ii international symposium on medicinal plants in psychiatry organizide by cebrid (brazilian center for information on psychotropic substances) unifesp, november 2013, sã£o paulo, brazil ayahuasca, safety and biomedical research luãs fernando tã³foli, unicamp hello, good afternoon that is almost good night i'd like to thank the invitation to speak here professor marcia, i brought my presentation in prezi - laughs but i hope you do not get nauseated, right?
some people get a litle nauseated with prezi presentations, but once that we'll talk about ayahuasca and that one of it's collateral effects is exactly nausea and many times vomiting then you can understand this as an anthropological experience also, ok? well, my idea today is to speak specifically about ayahuasca differently than dartiu, who spoke about various plants with therapeutic potential or with abuse potential and that have therapeutic effect and other psychotropic plants used for treatments and as drugs of abuse and differently from marcia, who spoke about phytotherapy in general
i will focus in this specific preparation which has a series of peculiarities and that somehow has to do with some things already mentioned by prof. carlini by prof. gilbert and also by prof. dartiu let's see the agenda for this presentation i was asked to make the slides in english to make it easier to the guests, allright? but i think it will not be difficult for you to follow then il'd first like to give a brief introduction to the psychopharmacology of ayahuasca because there are some peculiarities important for those that don't know ayahuasca after that i will speak a little bit about the impact of ayahuasca on health, but i can already say that
based on our little understanding of it's impact, on average, is that it's positive and reminding you that if i leave something out or if you have questions we can discuss it later at the appropriate time for the questions you have i will speak about the importance of biomedical data considering this is an event to discuss the role of regulations, inclusive from the pharmacological point of view, toxicological, from the drug companies, in the context of regulations regarding ayahuasca, which is i brazil a legalized, authorized use for religious purposes therefore, to what extent the available data the biomedical scientific data, were enough
to favor the government opinion regarding this beverage and finally we will talk about future perspectives in this field so i will start by the pharmacology of ayahuasca so just to remind you, because it was already mentioned today, ayahuasca is a preparation a decoction made of two plants, a vine from from the malpighiacea family, called banisteriopsis caapi and here it is with its flowers and in a while i will show you the other plant which makes up this decoct it's popularly called a tea, but it's not a tea properly speaking, it is not an ifusion it is a decoction, ie, it requires prolonged cooking both plants
so that the active principles become present in the liquid and after cooking the plant material is disposed and only the liquid is drank. i will call it a tea, to make it easier, but it's actually, chemically, a decoction here we see monoamine oxidase, a molecule, an enzime responsible for monoamine degradation. monoamines are psichoactive substances and this molecule is extremely present in the digestive system, as a protective means to poisoning from monoamines or even as a form of defense towards psychoactive substances and it's responsible for the degradation of the best known psychoactive compound in ayahuasca at least the psychedelic component, which is dimethyltryptamine, which i'll speak soon which is also degradated by this enzime
however, you may see here, this little molecule fitting in the monoamine oxidase site and blocking it's biological action, hampering it in its degradation of psychoactive monoamines it is also present in the brain, but we believe that most of the blockage which allows dmt to access the nervous system when ingested purelly is because a peripheral blockage in the digestive system this molecule you saw there is a harmine molecule, which together with its companions harmaline, tetrahydroharmine and other substances, some already mentioned in this conference for example haman, nor/harman, harmalol and harmol, are also substances considered beta-carbolines. harman for example is found in passiflora
and harman is also a beta-carboline but specifically, passionflower, passiflora, is also from the malpighiacea family and here these are the main molecules present in the vine they are found in many different plant species but here we're speaking specifically about banisteriopsis caapi but as i mentioned it is present in passiflora, and in a plant from middle east called syrian rue, scientific name peganum harmala and for example, in a plant with therapeutic uses against malaria in mali, africa, called guiera senegalensis
biologically, i'll speak mostly about harmine, because there are some peculiarities we don't have time to talk about it all in details, but tetrahydroharmine for example it inhibts serotonine reuptake for example, which is not done by harmine or harmaline but harmine seems to be a very interesting molecule it has high affinity for monoamine oxidase a, inhibiting it in a temporary maner and speciffic also, because we have more than one type of monoamine oxidase, or mao and harmine inhibits specifically mao-a, but it also binds to, for example, a site regulated by a gene called dyrk1a, which is related to neurodevelopment we still don't know much about what is it for, but we know harmine binds it
and that it is related to neurodevelopment there is also a moderate binding to 5ht2a receptor, which is a serotonergic receptor which is the psychedelic receptor, activated by lsd, mescaline, psiclocybin which leads to the psychedelics subjective effects in this case there is a controversy if the vine's components, if used separately can cause psychedelic effects. from what it seems, if this happens, it is in a very modest way harmine also binds moderately to imidazoline receptors specifically the i2 subtype in which harmine binds to, is related to pain and neuroprotection there is also binding to 5ht2c serotonergic receptor and also with the dopamine transporter
which makes the reuptake of dopamine from the synapse to the interior of the neuron and here let's see the other component, i decided to start from the vine because in a general sense, in the scientific literature, and this starts to be questioned now when we speak about ayahuasca, the basic understanding is that we're speaking about dmt and that the role of the vine would simply be to make dmt orally ingested to access the brain but there are a lot of data which argues against this idea, there are various scientific discoveries showing the biological value of beta-carbolines and there is a pharmacological data which we can't forget all native tribes which use ayahuasca, give the beverage a name
and there are many admixtures present, the most common is this plant, psychotria viridis generally known ad chacruna or rainha, by santo daime specifically with this last name but there are other possible admixtures, with this being the most common, but what i was saying is that in traditional uses the beverage has the same name as the vine, therefore ayahuasca in quechua is the name of the vine and the name of the beverage. and it means vine of the dead or vine of the spirits psychotria viridis is a rubiacea, same family as coffee whoever saw coffee can see the similarities here and then we can notice the similarity between dmt molecule which i mentioned to you and the resemblance it has to serotonin
already showing that this molecule probably binds to serotonin sites however, it's important to take into account that, although i do not have the image here to show but there is a very complex binding profile of dmt's affinity with a series of different sites and receptors, we still don't know which of them has biological value, how much activation or blocking for example we know that in the case of 5ht2a there is an activation, as i mentioned to you that happens with psychedelic or hallucinogenic substances, so to speak an important point to mention is that it is already proved the dmt is in the brain mammals' brains, including the human brain, implying that
once this is a proscribed substance, which takes us to a strange peculiarity that we carry ourselves drugs all the time to wherever place we go showing one more peculiarities of the drug war as i mentioned to you, it is a 5ht2a agonist, it also binds the trace-amine receptor 1 which also we don't know the biological value yet, but there is a peculiarity a great body of evidence showing that dmt, which is present in our system is the endogenous ligand of sigma-1 receptor, whose function is still quite mysterious but that can be related to some emotional answers and possibly with the answer to some depressive symptoms for example
it is very funny because despite all this degree of speculation there are drugs already being marketed by the pharmaceutical industry as having specific action at this receptor and because of this it would have a special value, even though we don't have the slightest idea what it is for but only because it is special is already something for marketing, that's how it works, right? i'm not saying i agree with this... well, let's see some of the general biomedical aspects of ayahuasca only to illustrate it, we have the new book by beatriz labate and clancy cavnar which is not out yet, but it is already at the springer website, it will be released early next year where there are a series of discussions, some more speculative
some with more controlled evidence, about the potential therapeutic uses of ayahuasca for those that don't know, ayahuasca has a series of physical effects, i already mentioned nausea, vomits and diarrhea remembering that in traditional uses this is not considered collateral symptom vomiting, nausea and even diarrhea are considered purgative reactions necessary in some situations of negative emotions that need to be dispensed and liberated we know there's a little increase in heart frequency and in blood pressure some autonomic effects, some small alterations, for example increase in cortisol
that are extremely mild, very cinrcunscribed to the moments of ayahuasca use this increase in heart beats would be close to a light exercise like walking fast evicently, for those whose heart doesn't support even walking fast ayahuasca should be taken with much care or never be taken, depending on the situation but in general these effects are very discreet from the subjective point of view there are changes, and i mentioned riba here but i think the best reports are from people that subjectively talk about how it is the ayahuasca experience, even because this is one of those studies that, as dartiu explained used ayahuasca in a liophilized form, in a powder form. i don't think it's placebo as dartiu suggested
but probably there is something different in these reports of riba in relation to the physical effects. from the subjective point of view, it seems closer some body perceptions, some cognitive alterations and less from the intensity of the experience and in affect these experiences are less intense if compared to the effect of pure dmt that can be injected or smoked for example and then we have the most important aspect that is why do people use ayahuasca? we have a picture of around 30 to 50 thousand religious and ritual users in brazil this number is of course a guess, but definitely at least the uniã£o do vegetal
has 15 thousand users, and probably daime has between 10 to 15 thousand therefore it's not exaggerated to think about 30 to 50 thousand what are these people doing drinking ayahuasca? are they wanting a legal high, as once said in veja, brazil's largest magazine? what is this? do they want to hallucinate? what do ayahuasca drinkers describe as most important to them is an increase in the capacity to self-reflect, an increase in the capacity to see oneself and to notice things that need to change, mainly those things in which the own individual perspective is considered morally unacceptable. as well as the feeling of union with the universe
to be in communion with, the sensation of cosmic ocean, however you want to call it that can be felt not only with ayahuasca but with psychedelics in general from the point of view not of the acute effects but from the long term effects to those that drink ayahuasca we can mention a feeling of euthymia, of psychic well being that lasts a few days, approximately two weeks and that receives the name of afterglow in the psychedelic literature an antidependence potential, i'll talk about it later and an increase in the capacity to know oneself, evidently i'm not speaking here
of something miraculous, everything has limits, we are not talking about the universe panacea but somehow from this perspective ayahuasca can facilitate people to know themselves better regarding health risks, what the specific literature suggests, and there are more articles published later which are not included here, there's one from 2013, by rafael dos santos saying that, generally, what this literature says about safety, is that the experience with ayahuasca is safe with psychedelics in general, from the physiological point of view in a general way that's what we can say and i'm referring to the physical effects, not the psychological effects we have very preliminary studies from the therapeutic point of view
i'll talk about this later, when i mention perspective for future studies but it is important to consider that these are yet very preliminary results but in a general sense they consistently point to positive things to be discovered prof. gilbert mentioned that there were evidences a long time ago but nobody did anything about it remembering that there are many different settings a barquinha ritual is very different than a shamanic ritual, which is very different from daime rituals, which are very different from the uniã£o do vegetal ritual, and there are the neo-ayahasqueiros, so there is a great diversity
and we know that the impact of the setting is very important in the psychedelic experience since the times of alpert and leary, they pointed this out with psilocybin and dmt studies some of this centers, the majority of them, are religious centers, for example in brazil in per㺠ayahuasca use is regulated and authorized for therapeutic purposes, but not for religious uses but the frontier here, between what's religion and what's therapeutic is very thin therefore there are shamanic songs which invoke spiritual forces even though the use is therapeutic, and there are songs from the ayahuasca religions which are songs of healing remembering that we already spoke about ethnopharmacology, it's always good to remember
elements from anthropology, that that which is called cure to someone attending a ritual is not necessarily the biomedicine cure, therefore we have to check on it too in relation to mental health, particularly important in an event that's speaking about medicinal plants and psychiatry that drawing of ayahuasca in a pharmaceutic preparation is fake ok? not real do not get excited well, what do we know? we have also antidepressive effects, for example showed through animal experimentation we have reports of diminishing anxiety symptoms, already published
we have evidence of first time users of ayahuasca reporting a positive subjective experience with a reduction of psychiatric symptoms and an increase in the perceptions of assertiveness and vivacity an effect of ayahuasca against the inadequate use of drugs, or problematic use of drugs is also present in these studies, but there are also studies that came after this one also and we have some experimental data which are interesting, very interesting and promissing we know that bdnf, the brain derived neurotrophic factor has been systematically associated, when increased, to better results in depressive symptoms including from classical antidepressants, the delay in the increase of bdnf expression is approximately
the delay we see to the antidepressants' effetcs to appear, around 15 days some now, escitalopram specifically, which would have a fatser onset but somehow then bdnf would be related to some improvements in depressive symptoms some studies have shown that with the use of psychedelics, the improvement is immediate right after onset, the next day or the other the preliminar study made ar ribeirã£o preto with depressed patients also show signs of immediate improvements, and the increase in bdnf is associated with beta-carbolines in the case of harmine there are experimental data in rats but also the 5ht2a receptor, the psychedelic receptor also , when activated causes
increases in bdnf expression. there is also one study about the role of dopamine a very recent study from brierley and davidson, published in 2013, showing the possibility of ayahuasca having a therapeutic effect, sorry, not ayahuasca, harmine specifically having dopaminergic therapeutic agonist property , specifically regarding cocaine which allows us to think if maybe harmine could become some substitution therapy as methadone to the problematic cocaine use, which would allow us to understand why a considerable number of people that uses cocaine, when stars using ayahuasca stops using cocaine, and they stop using for real, and also alcohol, they drink much less therefore these authors brought up front the possibility to discuss harmine
as molecule, better saying it, that beta-carbolines can be important alkaloids regarding the therapeutic uses of ayahuasca, and that not only dmt would have a role regarding antidepressants, there is a paper that it~s now somehow old from callaway and grob, about a potential risk of serotonergic syndrome with the uses of antidepressants which are also serotonergic. all we have make us believe by the amount of use these medications have nowadays and by the frequency of use of ayahuasca in the churches, which i estimated between 30 to 50 thousand it would be expected some serotonergic syndrome to have occured in brazil we have no such data, not a single case occurred, and the data from the uniã£o do vegetal
shows us, and there are physicians following this, in this case physicians from the udv which follow up patients who take serotonergic antidepressants and drink ayahuasca and besides some reports of light symptoms, as increases in nausea or vomits or sometimes some patients say the effects diminish instead of increasing which seems to show us this risk is not so serious as hipothesized by callaway and grob regarding the psychosis risk, a very important thing is that there is a method in the udv which is to make a interview an interview to assess among those that want to drink ayahuasca, if the person already had
some experience with psychotic symptoms, and to this people in general, it is not authorized that they drink the tea, but it's an interview done by lay people but from the data we have, from the mental health department of the uniã£o do vegetal is that the chance for a psychotic episode to occur in someone who has no previous history of psychotic reactions is approximately the same for the general population. now, evidently, people that already had psychotic phenomena or maybe people with a very strong genetic profile a lot of family members with psychosis, it would not be wise or this use would have to be very controlled and very carefull with doses being verified with parsimony
this risk therefore exists, but it is a risk that should take into account that is also present with antidepressants, which also cause psychotic breakdowns, but nobody is questioning their legality because they have a recognized medical potential and maybe we should make a parallel here with ayahuasca well, what do the brazilian regulations say, what about the deontology of ayahuasca in brazil? it says the following, based on the experiences of the ayahuasca religions that those interested in drinking ayahuasca for the first time should make individual interviews in which it should be asked about the uses of psychiatric drugs or about serious mental illness
and that in this case people should not drink the tea and that the tea should not be offered to those under the effect of other psychoactive substances, although this in fact happens how much time do i have? is it over? well, and then the question is: is the biomedical evidence regarding ayahuasca's safety enough? what would be the determinants for us to interpret the biomedical data? and what is the role of the biomedical evidence in ayahuasca's regulations? to picture this i created an infographic which you'll see next then this is the idea, i won't be able to go into details, but i'll share the slides later on
online so you can see the details, but we must understand that what regulates any psychoactive substance are not only the biomedical data biomedical data are interpreted inside a plethora of human values that many times are the determinant ones. in the case of ayahuasca in brazil there extremely important factors first of all, the evidence that there was no huge harm obviously apparent that is for sure, because the biomedical staff looked for it but most of all the values of religious freedom in the context the country was at the time that was more democratic than nowadays, or less conservative, more progressive i don't know how it would be nowadays in this country, if we were going through this same process
maybe the whole thing wouldn't happen therefore, the positive effects in society, therapeutic effects, the perception of harm are modulated by values which include the conception of religion, human rights, religious rights the government's ideology, drug policy and even the repressive drug policies, the legal policies to conclude, let's look at the research we could think about regarding ayahuasca for the future this is an image from the recently published article by eduardo schenberg, published just a few days ago where he discusses the theoretical factors that could explain the potential anti-tumoral effect of ayahuasca related in some anecdotal cases we can't claim that ayahuasca has an anticancer effect
however some of it's components have positive effects in vitro but there is a possibility for having smoke, therefore of having fire, thus it deserves more research and then we know there is a potential to be explored in the treatment of substance use disorders for depression there is a study which is beying developed which i'm part of, regarding that in anxiety disorders and potentially also being discussed for post-traumatic stress disorder and as you can see, these are all in press from the physical point of view, there's the discussion brought up by edu schenberg regarding cancer
we know now some evidence that specifically the beta-carbolines can have very useful anti-parasite effects for toxoplasm, plasmodium, leishmania and even worms and also the speculation of the potential use for parkinson's disease all this to be studied, we have a lot of data from in vitro studies but not a single one with humans we have a series of problems which i won't have time to develop now because my time is up but there are problems to make the double-blind with ayahuasca because, as drinkers know it has a very particular taste, to say the least
and that the use of encapsulated liophilized ayahuasca is somehow associated to some problems in this process and another thing, how to better understand the role of ritual in this therapeutic effect? considering also that we would have room for research funded by the public health system me and dartiu are involved in a project like this we still need to better evaluate the use by pregnant women and children we need epidemiological studies about that use by pregnant women is authorized as well as by children, but taking into account that the church members are very restrained, they are not crazy people
who will give massive doses to children children dosage is symbolic and for pregnant women are very low doses, but this are questions that we haven't ansewered adequately mainly regarding the toxicological evidence, from monstrous doses given to pregnant rats we don't know how much we can extrapolate that to humans we need to better assess the interaction with other drugs, including with animal research these are extremely necessary, if there is people here from psychobiology, from neuroscience departments this is extremely necessary, to test the interaction between ayahuasca and other substances in animals if animal right activists allow
and then a whole group of explorations about the true nature of consciousness studies about the structure of consciousness, about the structure of the mind, there are good and promising neuroscience research, some will be shown here tomorrow how to understand this shamanic technology and adapt it to the therapeutic non-shamanic context because there is a technology, who knows, who worked with these people know that this religious-shamanic technology exists and i would just like to say some final words that it's important to always have respect, always respect the traditional ayahuasqueiros, respect those that drink, respect their traditions respect with all the traditions, to understand that our knowledge has limits, therefore also recognizing
and paying respect to the mystery, because it is the source of all knowledge and also to comprehend that to be into this field is many times required that you take a political stance in my case a political position against the war on drugs an anti-prohibitionist position, and that many times we will have to be activists in this process to make science there's my email, those that want to make contact later, and thank you very much for your attention and apologizing for the long talk, thank you applause
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