursor, nor in the enzyme that clips anandamide. So it's not a direct effect on the synthesis.

Fernando de Fonseca: And it's not a direct effect on the degradation. There is no inhibition of the fatty acid amide hydrolase. Why, then, we have this depression?

Fernando de Fonseca: Look, when we give ethanol, we got a classical increase in dopamine release in the nucleus accumbens, and a clear decrease in glutamate release. Glutamate is the main excitatory neurotransmitter in the brain that triggers anandamide release.

So because we have this decrease in glutamate release, anandamide is not demanded. Remember, anandamide is a state-dependent transmitter. If glutamate is recruiting excitation, we will have anandamide. If glutamate is being decreased, we will not have anandamide, because anandamide, what is being used is to control the excess of excitation in the glutamatergic synapses.

Fernando de Fonseca: So the idea is that acute stimulation with ethanol produces changes in glutamate, and practically GABA and acetylcholine, and these changes are reflected, then, in a less demand of anandamide. This is the link, and when we give it chronically, the picture is the opposite. Glutamate restores their levels, and anandamide starts to be increased. This was initially described in the first experiment. We give chronical ethanol; anandamide is found to be elevated in the brain.

Fernando de Fonseca: These changes mean something in an animal receiving chronically ethanol. Well, what we did is just a simple study in animals with different histories of dependence. We place animals, rats, in vapor chambers, expose it to air or expose it to ethanol.

Fernando de Fonseca: After they were exposed for many weeks, they were retired from the chambers, returned to their home cage, and then they were trained again to drink ethanol. So remember this name, 20, this number. This is the average lever presses that a rat press for ethanol, and the cannabinoid antagonist is not affecting this behavior. These are animals without a history of dependence.

Fernando de Fonseca: But look at these animals. They were formerly dependent, because they were raised in ethanol vapor chambers. They double the basal, press levers for alcohol. They were alcoholics at the beginning, and they remain when we reinstate the behavior.

Fernando de Fonseca: And then the cannabinoid antagonist, those dependent inhibit the system. That was, we'll describe it in expression profiling, the cannabinoid system is recruited for the phenotype of alcoholism after a history of dependence. So history of dependence is associated with long-term changes in the CB1 receptor, and it has been demonstrated almost in all animal models that have been studied.

Fernando de Fonseca: Then if these chronic changes persisted, and even we can just use it for a tool, as a tool for targeting relapse, which is the critical part in every addiction. Well, we have a type of a study for validation of this hypothesis.

Fernando de Fonseca: The direct hypothesis, which is testing, is blocking the cannabinoid system. We will prevent relapse, or the studies in which the stimulation of the cannabinoid system will boost relapse. This is a model of alcohol deprivation; this is a model of cue-induced reinstatement.

Fernando de Fonseca: The model of cue-induced reinstatement is very simple. The animals were Wistars or Marchigian Sardinian preferring rats, a genetic strain that likes alcohol a lot, were presented with a cue associated with the availability of alcohol. So the cue makes the animals that relapse to press for alcohol much more in the animals with preference for ethanol.

But in both cases, the cannabinoid antagonist is blocking that, so relapse is prevented by blocking or targeting the cannabinoid system.

Fernando de Fonseca: But look at this, which is extremely interesting also. This is the alcohol deprivation effect. This is animals that are receiving alcohol, and these are the lever presses within five days. Then we got two days off alcohol. The day eighth, they restate, so there is a clear alcohol deprivation effect, so the animals start lever-pressing more until they normalize again. So you can see the alcohol deprivation effect that they sustained.

Well, if we stimulate during this period, during these first two days or four days - we have several different models - with a cannabinoid agonist, for instance, like a dose that's very similar to those found in marijuana cigarettes, those dependent, we increased the alcohol deprivation effect that they sustained along the time.

And we have done this for only in this short term were exposed to cannabinoids. But the effect lasted at least, we have done up to eight cycles. It's almost permanent with four single or two single injection of the cannabinoid agonist. That is boosting, then, the surge and the increase of the cannabinoid intake.

Fernando de Fonseca: Well, what about behavioral genetics? I mean, I told you about that there is a mutation that is associated with the FAAH that is linked to alcoholism, but there is no clear pharmacology in this because there is no clinically tested FAAH inhibitors yet. The FAAH inhibitors are under clinical development, but it's not yet been given to humans, so we need to demonstrate that.

We were very lucky because we were using the alcohol-accepting or normal-accepting rats, and these rats were bred for their alcohol preference or avoidance. And we found in this system that this enzyme is linked to alcoholism. How?

Fernando de Fonseca: Well, first we found that when we were screening for the cannabinoid system, that in the prefrontal cortex, which is a key part for all the motor programming and behavioral programming, we found a decrease of the cannabinoid CB1 receptor, and that was linked also with a greater sensitivity in the alcohol non-accepting, remember?

Fernando de Fonseca: These non-accepting in rats, these are the preferent rats. So the preferent rats has less cannabinoid receptors, and they are less active. They coped worse to the transactional system. Why?

Well, first we tested them. This is fortunately relevant. When we were giving the cannabinoid antagonist in the alcohol-preferring rats with a history of dependence, these animals responds very nicely to the cannabinoid antagonist with a dose-dependent decrease.

Fernando de Fonseca: If we inject in the prefrontal cortex, we have the same dose-dependent decrease in the cannabinoid receptor -- they press levers for alcohol -- and then not in the striatum. So we demonstrated that there is something there in the prefrontal cortex.

Fernando de Fonseca: And remember, this is not only related to the cannabinoid CB1 receptor, could be linked also to any of these other targets. So what we did was to measure all these enzymes, and to make the story short�

Fernando de Fonseca: �what we found is that FAAH activity is lower here than here, the non-accepting rats. So in a way, it seems like in the alcohol-accepting rats, the tone for the endocannabinoid system is higher because there is less degradation, and then that will be more anandamide there and then probably a desensitization of the receptor.

Fernando de Fonseca: We need to demonstrate that, and we first found the expression of the enzyme is lower in the prefrontal cortex and not in the other parameters.

Fernando de Fonseca: And the most important thing: when we infuse to normal Wistar rats that don't like at all the ethanol, and we infuse in the prefrontal cortex the FAAH inhibitor, these animals double their alcohol work.

Fernando de Fonseca: So it's clear the message. In the prefrontal cortex, overactivation of the endocannabinoid system leads to an alcohol preference. In humans, we need to check that, but at least we know that mutations that change the activity of the enzyme is linked to alcoholism.

So, again, this is only the tip of the iceberg. What happens with the other receptors, with the other enzymes, with the other transmission system linked to the cannabinoid system? We don't know yet, but the picture arising only for the study of FAAH and the study of CB1 receptor gives a clear message: overactivation in specific areas of the brain, or the cannabinoid system, is linked to alcoholism.

That can be demonstrated pharmacologically or genetically. And probably this CB1 receptor function or this amide hydrolase function can be adapted after chronic drug of abuse. We have demonstrated with opiates, with cocaine, and mostly with alcohol that exposure to these drugs change the dynamics of the system in a permanent way.

So the history of dependence will change the phenotype of the individual among others by influencing the dynamics of the cannabinoid system. And probably this is the link between all these associations between alcohol use and cannabis consumption. But, I mean, it's not the only one that's clear.

Fernando de Fonseca: So yes, as a summary, again, alcohol inhibits anandamide production. History of dependence motivates endogenous cannabinoid system. Cannabinoid exposure during abstinence boosts alcohol deprivation effects.

Cannabinoid CB1 antagonist suppresses conditioned relapse, so it's a good target for treating alcohol relapse. And in animal models of chronic exposure to ethanol, the cannabinoid system has been targeted in mostly the CB1 receptor.

Fernando de Fonseca: This is confirmed with functional validation in animal models and in expression system. And for sure, there are much more than one cannabinoid target waiting for our research.

So I hope I have convinced you that a study with animals trying to parse out what happens in humans probably can just narrow the gap between the epidemiology, the sociology, and the clinical part on the basic research that we are performing.

Fernando de Fonseca: So this is, again, one of the reasons for working together and trying just to merge all the information in a more comprehensive way. I thank you for your attention and giving just the credit to all the work down for all these people that was here.

Audience: Thank you for that nice presentation. I have a question, just to make sure that I understand some of the data that you presented. So you showed very different responses following acute alcohol injection versus what you're saying occurs with chronic alcohol consumption, so let me make sure that I understand.

So chronic alcohol consumption is going to lead to an increase in endocannabinoid activity? And when you say "increase," are you talking about the synthesis, the binding to the receptor and the cellular effect, or what do you mean by "increased activity"?

Fernando de Fonseca: Okay. Increase in signaling. That means that there is more anandamide or 2-AG or the other cannabinoids, endocannabinoids, we still don't know. But what we do know is that chronic stimulation with alcohol enhances the production of anandamide and 2-AG; decreases activity of the FAAH, the enzyme of degradation; and modifies the sensitivity of the receptor.

We do not have yet evidence that chronic alcohol is affecting the synthesis, but what it's clearly affecting is the neurotransmitter release that triggers the release of anandamide. For instance, glutamate. Okay?

So up to now what is more pieces of information that we have is that probably ethanol modifies glutamate, acetylcholine, dopamine, opioid tone. This is associated with changes, then, in the excitability of the cells, less anandamide being released, compensatory mechanisms probably in the degradation for enhancing this anandamide also, and modifications in the signaling system. But at the end the picture is more endocannabinoid tone, not because of the synthesis but because of the receptor and the degradation.

Audience: And what is your evidence for making that last statement? When you say that there's higher endocannabinoid tone, what is the outcome of that?

Fernando de Fonseca: Okay. There is, I didn't mention that there is one paper measured by microdialysis by the group of, it's in the Scripps Research Institute, Larry Parsons, that demonstrated that self-administration and relapse has been associated with high vascularcellular levels of anandamide and 2-AG, first.

Second, that in cell culture and in rodents, chronical alcohol administration enhances the basal levels. But there is only one paper on the dynamics of that release which is in vivo, which is that of the Larry Parsons that was published last year in Journal of Neuroscience.

So there is in vivo demonstration that 2-AG and anandamide are being associated to chronical stimulation with alcohol.

And the other important thing is, animals studied after different cycles, repetitive cycles of dependence, abstinence, dependence, abstinence, at the end they have an enhanced sensitivity of the CB1 receptor. More receptors, more sensitive, and with less of amide hydrolase enzyme. Overall, higher sensitivity to the cannabinoids.

Audience: Fernando, the link between alcohol and the glutamate is presumably aided by GABA. Would you expect other GABA-related depressants like benzodiazepines to have the same link between, with a cannabinoid?

Fernando de Fonseca: We have no evidence, but I would love to do that. What I can tell you is the opposite.

Chronic cannabinoid stimulation produces changes in GABA. So at the beginning, there is some ___________, and after chronic administration - we have not published yet that - we found that, for instance, in the striatum and in the globus pallidus, the basal GABA is decreased 50% , so these animals are extremely excitable.

So I presume that after chronic benzodiazepines, we will have a very similar thing, because in a way, the benzodiazepines and the anandamide -- I'm not talking about natural cannabinoids because of a pharmacological difference.

But anandamide and benzodiazepines can be more or less the same. They are anxiolytics in a way - soft anxiolytics, but at the end, after repeated administration, they can change their profile. But we need to demonstrate that.

Antonio Cepeda-Benito: And our next speaker is Maristela Monteiro. Dr. Monteiro is a senior advisor on alcohol and substance abuse at the Pan American Health Organization, better known as PAHO.

Dr. Monteiro joined PAHO in December of 2003 after working for nearly ten years in Geneva at the World Health Organization, coordinating the area of alcohol and drug abuse. She's a medical doctor with a Ph.D. in psychopharmacology from the Federal University of Sao Paulo, Brazil, and Dr. Monteiro is the author of over 100 publications in peer-reviewed journals and articles.

She has been involved with this meeting in the past as well. Been very helpful in suggesting names of speakers who have attended the conference. So she's an old friend, and I'm very happy to have her back.

Maristela Monteiro, M.D., Ph.D.: So I'm going to present results from a study that was coordinated by PAHO, but is part of a much larger network of researchers from around the world. And that's how it started, actually.

The network was started over 15 years ago in the context of the Kettil Bruun Society that studies epidemiology and social studies related to alcohol. And a group of researchers there began to get together to discuss issues related to women and alcohol and then move on to gender and alcohol.

And after a few years of discussions, they came to realize that it was very hard to compare data because each one was using a different indicator, a different variable in their surveys, and there was nothing that could be concluded about relationships between alcohol and gender differences in alcohol consumption beyond the biological differences that we know.

So at one point, there was a will to develop a common questionnaire that could be used in surveys around the world, and that led to a collaboration with support from NIAAA for participation of the U.S., but also Canadian funding and European Union funding, to bring together about 20 countries or so around the world to do comparable surveys of the general population, using the questionnaire that was developed and had consensus in the scientific community.

At that point I was still in WHO, and I proposed that WHO would come in also to fund countries from the developing world, the developing countries. And we obtained funding on our own from Valencia, Spain, to support surveys in several countries of Latin America.

When I moved to PAHO, I continued to support the network and decided to get funding for a regional analysis of data from the countries in the region of the Americas that had participated already with surveys and fund a few new countries.

And that's how this study was planned, as bringing together existing surveys; new surveys that were funded by other sources, like Brazil, for example, and Mexico; and fund new surveys in three countries - Belize, Nicaragua, and Peru - and analyze them all together.

Maristela Monteiro: So this is the funding that we got. It was funding from PAHO. It was an award for, a research award, internal competition on multicentric projects, and we got the project to fund this regional analysis and study.

And also the Center for Addiction and Mental Health is a collaborating center of WHO and PAHO, and they also funded part of the coordination of the database and analysis that were done for this study.

Maristela Monteiro: These were the ten countries that ended up being part of the multicentric study: Argentina, Belize, Brazil, Canada, Costa Rica, Mexico, Nicaragua, Peru, Uruguay, and the U.S. The surveys were not necessarily national. Most of the time because of funding restrictions, they were not, actually.

Maristela Monteiro: Brazil I put here the sample of only one of the surveys. We actually had two surveys that were a part of the study. One was representative of Sao Paulo state, which is a very large state. It has the largest in population of Brazil.

But there was also happening at the same time the first national survey on alcohol consumption and patterns with a national representative sample that used many variables that were comparable to ours.

Canada was national. Costa Rica was not. Belize was national. Argentina was from the province of Buenos Aires. Mexico was national.

Nicaragua was, they selected five cities in different parts of the country, but the major city of Managua, the capital, was not included basically for safety reasons. It was very hard to get a representative sample at that time of the capital. But different areas of the country that had larger populations in large cities in five different parts of the country were made the sample.

Peru was representative of two regions: the capital and a region that has a lot of indigenous people. Uruguay was the capital, Montevideo. And the U.S. was national.

Maristela Monteiro: This is how the drinking was classified. There were questions about demographics, education, employment, and then alcohol consumption by beverage type, lifetime, last 30 days, episodes of heavy drinking, and the average beverage type - consumption of each of wine, beer, spirits, or local drinks as well.

Quantity and frequency was obtained, and we could divide consumption in four categories. One was the lifetime abstainers or very low drinkers that drank less than a drink a day in the last 12 months. And in category I, that would be the low-risk drinkers, between .25 that's below, way below one drink a day. Sorry, the other was, it's 10 grams using a standard drink in one drink, so .25 is very low, up to 40 grams (or four drinks or three drinks, depending on the size of the drink) a day for men, and one or two drinks a day for women on average.

Drinking category II includes already some excessive drinking in there. But it's still at higher risk, but not very high risk: for men, between 40 and 60 grams a day, and women, 2 to 40 grams.

And the third drinking category was those that drink, on average, more than five: men more than five drinks a day, and women more than four drinks a day.

Maristela Monteiro: This is the data that we obtained for the frequency of abstainers in each of the drinking categories. As you can see, there is a wide variation between countries and between men and women in almost every country.

So, for example, in Argentina is where you have the lowest prevalence of abstention among men, and the highest is in Nicaragua. They're in green. And women also has a very high percentage of non-drinkers. And women are very low in Canada.

And as you see, moving on, you have less prevalence of heavier drinking categories as you move on the drinking category. And in some countries you have closer prevalence between men and women, but there is a very wide variation.

Maristela Monteiro: In terms of average volume of consumption per day, among the drinkers, we also have a lot of variation between the countries, and you have 10, 20, up to 30 percent average grams per day drinking for men. In Belize, for example, or Nicaragua, they on average drink a lot per day, and women drink much less when they drink.

Maristela Monteiro: Now, only considering heavy episodic drinking - meaning more than five drinks on an occasion for men, and more than four for women - you have a much higher prevalence of heavy drinking among men than women. And still the same variations continue to occur between countries, but the range of difference decreases.

Maristela Monteiro: And some of the consequences of the drinking here: fighting after drinking and an injury after drinking. You see, for example, in Brazil's sample, number two is the national sample. You have 32% prevalence of drinking among men after - or fighting after drinking, and very high as well among women. But injury is much more prevalent among men.

All the data here. Lowest, for example, in terms of consequences or in fights or injuries, is not as high in Canada, even though if you paid attention to the previous slide, you have on average the majority of people drink, and you have heavy drinking. But consequences are different; that's where cultural difference can help to explain some of these findings.

Maristela Monteiro: Well, the data was used. It was put into a model to analyze the effect of alcohol on the burden of disease. What is the consequence in terms of mortality and morbidity for the regions?

This is part of the region analysis. So the region was divided in three subregions.

American A is the developed countries that have very low infant and adult mortality.

America B is the majority of countries in Latin America that have an average mortality for infants and adults.

And America D is the very poor countries that have very high mortality for both adults and children. And here are only six countries, and two of them participated in this survey.

Maristela Monteiro: So the data was adjusted and used as average for the subregion, and also there were data from other surveys that were used in this very complex model. That's a WHO model for the burden of disease.

And from this table, what can be seen is that you have more drinking where you have more development. In terms of consumption, unrecorded consumption is highest among the poorest countries.

That mean illegal or non-taxed alcohol is more prevalent in the poorest subregion. And the last column that says "pattern value," this is a criteria category that was developed, validated by WHO, on the impact of alcohol consumption of the population on the harms. And the higher is categories from one to four, and the highest is the most harmful to health.

And you can see, again, the lowest scores is for the developed countries, in the middle - no, three out of four in America B, and the same for America D.

So except for Canada and the U.S., all the other countries have a relatively high risky consumption, meaning not everyone drinks, but when they drink, they drink excessively. There is practically no moderate drinking, a pattern of drinking that we see in Europe or in the West, for example, on average, drinking with meals and just not to get intoxicated.

Maristela Monteiro: These are the deaths attributable to alcohol consumption, with mortality data from 2002, and you can see - just for the matter of time that we have - the total at the end: 8.7% of all the deaths in the region in 2002 were attributable to alcohol, and for women was 1.7%.

This compares to the world calculation: that's 6.1% of all deaths in the world were related to alcohol in 2002. That means that in the Americas, the toll of alcohol is higher than the global average, for men and for women.

Maristela Monteiro: Years of life lost attributable to alcohol. Now you here see 14%. This combines not only the people who just die, but they die earlier than expected or live not a number - one person, one death, but the years of life that were lost with that death. And because alcohol kills young people, particularly men, for males 14% of all the years of life lost across all ages among men is related to alcohol, and 3.2% for women.

That compares, that's more than double the global average of 6.6% - I don't know if you can see that - for men. And DALYs which brings together mortality, because, well, you die early. But also when you don't die but you continue to live with a disability for some period of time with less than the average or perfect health.

Maristela Monteiro: So this is a disability-adjusted life years, and 15% of them among males are due to alcohol, and 4%, basically, of women are due to alcohol in the region. That compares, again, with the world result of 7.1%.

So the burden of alcohol in the Americas is much larger than the global average. It is the region in which alcohol is the first risk factor for the burden of disease. On the global level, it was the fourth, but in this region was the first. It's more than tobacco, its impact.

Maristela Monteiro: So the basic conclusions of the report. The report was published last year and is available in print and online.

There were wide differences between countries in consumption variables, and the overall consumption is high in all countries of the region. Even among the poorest, alcohol is a more important factor to life lost than malnutrition, lack of sanitation, unsafe water, poor diet, or overweight, which exists also in poor countries.

Beer was the beverage of choice, and there is also still a concept that distilled spirits are preferred in Latin America. It's not true. The pattern of use, on average, is harmful to health. Heavy episode drinking is also very high among young men and women, and the gender differences were seen in all countries, but men overall report more consumption.

Maristela Monteiro: The consumption was comparable with reports of fighting and injuries. There are also data we have on alcohol dependence, alcohol abuse, and other problems. It's just we did not have time to analyze all this data.

And consumption increases with economic development and also with gender equity, meaning the more a society decreases gender gap, there are more equal rights between men and women. Women have more access to education and jobs. They are also exposed to more consumption and the pattern of use of males.

And they adopt those patterns, but they are biologically more vulnerable to alcohol and, therefore, suffering more consequences, not only because of their drinking but also because they become victims of their partner's drinking.

Maristela Monteiro: And this is what is coming out next, is the next publication that is going to be launched in December 4th this year, a book that is called Unhappy Hours: Alcohol and Partner Violence in the Americas. That has analysis from each country on the relationship between gender and domestic violence and partner aggression, basically. Not only analysis of the victim, but also the perpetrator, what are their patterns of consumption.

And here, I didn't give all the details because it takes the meat out of the book. It is going to be very new in the field. It's the first time that we have this type of analysis done.

And regardless of gender, when people drink, they are more aggressive, and they have more reports of aggressive behaviors, violence, with or without an injury. When women drink with their partners, and that leads to an aggressive episode. If they were drinking, the severity of the aggression is higher, and they're more likely to end up in an emergency room. So this has implications for policies and services attending women, as well as policies to curb the aggression among men.

Because it increases with economic development, you need to be aware of people, not only in health but also in economies. And people talking about development need to be aware that there are setbacks and there are ways of bringing development without promoting alcohol consumption in countries, but they need to be available.

So the conclusion in terms of policies is that decreasing the availability of alcohol, not prohibiting, but regulating it, regulating the illicit market of alcohol, and creating services for victims of violence, for example, can have a significant impact in interpersonal violence in the region.

Maristela Monteiro: Last slide is this study doesn't stop there. We're probably starting in early 2009 with four new countries that will use the same questionnaire and collect data in their general population as well.

And we continue to use this information for building capacity and political will to afford alcohol policy. In each country that participated in Latin America, they publicized the results of the study, and this is leading to new policies in the country. Thank you.

Audience: Thanks for an elegant presentation. Quick question on how these findings are used for prevention, for intervention in different countries. I'm thinking specifically about health education, if there've been programs to educate women so they can understand the implications of alcohol abuse and the relationship to partner violence and that sort of thing. Has that been done, and if yes, have you seen any changes in behavior?

Maristela Monterio: Now, the results are too new to know if there were changes. The results were disseminated at the country level with national workshops in which women's groups and coalitions that work on alcohol and domestic violence and people from ministries attended, and they are aware of this.

We now, in PAHO, are working with the gender unit to show to the people who work in domestic violence and gender equity that alcohol does matter. It's important for the policies, not natural, and people only think, "Oh, yeah, alcohol," but they don't know what can be done.

And in specific, for example, in Uruguay, this has led to a national plan for alcohol policies. It is not only because of this study, but there were also studies supported by CICAD, along with students, and the issue of alcohol becomes very strong when you begin to ask questions and see how prevalent is the consumption.

And so basically, this is a process that is starting, and that's the plan is to include specific messages for the development of services, protection of women, and also implementation of alcohol policies in general that will benefit women and decrease consumption among men and women.

Audience: Buena presentaciÃ?n.

Maristela Monteiro: Gracias.

Audience: In your conclusions, you had a bullet that says that the alcohol consumption increased with economic development. Yet if I read correctly, there was a notable exception with Peru that had a higher, perhaps the highest, of alcohol consumption in one of your slides.

Maristela Monteiro: On average.

Audience: On average, yes.

Maristela Monteiro: Yeah, compared - yes.

Audience: I was wondering what your . . . could you talk to us some about that?

Maristela Monteiro: Peru fits exactly the profile of America D. Even though the general overall prevalence of drinking was higher than in other countries in the subregion, what matters is that when people drink, they drink heavily, and that was also found there, and that's why you get the results so much worse than with America B.

You can have less prevalence, overall in the population, of drinking, or even more prevalence. But when people drink, they drink heavily. That's when you get problems, and that happen in Peru too.

And there are in the study, the comparisons between Lima and Cusco that have the same type of prevalence. You have less drinking among the less prevalence of drinking among the indigenous, but when they drink, they are much higher.

And you have more consequences reported than in Lima, in Peru, where you have a mix of the population.

Audience: Thank you for your presentation. On that same point, the related point about consumption increasing with development. One of my research interests is the relationship between acculturation and worsening health outcomes. We're living with this notion that American culture somehow causes that and trying to disentangle that. So I was wondering if you could comment to what degree in some of these countries, increased development perhaps means a closer approximation to U.S. cultural norms and values and beliefs and behaviors.

Maristela Monteiro: I believe it's beyond the U.S. It's related to globalization, because alcohol is a global product. It's a commodity that is being sold with a single message: the more you drink, the better.

With development, each country has access to not only better roads, but also Internet, cable TV, sponsorship of events. And they all bring the same general culture of heavy drinking, intoxication, drinking.

You need to get drunk to have fun and to be successful and all that. So the culture, in that sense, isn't acculturation, but it's not only a U.S. phenomenon. This is global now, and some companies are in the U.S., but others are not. They're multinational companies.

They all use the same strategy, and they all learn from tobacco. Actually, most of them are owned by tobacco companies now. There is a link.

Antonio Cepeda-Benito: Our last presentation is by Marya Hynes. Marya works for CICAD, which is the Inter-American Drug Abuse Control Commission. And she is a person who has been very helpful to our organization. She has led the effort to create REDLA, the Red Latinoamericana de, in drug addiction. And she's going to make a presentation of some data that she coordinated together with Pancho Garcia to collect in South America.

Marya Hynes, M.H.S.: Well, we've been looking sort of fairly in-depthly at cannabis and at alcohol, so I'm going to try and do exactly the opposite here and really pull back the microscope a little bit and show what we kind of see in Latin America in a very broad and general way.

But I think it tells us a lot about the drug problem as a grand phenomenon that there's a great deal of diversity of patterns of use from country to country. It's not always apparent when we dive deep into a certain subject, and I think to understand the way the drug problem plays itself out, it's important to understand these differences from country to country.

So if my presentation is successful, you'll come out thinking that, well, actually, maybe the problem's more complicated than we imagined, but at the very least, that we're not looking at a single phenomenon.

Marya Hynes: And quickly to tell you who we are, I work at the Inter-American Drug Abuse Control Commission. It's part of the Organization of American States, and we have a research unit there known as the Observatory on Drugs, and we do research and statistics in Latin America.

Most of what we try and do is make sure our information is always comparable between countries, and so what I show you when we get to the data will be about as comparable as you can get. I'll explain a little bit about that.

Marya Hynes: We work through national drug observatories in each of the countries, the drug commissions, the CICAD Executive Secretariat. There is an evaluation mechanism that also gives us orders, and we take orders from the heads of state as well. So we get pushed in a lot of directions, and we try and make sense out of all of the instructions we get, and come up with good science as a result and something that is useful to inform the policymakers.

NDO means National Drug Observatory. Every drug commission in Latin America and the Caribbean has an observatory, a research unit. Some are more functional than others, but they all exist in one way or another.

Marya Hynes: That is our network. We work through the government, and since there's no NIDA in Latin America, that's usually the closest you can get in terms of somebody who deals with data and policy at the same time.

We have a second network, a smaller network, known as - in Spanish it's the Red Latinoamericana de Investigadores en Drogas, just means Latin American Drug Research Network. It's maybe not the most creative name, but it works for us. The REDLA: this is more scientific, academic researchers, and that's where we try and get at more of our in-depth look, not just your big national picture. Just to give you a sense of our network and how we function.

Marya Hynes: And now I'm going to dive into data because we only have 15 minutes and it's a big hemisphere.

Marya Hynes: So what we're looking at here in the beginning, this first set of data, and just to give you a sense of what we're working with, the countries you see here below are nine countries where we carried out drug use surveys in secondary schools simultaneously, during the same 12-month period.

It was between 2004 and 2005, using the same survey instrument and the same methodology. All of these were national surveys. And unless I tell you differently, that's where the data comes from that you're looking at. Secondary-school students, and about as comparable as you can get. This data's been adjusted for population size differences and gender structure, so the prevalence rates are a little bit different from what you'll see in the crude data, which I'll throw a little bit of that in, too, to mix things up a bit.

I always begin with this slide because I think it is very useful in the way that it distorts, actually, what you see in Latin America. From where I work at CICAD, my experience has been that from North America and Europe, Latin America is often viewed as one big Spanish-speaking country.

And I get questions like, "Well, what is the drug problem in Latin America? What does it look like in Latin America?" And, in fact, Latin America is a very diverse place. Not everybody even speaks Spanish in Latin America, but yet in North America, I think we, even those of us who are from Latin America, make the same mistake sometimes when we turn around and look south again in thinking of this one big place.

In fact, if I were to look at it more accurately the way I think Latin America is viewed, I'd lump all of this into one big block, and it would be the United States of Latin America.

So what I want people to understand is that what we're about to see is how, when you look at the data, things break down very differently. So let's, if you were to look at past-year illicit drug use among secondary-school students in a very broad and general way, you may look and say, well, Colombia, Chile, Brazil, high-use countries. Kind of in the middle you've got Uruguay and Argentina. In low-use, Bolivia, Paraguay, Peru, okay.

Marya Hynes: And yet when we start looking drug by drug, we see different things going on. So this is past-year marijuana use among the secondary-school students.

Again, this is all the same survey data done at the same time, and here Chile stands out as a very high-consuming country in comparison to its neighbors. Now, this is not, 12.7% in the past year isn't very high for, say, United States, and yet around the region this is the highest rate that you see. And most of drug use in Chile is actually driven by marijuana use, and that can be seen very clearly when you look at the national data.

Marya Hynes: And if we were to look at cocaine, Chile still stands up, but then we have Argentina, Uruguay kind of showing up as slightly higher use. And I'm going to talk a little bit more about cocaine in Latin America and some of its unique issues a little bit more if I have some time.

Marya Hynes: And then we look at Ecstasy and we see Colombia kind of stands out now as a higher Ecstasy-use country, where we didn't quite see it so much before.

Marya Hynes: And I always like to pause here because this one is a bit of a loop that we throw. Brazil, past-year use of inhalants definitely stands out as the highest rate, and it's almost incredible to see rates that high. And we went back when we did this study, to Brazil, and made sure that this in fact jives with the rest of what is seen in the country, and, indeed, all of their usage surveys show something very similar.

And Brazil actually has kind of a cultural tradition when it comes to inhalants. There's a particular substance called lanÃ?a perfumes. It's also lÃ?lÃ? as kind of a homemade version of the same. It's ether and alcohol and perfume mixed together, and it's used as a party drug. And so when we look at Brazil, we're actually looking at something very different than inhalant use in other countries.

And if we can imagine that Brazil's not there for a moment and just look at the other prevalence rates, these are not low rates for inhalant use. And, in fact, inhalants, I think, are one of the least studied important drugs in Latin America. Very consistently, they show up as the second most common used substance, after marijuana, in any of these countries, the exception being Brazil, where they're first.

And yet there's very little legislation, very little attention paid to inhalants as a substance. And the reasons for using inhalants are often very different for those for other drugs. They tend to be associated with street children for hunger repression. And yet these are secondary-school students; these aren't kids who are going hungry.

Marya Hynes: Pharmaceutical use. When the REDLA group met, this information provoked quite a lot of discussion. In our broad surveys, we actually don't, in my opinion, do a great job of looking at the use of pharmaceuticals. We have two broad categories: tranquilizers and stimulants. And we don't break them down, and we would like to change that. But this really brought us to sort of a general issue of the cultural self-medication in Latin America, and when you look more in depth at different national data, it's very common, the use of pharmaceuticals without medical prescription.

Marya Hynes: What really gets my attention about this information that you can't see very clearly from this slide if you - I'm sure you memorized everything I've shown you so far. But the back, the very first slide where we had general substance use, the lowest-use countries were Peru, Paraguay, and Bolivia, and, at least for tranquilizer use, they're the highest.

These are also countries that don't have a lot of controls over obtaining pharmaceuticals without your medical prescription, and certainly that has something to do with what we're seeing. But, again, an issue worthy of study, and more careful study in Latin America, is the use of pharmaceuticals.

Marya Hynes: Okay, marijuana. This is the hemisphere. I think this is everybody. What I tried to do -- a lot of this data hasn't been seen before - is take all the information we could get from every country in the hemisphere, and I popped in the United States and Canada to kind of give a bit of perspective on where we are for marijuana use.

If you recall, Chile was the highest in the South American countries I showed you earlier on. They're kind of upper-middle here when you look at the hemisphere.

It's hard for you to read the names, probably, of the countries, but if we begin, the highest rates, you see the United States and Canada. I don't think that's a big surprise to anybody.

And then just going in order, you see Dominica, St. Lucia, Grenada, St. Kitts, Antigua, Jamaica, St. Vincent, Barbados. Then we get to our first Latin American country. Everyone up until then has been in the Caribbean. Then Chile. Then Belize, Guyana, Trinidad, and then you see the rest of Latin America starts to fall into line.

So what was interesting for us at CICAD is, there's this very clear split in terms of marijuana use between regions, and, again, I think it's broadly known they use a lot of marijuana in the Caribbean, so maybe that's not a big surprise.

Marya Hynes: So when we compared it to tobacco use, what we found is that in a lot of the Caribbean countries, marijuana use actually exceeds tobacco use.

And when you look at the ratio of marijuana to tobacco use, you can see that, in fact, quite a few countries in the Caribbean, the rates of marijuana use far exceed tobacco. The highest is Antigua, four and a half to one, St. Kitts, St. Vincent, Barbados.

So here we actually have populations that, at least in secondary-school students - we haven't looked in the general population, but I'm fairly certain it's still true - that groups that smoke marijuana exclusively and don't smoke tobacco.

Marya Hynes: This is past-year cocaine use lined up in the hemisphere. And I only have, like, two minutes left, I think, so I'm going to try and wrap up, actually. But cocaine, I want to say a few words about cocaine because when we got beyond our secondary-school students and looked at the general population, it seems that the cocaine use is one place where Latin America starts to look like the rest of the world, which is a concern given that most cases, drug use is far lower in Latin America than it is in United States or Europe.

Marya Hynes: So what we have here, I have cannabis and cocaine on this little chart. And we're looking at, what we did was we combined six countries in South America that had done household surveys with us simultaneously in 2007. Right? 2006? And looked at their combined rates and how they compare with the rest of the world.

So if you look at cannabis, the worldwide rate, about 3.8%; in Europe, around 7; United States, 12.4; and in these six countries in the general population - I'm now talking about not just students - 4.8. Still lower than what you see in the United States and Europe, higher than the worldwide average.

But when we look at cocaine, the worldwide rate is about .3 percent; in Europe, 1.3; United States, 3.0; and these six countries, 1.4.

I guess the point here I want to make with my presentation is that there's a lot of diversity of use, and there's a lot of, patterns of use across countries are not the same from one place to another, but in fact there are areas that we start to look like the rest of the world.

And I think that ties in a lot with the discussion that was taking place at the end of Maristela's presentation. One thing that you can see this phenomenon quite clearly with Latin America in illicit drug use, just as Maristela pointed out with alcohol, that as indicators for development increase, so do your drug use rates. And the countries with the highest indices of development also have the highest rates of drug use.

This may have to do with lots of different things, as discussed, but perhaps it's something we need to keep our eyes open about in terms of development, that there perhaps are some things that aren't so nice that come along with it. So that was my presentation. Thank you.

Marya Hynes: This has my name here, but I can't take credit for this. This really is a result of work from all of the countries in Latin America that carried out these surveys. There's only four of us at the observatory, so we didn't do this alone.

Audience:I have a question. Has your institute ever thought of maybe scoring some of these issues qualitatively? For instance, the high use of marijuana in the Caribbean. Instead of doing a survey, have you given consideration to say, doing a small ethnographic study in those countries to sort of see what processes in the context of why that would happen in that particular country, in those countries and not in other countries?

Marya Hynes: Yeah, I'm glad you asked that question, actually. As I was saying, there's only four of us at the observatory at CICAD, so we can only do so much. And we are constantly looking for partners, for collaborators, people who would be interested in doing some of these more in-depth studies.

There's nobody at the observatory who could actually write a grant right now, so it's a little bit out of our scope. But definitely we can partner with people who are interested in doing that sort of work as well. These are things that we think really need to be done, and part of my idea of showing the data in this way is to get people thinking about there are a lot of issues that need to be explored more deeply.

Audience: Has there been any look to see if they're sinking harder, actually, that there's an increase in health consequences in those countries?

Marya Hynes: Health consequences associated with illicit drug use? In those particular countries, I don't think so. There are six countries that have done economic impact studies, which involved looking at morbidity and mortality associated with drugs.

Peru, Paraguay, Bolivia were not among that group. Peru has some excellent research. In fact, one of the REDLA members from Peru, Fernando Salazar, is here in the audience and probably could answer about Peru better than I could. There's not as much work that's done in Bolivia and Paraguay.

Audience: Do you have, in the questionnaire that you use across all these studies here, questions about age of onset?

Marya Hynes: Age of onset, yes. Yeah. Yeah, I don't have that in this particular presentation, but we do ask about age of first use. I think in the, there's a very broad, general report from the student survey and a second one from the general population survey that are both on our website, and I can give you the website. But that information should be in both.