Renato Malcher: “Recreation is medicine. When we feel happy, we are self-medicating with our endocannabinoid system.”

Neuroscientist Renato Malcher Lopes, professor at the University of Brasília, is one of the main speakers at the ExpoCannabis Brazil, which premieres tomorrow, in São Paulo. Next Sunday, September 17th, Renato Malcher will give a talk at the event's International Forum, entitled “Facing prejudice: Science in the use of cannabis for medicinal purposes”, where he will talk about his interest in the medicinal exploration of cannabinoids, more specifically in the treatment of Autism.

A ExpoCannabis Brazil arrives in São Paulo for the first time this weekend, bringing together more than 100 experts and authorities from countries such as Brazil, Argentina, the United States of America, Mexico, Paraguay and Uruguay. The event also has more than 140 exhibitors and expects to receive around 30.000 visitors to hear more than 100 speakers in different areas of specialization in the cannabis sector.

We spoke to one of these speakers, neuroscientist Renato Malcher, to learn more about his work and the research he does with cannabinoids.

As a neuroscientist, what has been the focus of your work in recent years?
My interest has been the medicinal exploration of cannabinoids – the products extracted from cannabis. We have an article already published on the use of cannabis extract for the treatment of Brazilian autistic people and two more studies where the composition of the extracts varies, more or less. One we do with the support of a private clinic and these doctors' patients actually use a product produced by patient associations. In another project, with colleagues from the University of Brasília hospital, we used an industry formula. There are two different comparisons: a use with a formulation that is not so rigorously defined and one that is a well-defined formulation of a pharmaceutical product. One of them has a much higher ratio of CBD to THC and the one in the family groups has a little more THC, so we are exploring the comparison not only between the formulation, but also between the style of use. On the one hand, a more controlled use, better defined in terms of dosage and, on the other, a more flexible style of use, more similar to a phytotherapeutic use. Furthermore, with the same clinic with which we are carrying out autism work, we will also carry out a retrospective analysis of other types of diseases, such as chronic pain, anxiety, dementia, Parkinson's and Alzheimer's. We will produce articles based on retrospective reports from people who have already used it, we will analyze their medical records to do some tests with them as well and some questionnaires to enrich the data. The biggest focus of my work lately has been this.

Renato Malcher has dedicated his research to studying the endocannabinoid system in pathologies such as Autism

But I imagine you haven't always worked with cannabinoids. Since when did you become interested in this research?
This question is very interesting, because I did my PhD in the United States and the objective of my PhD was to try to understand the mechanism that regulates the production of a hormone called cortisol, which at normal daily circadian levels, serves to make us eat. In other words, it is a hormone that stimulates the appetite. When lunch time arrives and you start thinking about food, feeling your stomach moving, it's because that hormone is rising. But this hormone is also important for situations of stress. This is very interesting, because, in nature, when an animal has to eat, it is in a situation where it is exposed to stress. If it is a herbivore, for example a rabbit, it has to leave the hole at some point to eat and is more exposed than when it is in the hole. If he is a predator, he will have to fight to get food, so it is interesting that the same hormone that leads the animal to a potential situation of stress, is also produced in situations of stress. And why is it produced in both situations? Because it has an effect on controlling our energy reserves. When we wake up in the morning, for example, hungry, we haven't eaten yet, so the energy we will use to get food is the energy from the reserves we have of glucose, of fat. That's why cortisol, in addition to making you hungry, helps to break down this reserve, to give you energy until you find food. This same function is also important in any stress, because, in general, it is a situation in which you either need to fight or flee or invest energy to fight microbes through inflammation. So, cortisol has this initial effect of stimulating the metabolism process, but it also has a long-term effect, which works in waves. The first wave is to help with stress acute, to fight, to look for food, to use the body's energy resources. But then there are effects that take longer to establish, which are precisely to bring the body back to normal, after the stress. For example, reducing the activity of the immune system, which is stimulated by stress; If the immune system remains overly stimulated, we begin to attack the body itself. Inflammation is something our body uses to protect us, but too much can be bad. Covid is an example of this. What usually causes the most severe cases of Covid is precisely the body's excess response to this inflammation and there are several diseases that are chronic inflammation. This hormone is very well regulated, it is produced from a signal from our brain, in a region called the hypothalamus, where there are neurons that release a substance in a gland located at the bottom of the brain – the pituitary. That substance causes it to release another substance into the blood, and that substance will cause the adrenals to produce cortisol. Cortisol organizes everything it has to do in the body and then returns to that starting point and says “It is no longer necessary to send me to be produced in the adrenals, because I am already at the right level”. This mechanism, of cortisol turning off these initial neurons, no one knew how it worked. So, we went to investigate, in my doctorate, as part of a project that I was already having in the laboratory, what this mechanism was like, and then I became interested in the project and we discovered that what controls this are the cannabinoids that our own brain produces . The exit mechanism stress it depends on cortisol returning to the brain and telling it to produce cannabinoids and we know that this mechanism is important for regulating the level of cortisol itself, but also the level of thyroid hormones; growth can also be regulated like this, it is also important to regulate memory, emotions, and to regulate motivation and pleasure to get things. Therefore, this mechanism that links the hormone cortisol with endocannabinoids has become very interesting to understand how the endocannabinoid system governs all important aspects of our biology, including emotional, cognitive aspects, physiological aspects themselves, mediated by several hormones.

“Endocannabinoids serve to bring us from a “war” situation back to normality”

What main conclusions did you reach with your research? 
This discovery from our work made very clear the central role of endocannabinoids in the holistic control of all biological processes that maintain well-being, functioning at two key moments: it works throughout the day for small fluctuations (for example, when we are hungry for lunch, it increases cortisol and increases cannabinoids in our brain, which is why people feel hungry when they smoke cannabis, because cannabinoids are what generate our desire to eat again) and it also controls the return to normality after stress (turning off the circuits that activate the sensation of pain, nausea, the specific suffering of anxiety, fear, anger, frustration). Endocannabinoids serve to bring us from a “war” situation back to normality. The “going to war” mechanism is important from time to time, but it cannot last long, so endocannabinoids come to try to get the person out of that situation. And another situation is the opposite, because in the same way that we, as animals, need a mechanism that dedicates the entire body to dealing with a life or death situation (for example, a predator is coming to chase us, someone is going to attack ourselves, or we are in a fight for a social, emotional issue), all of this is very important for our biology and is a stress, and then we have reactions, our adrenaline increases, the speed at which our brain works increases, we feel emotions typical of antagonism. So, endocannabinoids are good for getting us out of this, because if it lasts for a long time it's worse, but they're also important, because we need to organize our brain, our entire biological function, to take advantage when things are good. When there is plenty of food, when we have our social network well established, when we have shelter, we are not thirsty and everything is calm, cannabinoids help us to be more creative, to have more social connection, to have more stimulus to take advantage of this situation, we have the impetus to remodel the house, redecorate the “nest”, look for new partners, if necessary. That's when my path to medical cannabis began. For a long time I didn't study anything specifically related to the plant. I studied what our brain produces that is imitated by the plant.

What year was that?
My PhD was between 2003 and 2006 and it was at that time that we made these discoveries.

At that time, people were already talking about endocannabinoids and the endocannabinoid system had already been discovered.
It was discovered in the late 90s and we published this in the early 2000s.

But when he started doing his PhD, he already knew about the existence of endocannabinoids…
We knew. We just didn't know they had anything to do with cortisol. It was the first time that the hormone was shown to regulate the endocannabinoid. The only regulation we had was like this: if we have a synapse and it becomes very active, the neuron that is receiving the signal to be activated produces endocannabinoids to go back and say to that neuron “Stop, I got the message.” It is a feedback negative. So, this is the mechanism that established the discovery of the endocannabinoid system as a system for regulating the flow of information, to prevent the flow from becoming noisy, to maintain a clean flow. But we ended up discovering that there is also a direct relationship between hormones and endocannabinoids. Another curious thing we discovered is that we have a cycle that is the fasting > high appetite > food > satiety > hunger cycle. We discovered that in the center of the brain — which participates in regulating this entire process of metabolism, hunger, appetite and adaptation to stress and the control of several hormones, which is a very integrated thing, everything is interconnected like a clock —, on the one hand, the hormone that stimulates appetite, which is cortisol, causes the release of endocannabinoids in the brain and this articulates all the processes that lead the animal not only to eat, but to feel pleasure thinking about the food before eating it and to feel pleasure when eating it; we saw this connection. On the other hand, we also discovered that there is a hormone called leptin, which does the opposite – it helps to establish satiety. And what we saw is that, when we are fasting, leptin drops and cortisol increases, therefore the cannabinoid increases, appetite increases. If leptin increases, it prevents cortisol from causing an increase in endocannabinoids and, therefore, promotes the establishment of satiety. So we saw, on the one hand, that cortisol stimulates the production of endocannabinoids and this is part of the mechanism that stimulates appetite and the return at the end of the day. stress, let's say; on the other hand, leptin prevents cortisol from continuing to produce the endocannabinoid, it decreases, and satiety sets in. We thus discovered this exchange between two hormones: one that stimulates appetite, stimulating the endocannabinoid, and the other that establishes satiety, preventing this other hormone from producing the endocannabinoid. And the interesting thing is that this mechanism is not only present directly in appetite control, because it actually orchestrates all biological processes. We talk about sexual aspects, physiological aspects of inflammation, appetite, metabolism, but the brain is always sending signals through neurons and hormones: “Look, liver, now we are in this situation, so do this”, “ Pancreas, this is the situation now, do this”, “Testilles, now it's time to go to battle” and the testicles say “No, now we are in another battle, not now” and the brain does this all the time. And endocannabinoids are very central, returning to context, in two specific situations, as I said: to get out of the “war” and return to normality and to make the most of things when everything is fine. Endocannabinoids work like this. That's why they have such vast medical potential. After all, what are endocannabinoids? It is the substances that our brain produces that are imitated by the plant; the plant produces things that enter our brain and that fit into the same lock as these endogenous substances that we produce. And these endogenous substances are part of the repertoire we have, precisely to generate well-being or to switch off discomfort, which is why it can be used in any type of disease that causes symptoms of discomfort. Cannabinoids are potentially helpful in these cases, because physical pain, nausea, inflammation, and any type of psychological distress can all be treated with cannabinoids. And what is the disease that does not have these types of symptoms, that cannot benefit from it?

“We know that autistic people have an abnormal, low amount of cannabinoids”

In other words, it is as if in some diseases there is a deficiency of endocannabinoids, which can be compensated with exogenous cannabinoids?
Exactly. In some people, apparently, there are diseases that relate to a difficulty, an incapacity, a loss of efficiency in the production of cannabinoids. Nowadays we can find this, for example, in the case of Autism. We already know that autistic people have an abnormal, low amount of cannabinoids and there are other situations that can lead to chronic inflammation, which can also involve cannabinoids. So, there are situations in which the body apparently has difficulty producing cannabinoids and is unable to self-regulate. For example, the stress chronic is the situation in which the cannabinoid was caused to take the person out of stress, but the person has no control over the stress. For example, a soldier who goes to war cannot decide “my life is hell, I’m going to go home”. The person who lives a miserable life, who has no financial resources, who has to work 14 hours a day, cannot feed his family, is always stressed, you can't escape the stress. The person who has lost a loved one and will have to deal with that grief for some time... There are ways to stress chronic cases, in which this mechanism, which is led by endocannabinoids, becomes desensitized, because the brain is telling the individual: “Get out of this situation”, but the individual does not leave, this mechanism is decreasing their ability to act. A typical characteristic of people suffering from depression, for example, is having less cannabinoids than normal and more inflammatory substances than normal, therefore chronic suffering, whether caused by inflammation or sadness, will lead to the body's inability to produce endocannabinoids, which deepens the problem. The person can enter a spiral of starting to have suicidal ideas and along with this comes physical pain, because all psychological processes are linked to a stimulus of inflammatory processes that continue. Then, the person who suffers psychically from sadness begins to feel physical pain and a whole process is created that can, unfortunately, culminate, for example, in suicide or other situations, such as arterial diseases, obesity, loss of metabolic balance. All of this involves, in some cases, a deficiency in the body's ability to produce endocannabinoids, because the individual was unable to leave the stress chronic. Sometimes it's a biochemical issue, but the most normal thing is for it to happen this way. And it is very frequent. Today we talk about the increasing frequency of depression and the main cause of depression is stress chronic.

Renato has been a speaker at several international conferences and will participate this Sunday in the 1st edition of ExpoCannabis Brasil

It's curious because, in Portugal, they carried out a study with cannabis users for recreational purposes and more than 60% said that they used cannabis to precisely reduce anxiety and depression. This, in essence, ends up confirming, on an empirical level, that people themselves experience a substance that makes them feel better. This proves the science you are describing here.
That's exactly what happens. We discovered cannabis many years ago, 6.000 years ago, by pure chance. Probably, someone lit a fire in the bush to hunt some animals... because heat is important for releasing the components of cannabis, and then they ate what was left there, the roasted tubers, the animals and so on... one of those times, someone experienced a roasted cannabis plant, felt the effects and became interested in that plant. Since then, the plant has only gained medicinal properties, because it has become a species that evolves with man, in the same way as dogs or cattle. Nowadays, it is very difficult to find an original cannabis plant, because we have been close to the plant for millennia. The idea of ​​cannabis as a substance of abuse, prohibited, linked to crime, is a blip in the history of men with this plant. Until 1937 it was used medicinally, and there was even a tree of production of cannabis derivatives, between the end of the century. XIX and the 1930s, due to traditional knowledge that came from India. This was then incorporated into the industry, but later, for various reasons (there are several historical accounts of political and economic issues) the issue of prohibiting cannabis was created. We always have to mention, of course, that any substance that acts on our biological machine can be beneficial or harmful, depending on the quality and use it is made of, but in no way is there a justification for people dying to prevent it from being used. a medicinal plant. But we know that there has to be conscious use, right?

“All substances that are called drugs of abuse are substances that alleviate physical and psychological suffering. (…) In people who end up developing really problematic drug use, the cause of the abuse is not the use. It is the use that took place in a context where that person was systematically deprived of the basic right to be happy.”

Clear. But with the advances in cannabis for medicinal purposes, there are still many people who insist on making this separation: “medical use is one thing, recreational use is another”. How do you see this separation between the two universes?
Recreation is medicine. In any situation where we feel happy, we are self-medicating with our endocannabinoid system. And if we're not coping for some reason and we use a substance that makes us feel better, that's beneficial. One might think: “Ah, so this person isn’t going to do anything productive in their life anymore, they’re not going to work, they’re not going to meet their friends, they’re just going to smoke cannabis”, but that’s not the typical reality of women. people. People who actually get into a circumstance where they are held hostage to a single source of reward… Because we need a sense of reward to survive. When we wake up in the morning, we wake up tired, still sleepy, and we need to activate the circuits in our brain that will tell us why we have to face that day, right? I have to face this day, because I like my profession, I like being a journalist, I like seeing the impact on society, I want to hug my children, I want to eat my meals... so we need this reward when we wake up. Some people don't have that reward anywhere. For example, people who live on the streets, in poverty, when they wake up, wake up in a nightmare. For them, finding a substance that activates this system, which they cannot activate otherwise, is the medicine they have. All substances that are called drugs of abuse are substances that alleviate physical and psychological suffering. Cannabis is analgesic and relieves psychological suffering. Alcohol is an analgesic and relieves psychological suffering. Opioids are analgesics and relieve psychological suffering. Cocaine is an analgesic and causes euphoria. In fact, when people succumb to centering their lives around a substance, it is not the substance that causes it; it was their lives that put them in a position where they only had the substance left to give them what they needed, that little rush of “let's stay alive”. The concept of addiction itself has been reviewed in this context. Nowadays, the standard view of society... for example, in Brazil we have many socioeconomic problems and obviously this is reflected in the connection between this circumstance and drug use, so there are several situations of people living on the streets, without economic conditions, with dysfunctional families and using crack. The focus of TV is to say “It was crack that put these people on the streets”, but that's not it. Their lives went bankrupt, in some sense, and then they had to use their crack to be able to deal with life. So we have to be very careful when evaluating this. It is clear that substance abuse is a problem in itself, but today we can safely say that the majority of people who use problematic substances, who deal with this reward circuit, do so because this reward circuit is historically impaired. in their lives. There is a very famous psychiatrist (who was the psychiatrist of Keith Richards of the Rolling Stones – allow me a little humor in a very serious situation) who had a lot of trouble looking after these people. He says that most of his patients are people who had a childhood of abuse and violence or sexual abuse, or deprivation, or lack of food, resources, or being in a context of “war”, even within the womb… Children suffer the effects and are born with a propensity to have a different relationship with these substances, which act on these circuits. In people who end up developing truly problematic drug use, the cause of the abuse is not the use. It is the use that took place in a context where that person was systematically deprived of the basic right to be happy.

“The adolescent brain is not a suitable brain for using cannabis, because cannabinoids will contribute to how the brain will mature”

And in relation to demystifying some myths or the addictive potential here, another question I had to ask you was in relation to the fact that certain people can have psychotic episodes with cannabis.
This is real. Around 1%, at most, of the world's population has some propensity to develop a psychotic or schizophrenic disorder. There is a set of genes that make a person predisposed to this and this predisposition only means the following: with these genes and a life of this type, that person can develop the disease. That doesn't mean it will have to develop, right? But in general, we can say that those who have schizophrenia have a gene pool that leads to this path. And this path does not directly reach complete schizophrenia, it goes through stages; and a very common stage before a person is diagnosed, before having the first outbreak, is feeling anxiety. When you have a symptom that precedes a more important diagnosis, we say that the person is in the prodromal phase. The typical prodromal phase of schizophrenia, which occurs a lot, especially in youth, before people actually start to develop schizophrenia (which often happens later, but can happen earlier) is a phase in which the person feels a lot anxiety. A teenager who has this genetic makeup and who has a tendency to have anxiety, when he uses cannabis with friends who don't have this tendency, the effects are different. For this friend who has a normal life, who doesn't have anxiety, who isn't normally suffering psychically, he just added more color to his day. The next day, he won't miss it, because he has the rest of his life, he might want it again eventually. For this individual [who has the predisposition], he didn't go from there to here, he went from here to there, he went from a state of psychic suffering to a state of joy, so for him the relationship with the substance is much more complex , because the absence of the substance now, for him, means returning to a state of anxiety, which is why these teenagers tend to use more chronically, to use more again. This is where a problem arises, because if cannabis has a very high THC component, the THC itself has an effect curve that takes the person... we have a way of graphing the emotional sensations that can be placed on two axes main ones – the salience axis and the valence axis. Valence is whether it is bad or good; the salience is whether it is too much or too little. Euphoria has a very large positive valence and a very high salience. Panic is the opposite – the salience is very high, but the valence is very negative. THC, due to the way it acts in our brain, can go from the high positive salience, which is euphoria, to the high negative salience, which is the feeling of paranoia, and this feeling of paranoia, in a teenager who has this predisposition to schizophrenia, can trigger the first [psychotic] ​​episode. It doesn't mean that it was cannabis that caused it, but it does mean the following: for this teenager, it would have been better not to have used cannabis in that way and perhaps to test a composition rich in cannabidiol, for example, which is a component that favors the anxiolytic side. of cannabis use. The message to remember is that any substance that acts on our body acts differently on each individual. And, among individuals, there are those who will only have more positive effects than negative and there are those who have a tendency to have more negative effects. So, people, and first of all young people, unless it is for a clearly oriented medical issue, epilepsy, autism, have no reason to use cannabis. The teenage brain is not a suitable brain for using cannabis, because cannabinoids will contribute to how their brain will mature. We consider that the use of cannabinoids is acceptable when clinically indicated, because they will be used in dosages that will not harm more than benefit, but unnecessary recreational use in youth is not recommended, because it can modify the way the brain goes mature. And this also includes the most tender stages, in the belly. It is also good for women to avoid smoking cannabis so as not to affect the development of the fetus; There is nothing very clear that indicates that mothers who smoked cannabis, their children got it, but the problem could be a tendency, towards middle age, to have depression, to have anxiety and we have a suspicion that this It could happen, but it will be very difficult to prove it. Then. Just in case, we say that it is better not to use it unless it is recommended by a medical situation. There is no need to panic, because medical use is a use where the dosages are known and these are oriented to produce the benefit. Above all, teenagers who show signs of anxiety, who live in a family where there is a history of psychosis and schizophrenia, need to be much more careful, even as adults, regarding the use of any cannabis. On the other hand, they can soon, I hope, start going to a doctor and asking for a cannabinoid composition specifically aimed at treating schizophrenia.

“There is indeed the potential to use cannabinoids to treat schizophrenia, paranoia and psychosis”

That's what I was going to ask you, about the use of CBD to treat psychosis or schizophrenia... What evidence do we already have?
An interesting thing comes from the past, which was when they discovered that these episodes, from euphoria turning into paranoia, normally happen when the person smokes cannabis that has little CBD. When there is a greater balance of CBD, the person does not have this experience. THC can be potentially anxiogenic, causing anxiety, depending on the dose, but CBD counterbalances this effect, is anxiolytic and has another effect that we call antipsychotomimetic. What is psychotomimetic? It is precisely the effect that THC can cause to simulate a situation of paranoia. This is a psychotomimetic effect that THC can have. CBD prevents this. Whether it is a pure CBD formulation or one with an appropriate ratio of plenty of CBD to THC, there is indeed the potential for using cannabinoids to treat schizophrenia, paranoia and psychosis.

Renato Malcher is one of more than 100 speakers at the first edition of ExpoCannabis Brasil, which starts tomorrow, in São Paulo

Wouldn't it also be important, from a perspective of reducing risks for youth, for governments and countries to make this information available to young people, so they can make better choices? And, perhaps, in the future, there could be dispensaries, like there are in Canada, where there are several genetics and varieties available, according to each person's profile?
We certainly need regulation and a public that is educated and not just treated as “if you’re wrong, you get hit; If it’s right, fine.” We have to treat people based on knowledge, we have to believe and trust in the importance of raising young people with a base, with a life focused on choices based on knowledge, not on fear, not on prejudice, not on panic. Therefore, for society in general, including young people and adults, would it be appropriate to be able to buy an alcoholic drink without knowing whether it has 10% or 70% alcohol? Would not be! That is why it is regulated and we can read on the label “this wine has so many % alcohol”; we know what we are taking home. If cannabis is not regulated, a person does not know what they are taking home! Therefore, if the person is aware, if they have chronic anxiety and have had a good experience with cannabis and at the same time recognize that they have a risk of having a bad experience and simply don't know what they are buying, they will continue to take risks- if; On the other hand, if she's in a regulated environment and she's enlightened, she goes to the store or a dispensary, and says, “That cannabis isn't good for me; I want this one, which has a lot of CBD and less THC.” And then you return home with a positive effect, without running the risk of having a negative effect.

What future do you see for the use of cannabinoids, specifically in autism?
I see a very promising future. The road is long, because under the “umbrella” of autism we have several different biological causes. There are several different 'machines', in which you put a substance to move them, and then we have to do a lot of research, better identify the types of organisms and problems of autistic people, and then explore the variations in cannabinoid compositions for each case. We have to do this first in animals and then, as the results come out, carry out more specific treatments for that group, in a more precise way. With this, I believe that we will have results, not only of palliative gains, which are not few, but also of real evolutions, of improving the ability to understand reality itself, improving the ability, eventually, to communicate better. Even if you can't speak, if non-verbals can establish some type of language, it will be beneficial for the way they organize their way of thinking. Really, I see that we can reach the point of having gains that are not just palliative, and when I say palliative, I am not diminishing their importance, because, basically, in some cases of autism, the person is chronically stressed, even because of what happens inside her brain, so this affects everything, including the person's well-being. Therefore, perspectives on the entire palliative aspect we are already beginning to have, in a palpable way, we are already seeing this result, although not all autistic people benefit to the same degree. We have to move to expand which groups can benefit and I believe that, at a certain point, we will have, not cases of cure or reversal of autism, but cases of improvement to another functional level that, otherwise, would not exist. Nowadays, this is the only prospect I see for a gain of this type in relation to autism, for now in cannabinoids, and perhaps, who knows, as knowledge about some psychedelics advances, it may be that they can collaborate also on the issue of cannabinoids for autistic people.