Luana Colloca, MD, PhD. October 2023

October 23, 2023

Information

Title: Mind Over Molecules: Unraveling the Neurobiological Aspects of Placebo Effects and their Implications for Psychedelic Medicine

Description: Placebo effects pertain to the positive outcomes resulting from a placebo or a treatment, primarily influenced by the participant's belief, not the treatment's actual pharmacological properties. Factors such as expectancy, prior therapeutic experiences, witnessing benefits in others, contextual and treatment-related cues, and interactions between patients and healthcare professionals can trigger these responses. The mere act of taking a treatment can activate various neurobiological and physiological mechanisms, involving systems like opioids, serotonin, noradrenaline, endocannabinoids, oxytocin, arginine vasopressin, dopamine, and the modulation of cytokines. Phenotypes associated with placebo effects can help tailor treatments to the needs of each single patient and advance a more personalized and effective healthcare interventions.

ID10889

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00:00I'm
00:03thank you everyone for coming
00:04to the Psychedelic Seminar.
00:05This is the first time this year
00:07we've had in person speakers.
00:09So thank you so much for being here.
00:11We are scheduled, we have,
00:14we have November and December scheduled.
00:15Jessica, do you have the the dates
00:17of November and December handy?
00:19It's typically the third Friday of the month.
00:23We're looking at November 17th talking
00:27about psychedelics and addiction.
00:29And then December 15th,
00:31I believe will be Jerry Sanacora.
00:36Yeah, Jerry and Ben will talk about the
00:37you saw in a depression study and the
00:39psychedelics and addiction. Who is that?
00:46It's cocaine from Alabama.
00:48I'm thinking on that.
00:49I know I can. Let me think of the
00:57anyway those those should
00:58be good and then we're working on thanks
01:02to Julian Orutzi who I saw on here.
01:05We're putting together something
01:07in in February that I think will
01:09be really interesting which is a
01:11discussion panel of the regulatory
01:13framework surrounding psychedelics.
01:15The Department of Health and Human Services
01:17is putting together draft guidance,
01:19not for the FDA put out draft guidance,
01:22you know, real guidance a couple of
01:23months ago, but this is HHS guidance
01:25about clinical use and that that
01:28should be coming out in November.
01:29Then there'll be a commentary
01:31period and it'll be finalized by
01:32February and we'll have a number
01:34of of this academic discussions,
01:36but also to people from HHS who are
01:38like in the process of developing this.
01:40So I think it'll be a really interesting both
01:42informational and and discussion session.
01:44We're going to do that in person.
01:45I expect that it'll be, you know,
01:47we'll advertise and I expect it'll
01:49be popular beyond our local community
01:50in the TAC Auditorium and it'll
01:52be a bit longer than usual.
01:53So keep an eye out for that.
01:54That's in the the third,
01:57the 3rd, February,
01:583rd Friday in February.
02:01So Chris, in November,
02:03it's Peter Hendricks. Thank you.
02:07All right. So
02:11with that, I'll turn it over to Jerry
02:13Sanacora to introduce today's speaker.
02:15Great. Thank you.
02:16Well, I'm really happy to have Luanne here.
02:19We managed to become friends and
02:22collaborators over the past few years.
02:25I I got to know Moana's work actually from
02:27reading some of the stuff in ketamine.
02:29But then really started to read a
02:31lot of of your other work and how you
02:35incorporate the practice of placebo or
02:39the study of placebo into all of medicine.
02:42And you know starting with pain.
02:45I know you did your training back in Italy
02:47with Benedetti was one of the sort of,
02:49I don't want to say the father's,
02:50but one of the big names and placebo
02:52research one of the biggest names.
02:54But you've really managed to continue
02:57that line of research largely in pain.
02:59But now I know your interests
03:01as a psychiatrist,
03:02also very interested in spreading
03:04out into a range of other illnesses.
03:08And I think some of our discussions
03:13have really highlighted how
03:17you're looking at placebo.
03:19Not just as this sort of
03:22pejorative negative thing like,
03:24oh, this is the placebo response,
03:26but how the some of the core components
03:28of placebo would be playing a major role.
03:31Especially when we start thinking
03:33about the effects of psychedelics,
03:36how psychedelics can actually
03:39obviously be influenced by things
03:41like expectancy and conditioning,
03:42but also how they may actually have an
03:45impact on expectancy and conditioning.
03:47So comes this very interesting
03:48way of thinking about it,
03:50and I think Glenn has raised it to another
03:53level in the way of thinking about it.
03:54Not just so straightforward like,
03:56oh, this could all be
03:58explained just by expectancy,
03:59but actually thinking about the interaction.
04:00So really interesting about
04:02hearing more what you have to say.
04:04Thanks a lot.
04:06Thank you very much for having me.
04:07And thank you for making this visit
04:10very insightful and thoughtful
04:12and wonderful conversation with
04:14all the people I met so far.
04:16So I gave us title to Chris,
04:20Jessica mind over Monaco's because
04:23sometime Placib effects bring a lot
04:27of negative connotates and people tend
04:29to believe that this Marilla bias
04:32you know when in reality we started
04:35this year because underlying changes
04:37across symptoms across disease.
04:39And today I wanted to explain a little
04:42bit of neurobiology aspects of placebo,
04:44but also some implication towards
04:47the end about psychedelic and how
04:50this kind of knowledge can inform us.
04:53And I have to say that folks here
04:56at Yale brought me to these fields
04:59and in particular Jerry's and Akora.
05:01So thank you.
05:04So
05:10Preston,
05:15let's talk about what placebo effects are,
05:18which are the mechanism.
05:19And obviously I will talk about chronic
05:22pain because it's the main area of
05:24research we haven't been tackling.
05:26But I hope what I will show to you
05:28can be translated into psychiatry.
05:31And finally we can talk and tackle a
05:34little bit the show psychedelics and
05:36how Placip when treatment responses can
05:39interact and which are the controls or
05:41the design when we study psychedelics
05:45or antidepressants and so on.
05:50So placebo and drug effects no
05:52matter which treatment we use.
05:55This can be for example opioids,
06:00surgical interventions or
06:02complementary and integrative medicine.
06:04There is some ways specific do
06:08I tend to dislike this word,
06:09pharmacodynamic component and the
06:12placebo psychosocial component.
06:14The placebo psychosocial component
06:17is the context around any treatment
06:20and at least when we talk about pain,
06:23the top down the descending pain
06:26modulator system can play a critical
06:29role in modulating pain outcomes
06:31sometimes more than the you know
06:34input not susceptive input coming
06:37from the periphery.
06:38And one of the first study we
06:42conduct while I was a PhD student in
06:45neuroscience was to try to understand
06:48how the context can change outcomes.
06:51So a very clinical simple observation
06:54where the same thing killer were
06:56given to a pump of infusion or
06:59with a physician a nurse at the
07:02bed decides telling patients now
07:04we're starting the treatment.
07:06When we wrote to this paper,
07:07we had called this hidden
07:10versus open administration,
07:12but the editors suggest over to
07:14versus covert but still hidden.
07:17Open paradox is very common
07:19in the placebo literature.
07:21So the Eden administration is this one.
07:25The open will be with physician,
07:28a nurse around the patient.
07:31And we were tackling the question,
07:34can we study Placib effects without
07:36any placebo, without tablets,
07:38without selling solution.
07:40And in this case we study patients
07:42who were you know in the hospital
07:45for removal of lung cancer.
07:47And the goal was to understand
07:49how we can improve the outcome by
07:52manipulating the route of administration
07:54and the context around the drug.
07:57For for those of you who are
07:59familiar with Penn Therapeutics,
08:01buprenorphine and Tramadol are opioids right.
08:05Keterolac,
08:05metamazole are non opioids and you
08:09can see that opioid treatment like
08:13buprenorphine can reduce clinical
08:15post operative pain significantly.
08:18But when we provide the same drug
08:22with the disclosure with the presence
08:24of the physician or the nurse there
08:28there is a optimization of the
08:30reduction of the pain For some drug
08:34this you know augmentation is even
08:37larger like tramadol if we merely
08:39use the gold standard to interpret
08:42clinical trial results merely the
08:44difference between hidden versus
08:46soap and represent to this specific
08:49component and all this part will
08:51be the placebo or psychosocial
08:53components and you can see that can
08:57be larger than the active drug.
08:59So the same for Cathedral Ecometamazole,
09:02but they're non opioids based,
09:04so the observation was poorly
09:07clinical and we state that open
09:10administration of a drug working
09:13through psychosocial context can
09:15be more beneficial for patients.
09:18What we did,
09:20we used the same paradigm with
09:22the ads department.
09:23Given that I'm talking to
09:25psychiatrists and psychologists,
09:26this can be more informative
09:28than pain treatment.
09:29So open injection of the adzipan again
09:32in patient who are cancer patient
09:35post operative setting can reduce
09:38situation and anxiety substantially.
09:41So when the same drug,
09:42same dose was given in a hidden way,
09:45there is no reduction.
09:46So the question here is,
09:48do we need somehow to have an
09:51expectancy for a drug to start to work?
09:54Also we try the opposite.
09:56We inform a patient,
09:58we interrupt the drug.
10:00So those who had the responded with
10:03the open administration of the azapam,
10:05when we're told now we are not injected,
10:07we stop the treatment.
10:09You can see that there is a worsening of
10:12anxiety and no change for the interruption.
10:15So with that, I hope I convince you.
10:22With that, I hope I convince
10:24you that somehow the open Eden
10:27administration can help us to study
10:30a drug by eliminating silencing,
10:33eliminating placebo.
10:35So ethical issue related
10:37to placebo treatment.
10:38But there is a way to silence
10:41expectations and I don't know,
10:42maybe we can use this kind of
10:44paradigm with further, you know,
10:46treatment and depressants
10:48that start working in acute
10:50like ketamine or psychedelics.
10:53This can be a paradigm to consider.
10:57The next step would be to talk a
11:00little bit more about how I start
11:02to be interested in this phenomenon.
11:05So we were studying Parkinson's
11:08disorder and this was a special
11:11setting that for someone who had the
11:13Finnish MDM practising for about one year.
11:16It was something very comfortable,
11:19you know to go back to intraperative
11:22room and study a changes that occurred
11:25at the level of neuronal discharge.
11:28So patients who do not respond
11:30to the classical cocktail of
11:32dopamine agonist and antagonist
11:34to receive DP brain stimulation.
11:36DP brain stimulation consists of
11:40implanting on electrodes and sub
11:43thalamic nuclide and a battery
11:47eventually so that we have series of
11:51stimulation 12 to this patient managed
11:54their symptoms mostly for those who
11:56are not familiar but here everyone
11:58we are talking the same language.
12:00You know these patients have rigidity,
12:02tremor,
12:03bradykinesia as main Parkinson's
12:06symptom together with a lot
12:09of psychiatric problems.
12:10Here we try a pharmacological conditioning,
12:14so I work all of us.
12:15So to give a little of relief
12:17during the surgical implantation,
12:20this is a longer you know surgical procedure.
12:22We start early in the morning and
12:25then six 7-8 hour of intervention.
12:27So before the day of the surgery we
12:31condition patient with Apomorphine
12:33day one day 2 day three.
12:35Apomorphine is a dopamine agonist
12:38and producer reduction of the
12:40three symptoms I mentioned to you.
12:43But the time life is very short,
12:47the volume prover about 20 minutes
12:49some for maximum one hour.
12:52Therefore we were in the intraoperative
12:55room and the gun was to replace the
12:59drug Upomorphine with saline solution
13:02being injected subcutaneously while we
13:06were recording the neuronal activities
13:08from this this part of the brain.
13:11So for those who are not familiar,
13:15we are designed very well in terms of human
13:18being or also monkeys and other animals.
13:21So there is a zona incerta and then the
13:25supratalamic nucleus and then again a
13:28silent area before the substancia negra.
13:31So our goal in terms of neurophysiologists,
13:34surgeons was to identify this part
13:37of the brain and in order to make
13:40sure that we were there we record
13:42the several neuronal activities,
13:44many and so we had over 100 you
13:48know recordings and usually you
13:51see the typical firing.
13:53So and also this first activity where
13:56the spike become close to one another,
14:00so we counterbalance the nuclear
14:02serving gas control and the
14:05nuclear serving gas target.
14:07So the goal was to see if some
14:10other suggestion of improvement
14:12along with the administration
14:15of selling solution can
14:17change the pattern of firing
14:19in the Subitalamic nuclear.
14:22And you can see that it's a very small area.
14:26This is smaller than a bin in humans and
14:31was very you know unique cast contest.
14:35So what we were interested was
14:37the self report by the patient.
14:40A neurologist entered into the surgical
14:43room and in a blind way assess rigidity
14:47and the scale that they use is the
14:50UPD RS4 point scale to assess rigidity
14:54and you can see here the circles and
14:59then we also measured the firing.
15:02So these are only two examples of the
15:05many patients involved that but mostly all
15:08the neurons that we were able to record.
15:11We found congruency between what patient
15:14experience the reduction of clinical
15:16symptoms and the reduction of the
15:19firing at the level of subitalamic area.
15:22But there were also patients who
15:24didn't improve and for those patients
15:26who didn't improve,
15:27they didn't experience a benefit.
15:29The neurologist didn't detect any change.
15:32And so it when we compared the neuronal
15:35discharge before and after selling solution,
15:38we found in a changes that was you know
15:42important study to me for two reasons.
15:45First was a sort of epiphany you hear
15:48the spike and then when you go back
15:50towards these neurons and see this
15:52change associated with plasymbi fats 10.
15:55Last one,
15:56there is something here more than a bias,
15:59more than another effects as many
16:02people try to think about placebo,
16:04but also this question why some people
16:06respond and some other people don't respond.
16:09It's still an open question and the main
16:11line of the research in my lab today.
16:20So from this sort of pioneering studies
16:23that was running when I start my PhD,
16:26we continue and I decided to
16:29transition from Parkinson to pain.
16:31But the simple reason that I had so many
16:35questions Parkinson patients are very
16:37difficult to be studied the disease,
16:40it's difficult to model enough controls.
16:42You don't make people becoming,
16:45you know, parkinsonian patient and
16:48also the amount of surgical procedure
16:51we were conducting was 2/3 per months.
16:54So I was literally too slow to finish a PhD.
16:58That's also not good.
16:59That's model to understand other
17:02questions related to placebo.
17:03So I thought pain can be a good model.
17:06We can work with pain with health control.
17:09So we have animal models.
17:10So we have chronic pain patients.
17:13So we started to do a variety of studies to
17:17understand some psychological questions.
17:19What can treat the ablazific effect,
17:22expectations,
17:23verbal suggestions,
17:26conditioning.
17:27And I really continue the line of
17:32research like hypomorphine where
17:33we were giving the administration
17:35of medications and you can do the
17:39same thing with pain by reduction
17:41of pain intensity you can simulate
17:44a benefit without giving 12
17:46participants morphine for example.
17:48Although we did this so too.
17:50So currently there is a sort of
17:54understanding that verbal suggestion,
17:56this is a wonderful antidepressant.
17:59Your depression can improve
18:01therapeutic prior experience.
18:03How many of your patients come and say I
18:06like this drug because I benefit from it?
18:09Observation from other people and
18:12contextual effects like the Open Eden
18:15paradigm and of course interpersonal
18:18interaction can trigger placebo effects.
18:22Expectancy is something that
18:24continue to intrigue us,
18:26and when we talk about expectancy,
18:29we can refer to something that we can
18:31measure and we call it expectations.
18:34With a scale from zero to 100 for example,
18:37how much benefit you have
18:39expect from zero to maximum?
18:42But also there are expectancy
18:44that we study in animals,
18:46we study in non human model or sometimes
18:48we are not even able to model in
18:51humans because can not necessarily
18:53be captured by a simple scale.
18:56How much do you expect to improve?
18:58And it is when we do modeling
19:00other brain imaging approach to
19:03understand how expectancy can
19:06modulate drug and Placid beefast.
19:09An interesting aspect is that at
19:11least for pain as you can see on
19:14this part of the graph is that
19:18you know the descending component in the
19:21dotted line in blue can be so relevant
19:24make pain disappear in some patient
19:26at least in the placebo responders.
19:29And so they're all of the descending
19:31pathway is so relevant to when we
19:34study placebo effects in pain to the
19:36point that the ascending component,
19:38it can become less prevalent
19:42from the part of the brain,
19:43at least for pain,
19:45that are critical in modulating
19:47placip effects are the frontal area.
19:50So ventromedia dorsolateral prefrontal
19:53cortex where ventromedia prefrontal
19:56cortex has been associated to the
20:00decision process versus the dorsolateral
20:03prefrontal cortex being more involved in.
20:07Maintaining A placebo effects and of
20:10course the nuclear compounds and then
20:12trastriatom become so critical because
20:15especially in patients seeking a reward,
20:17the seeking reduction of Parkinson's
20:19symptom or pain or depression.
20:21Mathematica. It's a big deal.
20:28So, and of course there are some genetic
20:32factors that can serve us predictors
20:36to see those people who respond and
20:37those people who don't respond.
20:44So
20:48if expectancy are so relevant,
20:50then we thought it's time
20:52to try to understand how we
20:55can manipulate expectations.
20:56When we study pain in health
20:59controls and placebo nocibo effects,
21:01usually we use thermal stimulation which
21:03is the thermal stimulation that has
21:05been used at first labs.
21:07And in this case we use visual cue
21:12red during the anticipatory phase.
21:15And then when the painful stimulation
21:18was used, you can see that we had the
21:22emotional component fearful phase.
21:24With yellow we had neutral phase and with
21:29green epiphase the most critical component
21:34was for us to create an experience of
21:37eye pain and low pain and control pain.
21:40So this is a visual analogue scale
21:42and we raise the intensity of the
21:45thermal stimulation to 8050 or 12 day.
21:49One participant received many stimulation
21:51seeks to be precise and that allow us
21:55to create an experience of eye pain,
21:58low pain as compared to moderate pain
22:01day 2 in the scanner we set all the
22:05intensity out to the same level and
22:08operationally we define a change in
22:11the red pair stimulation and green pair
22:14stimulation as placebo and nocible effects.
22:18We want to see how the
22:20prior experience day one,
22:22but also the anticipation,
22:23the expectation of higher low pain would
22:27have changed when we mismatch the conditions.
22:30That is why we use two visual stimulation,
22:33you know 2 cures.
22:35And so when participants receive
22:38identical stimulation in a match patient,
22:41you can see that same identical level
22:44of tumor stimulation produce lower pain.
22:47This is their circle report as compared to
22:50our control in dire pain when they expect IP.
22:53So what we expect can drive moderate
22:57level of pain to become high or
23:00low and that is what you know we've
23:03got nocebo and placebo response.
23:06However when we mismatch,
23:07so we manipulate the expectation,
23:09we manipulate the events and I
23:11bet that all of us had experienced
23:15violation of expectations.
23:16You know, you go towards something,
23:18you expect something and
23:20you get something else.
23:21And this is the story of many patients.
23:23They went to the clinic,
23:25they want to be healed and treated,
23:28but eventually their depression
23:30or symptom doesn't change.
23:31Every time we see a violation
23:34of expectation that can trigger
23:36a neurobiological response.
23:38And we can call this nausea if it's
23:41a worsening in symptoms.
23:42So nausea effects didn't disappear
23:46when mismatched cues were presented,
23:49but mismatched cues abolish plessive effects.
23:53So I was asked today,
23:55how can we somehow reduce placebo
23:57responses in clinical trials?
23:59One strategy will be to create
24:02mismatch of expectations and that can
24:05somehow help to reduce the placebo
24:07component and focus purely on the
24:10drug that we are studying.
24:12And of course, so if you are a physician,
24:15you may want to amplify
24:17the placebo component.
24:19So it depends.
24:20Can I ask you so all of this,
24:22the beautiful studies you've shown us
24:24are all acute acute change in anxiety,
24:27acute change in pain, right.
24:29Whereas clinically what's relevant
24:30is in including in a drug trial
24:32as you were just referring to.
24:34What's relevant is chronic effects
24:36and it's not obvious that those are
24:39going to be through the same mechanism
24:41or have the same characteristics.
24:42So the study I chose and we do in
24:44the lab are mostly one session,
24:46although now we are studying
24:48chronic pain patient who have
24:50long lasting effects and we call
24:52them back to the lab after six,
24:55one year time to see if they
24:57continue to benefit.
24:58And I mean we don't study
25:02a report or don't publish,
25:03but we have some of our patients
25:06who improve with this kind of sham
25:08electrodes and they went to buy
25:10because their pain was solved.
25:12So and of course there are many
25:15clinical trials show that the placebo
25:17component lasts over time And we
25:20know also from the failure of many
25:22trials the reason why we look at
25:25this response with cross-sectional
25:26studies mostly for you know brain
25:30imaging mechanistic approach.
25:31But that doesn't mean and that
25:34placebo effects extinguish over time
25:37or patient who have chronic disease
25:39actual experience placebo effects.
25:42And I guess the question I'm wondering
25:44if clearly there are long lasting
25:46placebo effects and we've all seen them,
25:48are the mechanisms of the later phase or
25:50the persistence of the placebo the same
25:52as the mechanisms of the CUE
25:54driven immediate environment?
25:55That's the question I was asking and
25:57it's an experimentally difficult
25:59question and there are other
26:00groups that are studying this.
26:02For example Vanya Caparia is interested
26:05in brain imaging and long lasting
26:09effect of placebo and the mechanism
26:12that he has been publishing are
26:14primarily related to the reward the
26:17system and there are similarity in
26:20terms of our expectation can trigger
26:22uplasi effects in chronic pain
26:24patients in particular osteoarthritis.
26:26For his line of research we are
26:30doing that in for a facial pain and
26:33yes the goal is to try to see how
26:36long we can maintain these effects
26:38and translate therapeutically.
26:39We are not there yet but that is one
26:43of the question we try to address.
26:46Another aspects that is relevant
26:49especially when we talk about clinical
26:52situations is the negative component
26:55Nasib effects because Nasib effects
26:58somehow amplify negative you know and
27:01worsening of symptoms in this case
27:04we show in a very you know simple way
27:08for time restriction that Nosibo the
27:11negative or component of placebo effects.
27:14Actually with pharmacological study,
27:16we know that work through the engagement
27:21of the coagcystokines systems in
27:24particular A&amp;B receptors with studying
27:27both animal models and humans,
27:30there is a change in the new opioids
27:33availability as well as the release
27:35of D2 and D3 dopamine.
27:37So this nocebo component can be even
27:40clinically speaking more relevant
27:41because every time we see worsening
27:44in symptom pain or other symptoms.
27:47There is also an engagement of
27:49circles that are not parallel to
27:51the placebo mechanism,
27:52at least in terms of brain imaging,
27:55but yet it can,
27:56you know,
27:57be triggered by expectation and
27:59similar psychological mechanisms.
28:07So to tackle the question about
28:09Placib effects in chronic conditions,
28:14we study chronic or facial pain
28:18and temporal mandibular disorders
28:20because after about had decades
28:22of studies in earth controls,
28:23we were wondering what if we
28:26study chronic pain patients,
28:27they do show the same placebo effects,
28:30this sort of huge change in
28:33the pain reports and you know
28:36affective component of the pain.
28:38So we brought in patients for
28:41in depth clinical screening of
28:44temporomandibular pain at UMB where
28:46the Brothman or official clinic
28:48that is one of the major clinic
28:50for this condition in the states.
28:52And then we did the same manipulation
28:55individual calibration of pen sensitivity,
28:57we call this quantitative sensory test.
29:00We assess baseline expectation
29:02and we expose them to conditioning
29:05with 24 trials where we you know
29:08we're in a pseudorandom way,
29:11deliver eye painful and
29:13low painful stimulation.
29:14And we told them that every time
29:17this sham electrodes was active,
29:18the painful stimulation was the same
29:21but eventually they perceive less pain.
29:24The idea is to avoid to create a
29:27conditioning with morphine or other
29:29painkillers rather expose them to
29:31low intensity stimulations and after
29:34that we reassess expectation and your
29:38expectation improve if you have a benefit.
29:41We call this reinforced expectation
29:44and then we test for placebo first
29:46testing phase where we use identical eye
29:49level log thermal stimulation to see
29:52if somehow there is a placebo response
29:54in chronic pain patient with this condition.
29:59These are the data and you can see
30:02that we match people for race,
30:05age and sex.
30:07The distribution of placebo
30:10response assessed several time,
30:13you know trial by trial are identical.
30:16So no matter if people had
30:19chronic pain or no chronic pain,
30:22there was some placebo analgesia.
30:26When we compare the proportion of
30:29placebo responders with permutation
30:31test to see some who are the placebo
30:35responders and for our you know the
30:38proportion of responders in TMD
30:41where the 53 percentage of placebo
30:44responders that was significantly
30:46lower but still quite high than
30:49pain free people 67.8 percentage.
30:52But this numbers make clinical trials
30:57fail because with this proportion of
31:00placebo responsivity is extremely high.
31:02But if we talk about patient benefits,
31:05that can be actually good because
31:08if we look at the number needed
31:11to treat anticonvulsionant and
31:13opioids vary from 1.7 to 3.
31:16And when we look at our
31:18depression in the lab,
31:19you can see that the NNT
31:22for TMD it's about 1.8.
31:26So suggesting that protein effects
31:28are real can be important in
31:30chronic pain patient and even with
31:32an empty the desired and controls.
31:38Do you want to maybe just go through
31:39that a little bit because I'm not
31:41sure people fully get the number
31:42needed to treat and what it would
31:44be compared to an active medicine,
31:47yes. So the number needed to treat
31:51is one of the way to assess it.
31:55But treatment is efficacious.
31:57So when we run a clinical trial that is
32:01the number that the index and then T and
32:04so for opioids and anticonvulsion and it
32:07has been published in the literature,
32:10this critical number is 1.7 for
32:14anticonvulsion and and opioids is 3.
32:16And the reason why we want to somehow
32:19compare for our placebo manipulation was
32:22to try to understand where we stand.
32:24And so you can see that it's within the
32:27range of current use pain therapeutics
32:30for neuropathic pain or chronic pain.
32:34And the fact that even manipulation
32:37in the lab, the reduction can change
32:40the mindset of a patient.
32:42And that is why I call this stock
32:45mind over molecules even you know
32:47the exposure to low pain that can be
32:51translated in improvements or mode for
32:54antidepressant can be so important
32:57in manipulating the expectation and
32:59trigger somehow this you know index
33:03to help us eventually to validate
33:07the drug or treat patients.
33:09So would you conceive of this number
33:10needed to treat number is essentially
33:12an effect size of treatments and
33:14what you're saying is the effect size
33:15of yes is the same as it's a that's
33:18that's amazing. Yes that's
33:20a that's a big point Yeah.
33:22Yes it's it's thriller.
33:26So the other thing,
33:29when I move from an age University
33:34of Maryland in Baltimore, I realised
33:37first that my lab was very diverse.
33:39I had a PhD student of
33:42American black white patients,
33:43but also the patients were quite diverse.
33:46So despite this not to begin
33:48a name of our everyone.
33:50I thought I needed to keep record
33:53because the data can be some biased
33:57by race and ethnicity and eventually
34:01you know our beautiful collegiality.
34:04It was environment with students a
34:08student of mine bogus Sago was you know
34:13very talent and Young came and say Lana,
34:16can I study race differences.
34:18That's a perfect we have the data.
34:20So we started diving into the data,
34:23see if somehow the race,
34:24ethnicity of the patient and
34:26the experimenter can change the
34:28money to the plus CB effects.
34:31And we have suffered that
34:32only for chronic pain patient.
34:34Same concordance of rays produce larger
34:37plus CB effects dark blue as compared
34:41to different experiment patient rays.
34:44But this doesn't become
34:47relevant for health controls.
34:50So we are still diving into
34:52this kind of differences.
34:55Why?
34:55And this is the disparities that
34:57we read in the literature and
34:59clinical practice when there are
35:02other groups earlier cram from
35:04Stanford that is studying this bias,
35:07something under the skin and so on.
35:09We are now tackling these questions
35:12with neurobiological measurements.
35:13Try to understand if it's an implicit bias,
35:17if it's related to immigration,
35:20media, where they live,
35:22where everything from,
35:23you know,
35:25social demographic position for the ancestry,
35:29because we are intrigued by this difference.
35:32Seems
35:32like the possibility that
35:33those effects in psychedelics
35:34is a bit more right.
35:36That's gonna be great.
35:38So definitely something to think about.
35:42But also chronic benefit is a
35:44disease for women in the sense
35:46that the prevalence of women
35:48affected by chronic pain is 3 to 1.
35:51So we were wondering within TMD,
35:54but no in health controls in
35:57T in TMD which is stronger,
36:00you know prevalence of the disease
36:02among women but also larger PLACIP
36:05effects in women and we don't see
36:08that again in health controls.
36:10So we dive into the data here and
36:13we measure very colorfully the
36:16menstrual cycle periods and the
36:19gonadal hormones Luter with the
36:24follicular phase register and versus
36:27estrogen And we found no effects of
36:31gonadal hormones for placebo effects.
36:33Yet we saw that the pain threshold
36:36out when we use the term and change
36:40in women based on the middle
36:42follicular or lutal phase as compared,
36:45you know,
36:46to the general understanding that
36:49men are more tolerant.
36:50So men are more tolerant than women
36:53only when a woman is in the looter phase.
36:57But also despite we didn't see any effects
37:00of gonadal hormones and placebo effects,
37:02we did the sea effects on expectations.
37:06But this effects didn't moderate
37:08mediate any change in placebo.
37:10That is why I tended to think that
37:12expectancy and expectations from a
37:14cognitive point of view is something
37:17different than PLACIP effects,
37:19at least when we use conditioning paradigm.
37:22So you can see that we found the
37:25difference in expectation of
37:27improvement when we compare men
37:29with women in with diluted face,
37:32but no in women in diluted face.
37:35And also of course there is a difference
37:37between the two places in women.
37:44And when we look at the concordance
37:47experimental where men or women,
37:50and I'm talking in terms
37:52of biological sex here,
37:55you can see that at least for now,
37:58we have not power to study gender effects.
38:01You can see that actually in women
38:06when we had a man experimenter,
38:09the effects in terms of placebo algea
38:13is different than when we had same sex.
38:17So same sex local Placib effects when
38:20a man experimenter was studying them,
38:23larger Placib effects.
38:25And again this is something that
38:27human wants to keep you know in mind
38:30when you study not just psychedelics
38:32but any antidepressants because you
38:35may observe this sort of participant
38:39experiment or sex biases or differences.
38:43Is there
38:44any That's a very cool finding fact
38:46that you know seems to be opposite in
38:48in men even though
38:50has that been done cross culturally?
38:52Sorry, I mean
38:55what is up battered good,
39:00this is the higher number
39:02more analgesia or less
39:04different more analgesia,
39:05this is higher and more analgesic
39:08improvement, larger plus.
39:11So a man experiment was triggering
39:15larger plus CB effects in our women TMD,
39:19but in men TMD patients we
39:22didn't see this effect.
39:25Sorry, sorry, no not at all.
39:27I'm wondering I I assume that I
39:29mean this is a recent paper but
39:31but thinking about this culturally
39:33like a different you know different
39:34expectations and gender roles could I'm
39:37glad that you asked that could influence
39:39because we have another PhD student
39:42now who is diving into spirituality
39:46and try to understand if somehow
39:49the interplay between sex race
39:52effects are you know dependent
39:54on spirituality and religiosity.
39:57So in terms of cultural difference
40:00we are tackling this in two way
40:03studying immigration and religiosity
40:05and spirituality to try to understand
40:08how this can influence both
40:11expectations and placing difference.
40:13I can tell you that we see difference
40:16for well this is sort of recorded
40:20then online but expectations.
40:22Somebody based on religiosity
40:25but no plessive effects,
40:27at least when we use our
40:30conditioning paradigm.
40:31So
40:31I mean if you go wait like in the
40:331950s Jerome Frank out of your,
40:35I mean he really distilled it down
40:37to three things basically competence,
40:40compassion and connective saying.
40:43I mean you can imagine
40:45how those play a big role,
40:47you know the perceived competence,
40:49you know something
40:51that we do for all our experiments.
40:54At the end of the experiment we
40:57ask participants health controls
40:59or chronic pain patients to rate
41:02our experimenter a warm confident
41:05they were and so far we didn't see
41:08any significant effects on placebo.
41:11So this is not so it's not looking
41:13at you to explain this effect.
41:15Yes. We were not able to explain
41:18with warm competency or empathy.
41:28But I mentioned to you, you know,
41:30I'm very intrigued about phenotyping,
41:31placebo responder and non responders.
41:34This was a project led by Doctor Wang.
41:38Currently she is an assistant
41:40professor in our department at the
41:43time she was supposed to talk.
41:45So we use a very large scale of
41:51surveys for psychological factors or
41:55personality factors and so using our
41:59placebo responders, no responders.
42:04Instead of using median or
42:06average or standard deviation,
42:07we use permutation tests to account for,
42:11you know, trial by trial placebo effects.
42:14This is the time course you know
42:16and in blue placebo responders
42:20and the two different shape here
42:24represents TMD and controls.
42:26You can see that having a chronic
42:29disorders for pain that affect release
42:31of endogenic fluids and so on didn't
42:34really change the ability to experience
42:36a placebo response over time and
42:39the same dose were not responders no
42:41matter if they have pain or no pain.
42:44The trend is similar.
42:46So below 0 we consider
42:49this nocebo responders,
42:50you tell them that they will benefit
42:53and they get worse and that will
42:55be the next I think cut chapter
42:57in our lab to try to understand
42:59who are these people and why they
43:02respond to like paradoxically.
43:03So this is the large array of survey
43:06that we have been using in the lab and
43:09it's intriguing because across countries,
43:13I mean we are a small community
43:15of people working on placebo,
43:16relatively small.
43:17So we know that Manchester has
43:20data with optimist placity effects,
43:23Toledo and and so on.
43:26So this was a collection of surveys that
43:29have been published in the literature.
43:31A single survey that a somehow was critical.
43:35Like how can a single survey
43:37predict plasive effects in one lab
43:39and then you move to Baltimore
43:41and doesn't predict anymore.
43:42Maybe because we are diverse
43:44so we use the NMH approach of
43:49distinguish the balance.
43:50So we did the
43:54PPCA to somehow create 4 domains
43:59of coming from all the 17 surveys
44:03for our 1000 questions that we do
44:05every time as part of the screening
44:08participant know that it's important
44:10they get to compensate for stay with
44:12us two hours to address all that.
44:15And so we define emotional distress,
44:17reward, the sickness, pain related,
44:19the fear catastrophizing,
44:21empathy and openness as critical violence
44:26to somehow study three different aspects.
44:30Expectation Learning index we call
44:33conditioning strengths that this can be
44:36called learning index or implacive effects.
44:40So our goal was OK based on this
44:43PCA approach and balance approach,
44:46how can this for violence help
44:50us to interpret expectation,
44:52conditioning and placive effects?
44:54The first question was do we
44:57see a difference between TMD and
44:59chronic pain patient?
45:01Yes, When it comes to reward the seeking
45:04chronic pain patients seek a reward.
45:07People who don't experience pain care
45:09less when you say this is analgesic
45:12and so expectation tended to be lower.
45:14As you can see from the scale,
45:16when people have a fear of pain
45:19and catastrophizing thoughts,
45:20they tended to be higher when
45:23people have open mind and empathy
45:26in terms of ability to learn.
45:28Trial by trial,
45:30emotional distress impaired the ability
45:32to learn and the personal to know in
45:35the literature and for Placib effects,
45:37fear of the pain.
45:39Catastrophizing was associated with
45:41smaller Placib effects in terms
45:44of magnitude and proportion of
45:46responsiveness and also emotional
45:48distress is associated with higher
45:51extension rate or Placib effects and
45:54lower money to the end responsivity
45:57proportion.
46:01And the last part of this talk is
46:04focus on more you know the topics that
46:07you study in here, you know at CL.
46:11So we've Todd Gordo,
46:13we decided to start doing some
46:16conditioning in mice for ketamine.
46:19So what we did,
46:21we know that ketamine is this rapid
46:25antidepressant slash anaesthetic
46:27drug and we study Anaidonia in mice.
46:30This is quite complex.
46:31All the controls so that we need
46:34the conditioning was done for
46:353 * 2 weeks apart to somehow
46:39eliminate the carryover effects.
46:41And our goal was to understand if
46:44we expose mice to the ketamine,
46:47can we create a ketamine
46:49like effects when we replace
46:51ketamine with placebo in mice.
46:55So the results show
47:00the morphic effects in the sense that
47:04in males we had some responses that
47:09were you know here you can see that
47:13we produce a ketamine like effects
47:16when we use saline solution and these
47:18are all the comparisons at one hour
47:21and 24 hours in females we didn't
47:25observe A ketamine like effects.
47:27So we were not able to create a sort
47:31of dose extension effects of the
47:34ketamine given for anedonia in in mice.
47:37Hey guys, goodnight to mine.
47:45So it is something that we publish here
47:50in collaboration with Professor Sinacora.
47:53So we start thinking more about
47:57expectations and therapeutic
47:59outcome in psychedelic surgeons.
48:01The idea is that this is a viewpoint,
48:04paper is still to be tested,
48:06but the idea is that when we use psychedelics
48:09we can change the mindset of patients.
48:12So we suggest that it's very
48:14critical to assess expectation in a
48:17patient who received psychedelics
48:19at the time Zero before we start,
48:22you know the procedure and also later on
48:25expecting that psychedelics somehow can
48:28change the mindset to the perception.
48:31And I show to you that we can
48:34manipulate expectation by exposing
48:35the people to a reduction of the pain
48:38that is a manipulation of experience.
48:40The psychedelics can create a strong,
48:44you know, different perception of
48:46the world around the patient from,
48:48you know, a mystical experience
48:50to improvement of the mood.
48:53And so this can somehow
48:55create new expectation.
48:57And the goal is when every time we
49:00study psychedelics to somehow keep in
49:02mind that we can have neurobiological
49:05phenomenon that we can call you know
49:08molecular effects and effects on
49:11expectation we can change through
49:14the biological effect expectancy.
49:17And of course this needed to be reflect
49:20at the level of recommendation so that
49:23expectation become a multiple assessment of,
49:27you know,
49:28the benefits induced by psycho,
49:31psychedelic and other psychotherapy,
49:33especially when we use
49:36psychedelics with psychotherapy.
49:38So then if we continue to think
49:40about what we learn from pain to be
49:43translated into the psychedelic medicine,
49:46one big question is what is the control,
49:48what is the design?
49:50And as long I read in the literature
49:54there are no placebo balanced
49:56placebo design for psychedelics,
49:58but it's a balanced placebo design.
50:00Essentially we wrote a very,
50:03you know,
50:04methodological focus review on
50:06osteoarthritis.
50:07And in preparing this talk I was thinking
50:11of paying us a lot to teach to psychiatry.
50:15So the balanced placebo design is
50:17a design where we have forearms and
50:20patient received the active drug and
50:23they are told this is not the active
50:26drug or they receive the active drug
50:28and they are told you receive the
50:31active drug and the same for placebo.
50:33They are then administration where
50:35they say this is a placebo deceptively
50:39or this is a placebo and actually
50:42the receiver placebo.
50:44Probably by manipulating
50:45expectation and what they are told,
50:48we can disentangle the psychedelics
50:52component versus the expectancy action
50:55in that play a role in this case.
50:59And so the hypothetical balance that
51:04can be a crossover or parallel design
51:07can help us to understand what is
51:10the placebo minus the interactive
51:13effects of psychedelic unexpectation.
51:16The guard.
51:17The standard of additivity may
51:18not work for psychedelics,
51:20especially if we believe that
51:23we change expectations.
51:24Therefore,
51:25we needed to talk about synergic effects,
51:28interaction effects between expectation
51:31and drugs and thinking outside the
51:34box with new design for clinical
51:37trials or psychedelics can help us
51:40to understand the drug versus the
51:43placebo interactive effects
51:46and action and expectations
51:54in concluding.
51:56So when we aim to understand more
51:59placebo must be first the design,
52:02the control group are the critical component.
52:05If we start a placebo effects,
52:07we do need a no interventional group
52:10and also an assessment of expectations.
52:14This is a call for all the people
52:16who work with animal models,
52:18the more the better, so that we can,
52:20understanding the molecular
52:22and genetic mechanism,
52:23underline psychedelic effects but
52:25also antidepressant where there is a
52:28need for more studies, larger study.
52:31We wanted to share our data because
52:33the modelling I do is different than
52:35modelling other people in this room can do.
52:38And by interacting with one another
52:41we can discover new mechanism and
52:44way to tackle impulsive effects.
52:46And of course, replication when
52:48it starts from a lab as we know,
52:50means nothing.
52:51So in doing clinical trials,
52:54then let's try to learn how to
52:57measure expectation of improvement,
52:59allocation, assessment,
53:00but also standardise the words you use.
53:04The longer the time you spend
53:05with your patients,
53:06the larger the PLACIP effects the
53:09larger the number of visits the
53:11larger the PLACIP effects more
53:12marketing like in this country where
53:14the largest placip effects over
53:16any other country in the world.
53:18Because I'm going to be I'm not we
53:20have a beautiful marketing strategy.
53:22So this increase placi be fast.
53:25So the number of sites more sites
53:27more placi be fast.
53:29So the checklist how to collect
53:31adverse events and preming it best
53:34can be so relevant and I'm glad to
53:37discuss more on these things I oppose.
53:39Just a talk where you can think
53:42about this is my team,
53:44so a bigger thank you to all of
53:47them that do an amazing job in
53:50that come with new ideas but also
53:53work hard to get all this done.
53:56And in about 2-3 weeks this
53:57book will be out and it's free.
54:00So if you wish to learn more
54:02about Placid effects,
54:04Oxford University Press are more from
54:07N7 to read this book for free online.
54:10So feel free to,
54:11you know,
54:12Google and a big thank you to
54:15the Funding Agency.
54:16But more important to all of
54:18you who are interested in this
54:20topic that can help us learn
54:22more about not just psychedelics
54:24but psychiatry in general.
54:26Thank you.
54:33Thanks. So I this,
54:35I mean from somebody who's
54:37actually doing psychedelic work,
54:38I mean it's hard to disambiguate.
54:42I mean they're so tied together,
54:44you know it's really hard to separate and
54:46then look at people doing animal research.
54:48If you're getting these results,
54:51how do you, you know,
54:53how do you make sense of the fact
54:55that you're able to get this without
54:57any objective or or you would
55:00assume any expectations on part
55:01of the animals said they're good.
55:03I mean I think these are the big
55:05questions like how do you get these
55:06results if you don't have expectations.
55:07But I think the the real question is
55:12how do you do these studies when there
55:15is such an acute effect of the drug
55:17that it unmasked every single time.
55:20So you can't really do a
55:23placebo-controlled study unless
55:24you have something else that can
55:27generate a similar effect acutely.
55:29But it I do have an idea
55:31how do you get around that
55:33This is a big equation. You know
55:35what is the control for secondary,
55:36I mean it's if you talk to
55:38the FDA, you talk to anybody.
55:39This is the big question
55:40how do you so and I I thought
55:43a lot before coming here.
55:45There are you know different studies
55:48where they try to change the dose so
55:52sub clinical doses but still you know
55:54the sub clinical doses people don't
55:57have the same mystical or you know wow
56:02reaction that the psychedelics can cause.
56:04So sub the therapeutic dose does the
56:09classical approach of you know know
56:12those has not been the solution.
56:15Some other people have tried placebo
56:17and of course you you know somehow
56:20destroying all the blinding because
56:22it's so clear that a placebo versus
56:25psychedelics is easy to guess what here
56:28is there so the allocation doesn't work.
56:32Other people try Tamizo or other
56:35drugs to have some sides effects and
56:38we do know that when we produce sides
56:41effects we increase the chance to have
56:44a placebo response because a patient
56:47say OK I'm feeling and as I feel sick
56:51probably I receive the active drug.
56:53So the question first I would suggest
56:56for any person who does psychedelic
56:59treatment to assess expectation and to
57:02tackle this kind of you know question,
57:04none with the gold standard of
57:07additivity that clearly this kind of
57:11you know urgent go beyond additivity.
57:14You can't merely compare PLACIP
57:17versus you know psychedelics or active
57:20comparators or sub therapeutic doses.
57:23Then it's time to think about other approach.
57:27Other approach can be you know challen
57:31challenging because of regulatory
57:33requirements that they may not,
57:35but also you know the balance
57:37plus simple design that can be
57:41double-blind plus simple
57:43design where we blind both the
57:46therapist and the patient with,
57:48you know, misleading information
57:50with that has not been tested.
57:53Maybe that can help somehow to
57:57see how you know, using balance
58:00plus simple design help, although
58:03that doesn't necessarily address
58:05the question about acute,
58:07you know, acute blind.
58:09I have I have a suggestion
58:12Cyril D'souza. One possibility
58:15is for example to use
58:18a drug that does produce
58:19hallucinogenic effects that is not
58:22predicted to, for example produce
58:24anti depression depressant effects.
58:26So that would be for example,
58:29a drug like Salman RNA
58:30which is, which produces
58:33potent hallucinogenic effects
58:36but is generally perceived as being,
58:39you know, unpleasant,
58:41at least for the moment. So that would be
58:46111 possibility. And the other possibility
58:48would be, for example,
58:50since in the case of depression,
58:52there may be patients who who go through
58:55ECT and receive anaesthesia for ECT,
58:58what if you,
59:01you know, give them an anaesthetic
59:02agent so they don't experience
59:05the acute psychedelic effects?
59:07And
59:10I can't comment on that.
59:12Let's comment on both points
59:13that are very stimulating.
59:14Of course, a positive comparator
59:17where we can create the experience
59:20somehow without having antidepressant
59:22effects can be a strategy.
59:25The idea to have this drug while people
59:29are anesthetized has been shown recently
59:32by Boris and this team from Stanford.
59:35And what do they have with ketamine?
59:38What do they did?
59:40They give ketamine to people who were,
59:44you know, prepared for their
59:47surgical procedure and the idea
59:49was and they had major depression.
59:52So if we inject ketamine,
59:54they should have long lasting effects of
59:58ketamine on their depression post surgery.
01:00:01And I suggest I little did this.
01:00:04The manuscript that is very intriguing,
01:00:06but probably,
01:00:07I mean this is something like self marketing.
01:00:11There is an accord and I comment on
01:00:15this manuscript and the article that
01:00:17came out today where we described
01:00:19by the challenging pitfalls,
01:00:22but also how somehow when we create
01:00:24a sort of silencing expectation
01:00:27like the Open Eden Paradigm,
01:00:30we may also destroy all the effects
01:00:32of the antidepressant like ketamine.
01:00:35In fact,
01:00:36patients who receive ketamine
01:00:38or placebo improve equally.
01:00:41Over 50% responded, Yeah,
01:00:43and they both improve.
01:00:44So that is the challenge.
01:00:46If 50 percentage improve and
01:00:47this is the same 53 percentage
01:00:49that I saw in my patient,
01:00:51no matter if they receive a placebo
01:00:54ketamine before beginning anesthetize it,
01:00:56then the medicine that we practice
01:00:58may need to be scrutinized because
01:01:01expectation needed to be studied.
01:01:04Because maybe that is a concept that some
01:01:08while some hours in 2003 very popular
01:01:12in the literature for antidepressant
01:01:15it's that you need the expectation
01:01:17to see an antidepressant effect.
01:01:20When we did the Adziban with an
01:01:23Indian administration especially
01:01:25didn't improve Boris.
01:01:26Today you have ketamine and
01:01:28placebo and they improve equally
01:01:30not despite begin anesthetized.
01:01:33So then let's tackle expectation.
01:01:35We truly needed to understand our wine
01:01:38desert that I molecular changes and
01:01:40merely rely on the concept that we can
01:01:43use the world standard of comparing
01:01:46A placebo armor with a ketamine or
01:01:51psychedelic are may not help us.
01:01:55And also Chris asked about
01:01:57the duration of this effects.
01:01:59There are a paper in the literature show
01:02:02that patients who had placebo responses 10
01:02:05years before they continue to be respondents.
01:02:09And anecdotally,
01:02:10when we were serious Parkinson
01:02:12patients that they received,
01:02:14you know,
01:02:15treatment with a battery,
01:02:17we had the patients who came to the
01:02:19lab were being reassessed clinically.
01:02:21They didn't know that the battery
01:02:25was off because they travel from
01:02:27the metal detector and they were
01:02:29continued to have huge improvement.
01:02:31They didn't realize.
01:02:33So what can we call this a long lasting plus
01:02:39CB effects expectation that makes them,
01:02:41you know,
01:02:42not realizing that that resolve
01:02:46and they continue to improve
01:02:47and conducting their life.
01:02:49I think,
01:02:52Luana, Luana, I have a question
01:02:53about how you would recommend we
01:02:57measure expectancy, because as yet
01:02:59I'm unaware of any standardized
01:03:01way of measuring expectancy,
01:03:04especially for psychedelic studies
01:03:10about expectations and expectancy,
01:03:11just so it's clear to everybody.
01:03:14So we define operationally
01:03:17expectations when we measure it.
01:03:20And there are several scales,
01:03:22like the Stanford Expectation Scale,
01:03:25the Credibility scale or
01:03:28merely visual analogue scale.
01:03:31We compare in the lab two
01:03:34different assessments and
01:03:37we see that the visual analogue scale,
01:03:40it's easy to understand and somehow
01:03:44helpful to understand the expectations.
01:03:48In the paper that we publish with the
01:03:52distribution of Placib effects in chronic
01:03:54pain patients and earth controls,
01:03:56the NMT and so on,
01:03:59there was an association between
01:04:02expectations versus Placib effects.
01:04:05But expectation didn't mediate
01:04:07the Placib effects.
01:04:09So if we want a simple tool,
01:04:12I suggest visual Analogue Scale where
01:04:14they just have a cursor and we can
01:04:18measure without any numerical anchors.
01:04:20But the expectancy to me is even
01:04:23more intriguing and important in
01:04:25a ideal world like us that are
01:04:28well funded and we have brain and
01:04:31resources to tackle questions.
01:04:33I suggest not to study middle expectation,
01:04:36measuring how much people expect to improve,
01:04:40rather measuring expectancy with modelling,
01:04:43brain imaging.
01:04:44And try to see how the interplay
01:04:47of beliefs and mindset at the level
01:04:51of neuronal change can help us
01:04:54to understand the responsibility
01:04:55to treatment
01:04:59about measuring expectation and
01:05:01studying the brain correlates
01:05:03of beliefs and expectancies.
01:05:05Thank you. Sure. OK.
01:05:09Mr. I got two questions.
01:05:10Yes, one is in that slide that you
01:05:13showed all of the components of
01:05:15expectancy and the placebo effect, all that.
01:05:18And then you mentioned certain
01:05:20components of expectancy, right.
01:05:21So the patient's priors,
01:05:23experiences or beliefs,
01:05:24how did you get to those elements?
01:05:26Like did you assess that?
01:05:28Did you openly ask them,
01:05:31so they're referring to this,
01:05:35correct.
01:05:37No, no,
01:05:38no way before like in the
01:05:39beginning of the present.
01:05:40Yeah, I think in your overview
01:05:42slide you were saying all the
01:05:43things that could influence.
01:05:44Yes, that, so that expectancy there.
01:05:48So this is a summary of what we have
01:05:51been studying over the last 1-2 decades.
01:05:53So the concept is that
01:05:55expectations can be measured.
01:05:57Expectancy is something more related to
01:06:00the brain changes when we don't measure
01:06:03expectations and so we know that we
01:06:07can study anticipation of treatment.
01:06:10So at least with brain imaging,
01:06:12we have been looking at anticipatory
01:06:15phase when you expect something acute a
01:06:19treatment and somehow this anticipation
01:06:22can trigger brain changes and it's
01:06:25our ability to predict future events.
01:06:28So another way to think about
01:06:30this is real ability to predict
01:06:33and anticipate future events.
01:06:35So we call this expectancy and in terms
01:06:39of expectation is more a measurement
01:06:42of patient believe and outcome.
01:06:46This is their ability.
01:06:49If your questions is about this part,
01:06:52this is just a summer of all the studies
01:06:55that we have been conducting where we
01:06:58can manipulate the suggestion therapeutic
01:07:00experience by asking patients about how
01:07:03many good clinical experience you had.
01:07:06There are studies show observation
01:07:08in other people and contestual
01:07:11and interpersonal interaction.
01:07:13It's made last summer over 20
01:07:15years studies that we conduct,
01:07:18other people conduct, yes, yes.
01:07:21And the second question.
01:07:24So second question was with regards
01:07:26to the question physician aspects
01:07:30that might influence patients.
01:07:33Yeah.
01:07:33And you said that you tested the warmth,
01:07:35encompass empathy that that was negative.
01:07:38But I was wondering if you investigated
01:07:41whether you can group physicians
01:07:44by their patients response because
01:07:47there's this paper on antidepressant
01:07:50effects that does that well.
01:07:52We did in our experiments.
01:07:54So I would refrain from generalizing
01:07:57because there are other studies show
01:08:00that the physicians the study you
01:08:03mentioned and to other study warmer
01:08:05and competency influence outcome.
01:08:09We are not observing that implicit
01:08:12effects through our paradigm.
01:08:14But of course there are you know
01:08:18this are elements that are part
01:08:21of the interpersonal interaction
01:08:23that may affect clinical outcomes.
01:08:25But even without sorry, sorry,
01:08:27I'm sorry but even without knowing
01:08:29the specific component did you observe
01:08:31like a grouping among physicians like
01:08:33a certain physicians have we see an
01:08:36experimental effect we know that in
01:08:38the lab there are some people that
01:08:40trigger larger plus if effects we
01:08:42should publish that the experimental
01:08:44effect and I bet that you see that
01:08:47with your experiment or your patient.
01:08:50It's something that we don't know if
01:08:53it's the verbal nonverbal communication,
01:08:55the attitude the way to connect
01:08:58with your patient,
01:08:59but we do see an experimental effect.
01:09:01Thanks for asking. Anything.
01:09:04So, I'm sorry.
01:09:04I have to run off and catch a train,
01:09:06which means I have to take my computer.
01:09:08So I'm going to take my computer in.
01:09:10But that doesn't mean that this.
01:09:11I think you have anyone enough. No, no, no.
01:09:13They'll stay on. Oh, they stay on.
01:09:16Your slides will go away.
01:09:21All right, that's me.
01:09:21Let me make sure. Oh, watch
01:09:23this. I'm not going to kill the meeting.
01:09:25I've done this anytime where
01:09:27I've accidentally killed
01:09:28the meeting conditioned to
01:09:33OK, Jessica, you're the you're the boss.
01:09:36Thank you. All right. OK,
01:09:40Chris, while you're doing it,
01:09:41I can say maybe address this too.
01:09:43It gets more complex though, too,
01:09:45because then there's contextual factors,
01:09:47right? So what could be a a
01:09:51favorable placebo response?
01:09:52Or who may be a person who's more
01:09:54likely to have a placebo response
01:09:56in one situation could be very
01:09:58different in another situation.
01:09:59So that and that's culturally.
01:10:02But even from 11 endless to another,
01:10:05a physician that may engender a good
01:10:08political response to a surgery
01:10:09intervention may be a different thing
01:10:13that would engender a good political
01:10:15response to some other type of intervention.
01:10:17They.
01:10:18I think that's.
01:10:18It's fair to say some of the more recent
01:10:22research suggested that it's very contextual.
01:10:24It's not so simple.
01:10:25It's not like,
01:10:26which makes a lot of sense,
01:10:27like things that the things that make
01:10:29you confident in a plumber's skills
01:10:31are going to be very different in the
01:10:33person buying the plane, Right? Yeah.
01:10:36Plumbing I mean the Super response,
01:10:42yes can I also so about the our last
01:10:45how how can we know how much of the
01:10:47effect of the psychedelics of placebo.
01:10:49I know that in some studies to know
01:10:52how much of the effect is placebo.
01:10:53I mean it's mostly for pain.
01:10:55I think it's they use naloxone because
01:10:57you know one of the underlying mechanism
01:11:00of analysis in a placebo response
01:11:03in for pain is intrinsic opioid.
01:11:07So they use another song to mask that
01:11:09and to see how much of the effect is
01:11:12there like the real right for example
01:11:14keterolac for keterolac we can't do that
01:11:16but I mean we have been using monabant.
01:11:19So the idea I mean well placebo analgesia
01:11:25has been you know study mostly with
01:11:29pharmacological approach before we had
01:11:31the brain imaging and so on in 197374
01:11:35a teenage a patient with wisdom you
01:11:41know withdrawal and surgical procedure
01:11:43were somehow randomized to selling
01:11:46and or morphine and pre injecting
01:11:49idols of naloxone block completely the
01:11:52effects of placebo energies because
01:11:54patients respond also to selling.
01:11:56But this is also the bitcher story
01:11:59when he was in Sicily and the post
01:12:01war and somehow he is failing to
01:12:03treat good that the patient when
01:12:06he had finished you know the pain.
01:12:08So actually my question is that can we
01:12:10do that for psychologics I don't know
01:12:12how much of the like an antagonist does.
01:12:14So there's there is talk about using
01:12:16like tanzarin and some of the other
01:12:185 HD two drugs to block the effect.
01:12:21But then what we can do like in the
01:12:24ketamine study with mice that use greater
01:12:27conditioning you know psychedelics 2
01:12:29weeks apart or one months apart and
01:12:32other psychedelics and then placebo by
01:12:35pre injecting psychedelic antagonist.
01:12:38Oh no no I'm actually not using about
01:12:41you're talking about not because I don't
01:12:44know the opioid you like the intro I'm
01:12:46talking about using something to block she's.
01:12:48Yes I know that intrinsic opioids are
01:12:50like one of the one of the main you
01:12:53know circuits in the brain that you
01:12:55know not that is an absolutely nice.
01:12:57Yeah ketamine
01:12:58also at Stanford using Nelloxon to
01:13:02reportedly block them the ketamine
01:13:04antidepressant response in a small number
01:13:07of people. So the idea is kind of
01:13:09we block the placebo components
01:13:10that are using in a given that
01:13:13the new opioid system is one of
01:13:15the most important system that has
01:13:18been done for ketamine for example.
01:13:21And that's a cool idea.
01:13:22The caveat is that OK,
01:13:26it's through the endogenous opioid
01:13:29system play a relevant role for placebo
01:13:31but it's not the only system we know
01:13:34that we have a release of dopamine,
01:13:36we have a release of endogenous
01:13:41but people try to block expectation
01:13:44with anesthetic drugs, you know. So
01:13:47I'm very curious about the nature of the
01:13:50stimulus that trigger the placebo response.
01:13:52Do we have any study that I don't
01:13:55know how an approach of more operant
01:13:57conditioning maybe engage people,
01:13:59maybe saying even a ritualistic behaviour
01:14:01and see if the behaviour is changed a
01:14:05magnitude of response and if there is
01:14:08a in some cases there is some effect of
01:14:11novelty and oddness of that stimulus.
01:14:14For example in case of psychedelics
01:14:17we have because they are odd,
01:14:19they are doing that and maybe if we use
01:14:22that multiple times it somehow has the
01:14:24effect wears off as it becomes more familiar.
01:14:28So the operant conditioning has been
01:14:32used both in humans and in animals.
01:14:35The number of studies is very limited.
01:14:38So we have not too much knowledge yet
01:14:42and the idea was that's the novelty and
01:14:45actually I quoted a paper and we designed
01:14:49a study with they grew up in Leuven.
01:14:51That study a lot of condition John named
01:14:55Lion and the results were not very appealing.
01:14:59I mean, we didn't find stronger PLACIP
01:15:02effects by using this operant conditioning,
01:15:05yes, but probably we thought
01:15:08that was too complex,
01:15:10too many stimulations that patients got,
01:15:12participants got lost in the paradigm.
01:15:17But I mean there are a few
01:15:20studies in animals as well,
01:15:21but there is also tend to be inconsistent.
01:15:23So yes and the novelty doesn't
01:15:28seems to be the critical component
01:15:31for placipic pets here.
01:15:34But probably this interesting in
01:15:36psychedelic trials to study naive
01:15:38versus non naive patient and see
01:15:40how this change and perspective
01:15:42longitudinal study can also help.
01:15:45You know if we go on with open label
01:15:48trials where they know that they
01:15:50receive the treatment and we follow
01:15:52this patient for 5-10 years then we
01:15:55can understand the more especially
01:15:56if we have a large court of patients
01:15:59when we can start phenotyping and
01:16:01try to study different aspects.
01:16:03I think
01:16:05one of the main concerns regarding
01:16:08sort of expectations is all the
01:16:12well most of the studies done,
01:16:14most of the patients and psychedelics
01:16:16have been highly educated people
01:16:19that are well aware of these effects
01:16:21and I know it's one of the real
01:16:23concerns the FDA has does this.
01:16:25If you look at many of these studies,
01:16:2898% college graduates,
01:16:30you know there there's a real
01:16:33need to make sure that you're not
01:16:34just selecting people that have
01:16:37very high expectations about,
01:16:39yeah, diverse people, larger studies
01:16:42also the number are very small. It's
01:16:45the same thing in
01:16:47psychodynamic psychotherapy.
01:16:47Going back 50 years ago if you
01:16:50weren't psychologically minded
01:16:51code word for intelligent and
01:16:53you've read about psychoanalysis,
01:16:54it wasn't positive in effect.
01:16:56So there is you just recruitment biases.
01:16:58This people wants to be
01:17:00in the trial you know.
01:17:02So I think once a week truly study
01:17:05beliefs and expectations probably change,
01:17:08you know the study design but also the
01:17:11change also I don't know if it's ethical.
01:17:14Maybe we can remove like
01:17:17eliminate non placebo responders,
01:17:18you know they're on a simple trial
01:17:22placebo responders and they can give you
01:17:25trial for the those who do not respond.
01:17:29But that's consistent though like
01:17:31are people consistently placebo
01:17:32responders regardless of their
01:17:34previous history with that specific
01:17:35treatment and that specific condition.
01:17:37There are studies we call this
01:17:40reproducibility classy effects.
01:17:41So that means a,
01:17:45he is a person who is a receiver responder,
01:17:47constantly a placebo responder.
01:17:51And our chronic pain patients came back
01:17:54to the lab and there is a good proportion
01:17:59of patients who continue to be a
01:18:01responder in terms of general disability.
01:18:04So someone who responded to a modality will
01:18:06be also a responder to another modality.
01:18:09There are some studies so that
01:18:11we can respond to pain.
01:18:13Also you know, a trigger to be a responder
01:18:17to emotional regulation and more resolvers.
01:18:20So if I,
01:18:23I, I
01:18:24know we're running well beyond,
01:18:25we can continue to go, but I don't
01:18:27know if I'm holding anybody up,
01:18:28but you can continue to go
01:18:31in terms of running the phase,
01:18:33that has been a big question.
01:18:35You know, kind of.
01:18:36We first to give a placebo.
01:18:37If they respond, we remove them.
01:18:39Ethically speaking is not the best practice.
01:18:43And also again, we select the
01:18:45pool of people who respond. Here,
01:18:49it it reminds me of one of the studies I
01:18:51was just reading going back to the 1930s.
01:18:53Harry Gold, who is one of the Harry Gold,
01:18:56one of the leaders,
01:18:57the reason we do placebo control trials.
01:19:00He was running a study with
01:19:01zantines for angina.
01:19:03You know cardiac pain and at the time
01:19:06it was about an 80% response rate.
01:19:08He takes his antenna and
01:19:10reduces cardiac pain.
01:19:11So he wanted to do a study in order.
01:19:12One of the early ideas of trying
01:19:15to rule out placebo responders,
01:19:17he was giving nitroglycerin to people
01:19:19who was having an engineer and the
01:19:21the goal was to exclude people that
01:19:23had a placebo response and only
01:19:24include the people that only had
01:19:26a real response to nitroglycerin.
01:19:28Do you know the results of this
01:19:29same exactly from everybody.
01:19:34So you couldn't you know
01:19:35it's really hard people
01:19:36new placebo responders emerged.
01:19:40Yeah. I was curious about about this
01:19:44effect at the very beginning across
01:19:46analgesic you have different level of
01:19:48placebo effect and I was wondering
01:19:50whether we know if some drugs will
01:19:53have like higher placebo effects and
01:19:55if there is any reason in the at the
01:19:58narrow biological level for this. Yes,
01:20:02our thought was that for drugs that work
01:20:05like opioids based as compared to some
01:20:10non opioids that stand to work less at
01:20:14least for the post operative pain the.
01:20:18You know money to the the placebo component
01:20:22may varies because that reflects how
01:20:25much if cautious or effective a drug is.
01:20:30We also think that there is an interaction if
01:20:34that like with metamazole that is non opioid,
01:20:39we saw that the interaction
01:20:41effect is very strong.
01:20:42I mean if you have also a placebo component
01:20:46through the expectation probably the
01:20:49money told of the same drug is larger.
01:20:51So in general drugs that per SE are
01:20:54very effective tended to have a smaller
01:20:57placebo component unless there is an
01:21:00interaction if that's like they trigger
01:21:03some molecular mechanism that can
01:21:06interact and we know how much the nuclear
01:21:09system interact with other system.
01:21:11And in that sense you don't see
01:21:14cumulative effects, you know
01:21:17but when isn't it fair,
01:21:18I mean to getting your point that
01:21:20some of the other points like a
01:21:22drug that has an immediate effect
01:21:24is more likely to have a placebo
01:21:26response than a drug that that you
01:21:28is blind is truly math correct.
01:21:31I don't know also well the question.
01:21:36The consciousness and self
01:21:38perception is very relevant.
01:21:40The I don't know actually.
01:21:42Now I understand the question,
01:21:44but so for example, if we give people a
01:21:50normal that can change the
01:21:54level of cortisol in the body,
01:21:57the Placib effect is not
01:22:00existing or an antibiotic,
01:22:03then the placebo component is not there.
01:22:06Somehow the placebo effects
01:22:08amplify the therapeutic benefit.
01:22:11When we have experience of that,
01:22:13I mean if you take a patient with
01:22:16genetic disorders and they don't
01:22:18feel pain and you tell them this
01:22:20treatment is analgesic for them,
01:22:23doesn't mean anything, you know.
01:22:24And so there will be not an
01:22:26analgesic plasibe effects.
01:22:28Or if we tell patients this drug is
01:22:31going to increase your cortisol level,
01:22:33they don't know what a cortisol level is
01:22:37or we use some Atriptan back in Turin,
01:22:40you know that it's used for migraine
01:22:43attacks if but also some side effects.
01:22:46So they can get an improvement at the
01:22:50level of migraine and pain related to
01:22:54the migraine but not necessarily the bio
01:22:57chemical change in markers in the blood.
01:23:01However,
01:23:01if we use air conditioning like that's
01:23:04been shown with you know cytokines,
01:23:07like if we use cyclosporine a several
01:23:10time and then we replace cyclosporine A,
01:23:13we see a modulation of Illinois 6 and
01:23:16interferon gamma in the blood because
01:23:19the body learn that kind of measurement.
01:23:22I am a big champion of framing plasy
01:23:25B effects as learning effects and so
01:23:30somehow we can either bypass our
01:23:35conscious perception of symptom.
01:23:36We can still act with conditioning paradigm,
01:23:39you know and train our body
01:23:42to produce a response.
01:23:44But this kind of effects can't be
01:23:48elicit with verbal suggestion.
01:23:50Yes, I think we, I mean,
01:23:52it's well beyond it.
01:23:53Thank you all. Thank
01:23:55you. Thank you. That was great, Lena. Thank
01:23:57you. It's very cool.