Natalie Gukasyan, MD. November 2022

November 28, 2022

Information

Title: Placebo, expectancy, and psychotherapy effects in psychedelic-assisted therapy

Description: This talk covered the challenges and biases that confound clinical trials with psychedelics, including the challenges of executing placebo-controlled research. It examined how many of these challenges are shared by the broader field of general psychotherapy research, and some of the debate and solutions that have emerged from that body of work. We also discussed the debate around the concept of placebo in interventions that employ psychotherapy. Finally, we reviewed implications of these concepts for future research and potential solutions.

ID9181

To CiteDCA Citation Guide

00:00Other time with the people
00:02who are here on time.
00:05So it's a pleasure to see everyone
00:07for this monthly psychedelic seminar.
00:09This will be our last meeting
00:11of the seminar this year.
00:12The December dates became difficult when
00:14we tried to figure out a Friday that would
00:17work because of the holidays and other.
00:20And other conflicts,
00:21so we'll we'll resume in January and
00:23they'll be emails and announcements about
00:26that the specific speakers yet determined.
00:29But for today, to round out 2022,
00:32it's really a pleasure to
00:34introduce Natalie Caucasian.
00:36I'm actually not sure I'm pronouncing
00:37your last name right, Natalie.
00:38I've always felt self-conscious about that,
00:40so close enough.
00:42Thank you.
00:44Thank you.
00:47Natalie is an
00:48assistant professor at Hopkins,
00:49where she trained as a resident and
00:52then stayed on as faculty training in
00:54Roland Griffiths storied psychedelic
00:55science group where she played a
00:58prominent role in their recent and very
01:01important double-blind placebo-controlled
01:02trial and depression as a therapist
01:05and A and a Co investigator and is
01:08now leaving their work in anorexia.
01:11But if I'm not mistaken,
01:12what she's going to be talking with with
01:15us about today is a different line of work.
01:17Have her to describe before and
01:19fundamentally thought provoking,
01:20which is the relationship between
01:22psychedelic effects in the therapeutic
01:25context and the generic effects of therapy.
01:28I think that'll give a lot of
01:30interest to this group and I hope,
01:32I hope it will prompt some good discussion.
01:35Natalie is also a partner with
01:37Ben and I together with Natalie
01:39and with colleagues at NYU,
01:41have an initiative to build up curriculum
01:44materials to teach about psychedelic
01:46medicine and psychedelic science.
01:47Within medical schools
01:48and medical residencies.
01:49And so we've had the pleasure of working
01:52with her over the last year in that context.
01:55And I'm thrilled to welcome
01:56her to our community in this.
01:59Natalie, over to you.
02:00Thank you for being here. Thank
02:02you, Christopher. The invitation to
02:03join you and chat about this topic,
02:06which I find pretty interesting,
02:08I think e-mail me, you said.
02:10Natalie, please share something
02:11about your very interesting ideas in
02:13psychotherapy and placebo effects.
02:15And so here I am.
02:17Sharing so hopefully my.
02:20PowerPoint won't be too ordinary today,
02:23so just some disclosures and
02:25acknowledgements at the top.
02:26I'm a Co investigator on a multi
02:28site clinical trial of still cybin
02:30for major depressive disorder
02:32funded by Usona Institute.
02:34And most of my salary is funded
02:37by generous philanthropic
02:38donations from these folks here.
02:41So today I hope to take you through
02:45an interesting tour of placebo
02:47effects and psychotherapy effects,
02:50and we'll start with a brief history of
02:52placebo and the randomized controlled trial.
02:54Talk about some challenges to
02:56the RCT that are posed by the
02:58study of psychedelic therapy,
02:59many of which are known to us.
03:01But I'll be talking about them in
03:02sort of a more granular way with
03:05respect to psychotherapy effects,
03:06which will lead us into what I hope we
03:08can learn from the many decades that.
03:11Consists of general research into
03:12psychotherapy effects that we can use
03:14to inform our work with psychedelics,
03:16along with some ways forward.
03:18Along the way you might see some fun.
03:21AI generated L2 art,
03:23including this right here,
03:25which is generated by the prompt,
03:27which is a female scientist
03:30choosing between a magic pill or
03:32placebo by Salvador Dali.
03:34So to start us off with some definitions,
03:37right, these are,
03:37these should be well known to us.
03:38But just to be extra clear,
03:40placebo is an intervention the
03:42physical properties of which
03:44are not expected to have any
03:46therapeutic effects on their own.
03:48So a sugar pill or a sham procedure
03:50would count and a placebo effect
03:52is what we call a measurable
03:54improvement in some condition
03:55that occurs due to something other
03:58than the physical properties of
04:00the treatment being studied here.
04:03The term placebo is Latin for I shall
04:06please it was used in the 14th century,
04:08or for refer to hired mourners at funerals,
04:11where the word naturally carried a
04:14connotation of depreciation and substitution,
04:17because those mortars were often stand
04:19INS for families of the deceased.
04:21And the word appears again in
04:24the medical literature,
04:25in a 1785 dictionary where it's used to
04:28describe a commonplace method or medicine,
04:31and again in 1811.
04:33Where it's used defined as an
04:35epithet given to a medicine,
04:37adapted more to please than
04:40to benefit the patient.
04:42And placebo therapies are actually
04:44widespread in medicine until about the 1950s,
04:47so it was not at all uncommon.
04:49And nice little note I have here
04:51is Thomas Jefferson in 1807,
04:52wrote in his diary at one point that
04:54one of the most sick physicians
04:56he had ever known had assured him
04:58that he had used more bread,
05:00pills, drops of colored water,
05:02and powders of Hickory ashes than all
05:04of the other medicines put together.
05:06Which is
05:06pretty pretty. But I think we
05:09have a couple of unmuted folks.
05:11But yeah, pretty great. Perfect.
05:15So at the time up until this period of time,
05:18basically the many of the medical
05:20codes of ethics actually endorsed this
05:23necessary deception, and somewhat.
05:27More upsettingly,
05:27placebo is thought to be more
05:29effective in unintelligent, neurotic,
05:31or inadequate patients of some sort.
05:35And in research, placebos didn't really
05:38make their debut until fairly recently,
05:41until about the 1950s.
05:43Most therapies are usually judged on
05:45the basis of some pathophysiologic
05:48rationales from authoritative experts,
05:50rather than the results of any
05:52empirical or comparative research.
05:53And perhaps the first example of a real
05:57placebo-controlled trial came from
05:58this gentleman John Haygarth in 1801,
06:01who used the study of the.
06:05Perkins Tractor,
06:05which is this metal rod right here.
06:08So back in those days,
06:09if somebody was having some sort of
06:12complaint of pain or other availment,
06:15these tractors would be laid upon the body.
06:18And John Haygarth was not so sure
06:21that the purported method of the
06:23methodologic mechanism here was really it.
06:26So apparently this is supposed to work by
06:29some electromagnetic influence of the metal.
06:31So hey, Garth mocked up some
06:33wooden Perkins tractors and.
06:35Compare their effects to metal
06:36ones and found actually there was
06:38no difference in a small trial.
06:40And he wrote this pretty
06:42interesting quote here.
06:43An important lesson in physic.
06:46Is here to be learned the wonderful
06:48and powerful influence of the
06:50passions of the mind upon the
06:51state and disorder of the body.
06:53This is too often overlooked in
06:55the cure of diseases,
06:56which I would agree with.
07:01And further along,
07:02and another example of placebos and
07:04research famously, was Austin Flint,
07:06who studied essentially an inert
07:08tincture that he gave to patients
07:10with rheumatism and found that many
07:12people actually seemed to improve.
07:14And he concluded that the disease
07:15itself essentially is self limiting.
07:19Into the 1930s we had several papers
07:22that were published that introduced
07:24the idea of using placebos actively
07:27prospectively in clinical research,
07:29and in 1938 deal and colleagues
07:32published the first study explicitly
07:34describing a placebo-controlled
07:35condition for a cold vaccine.
07:38Another landmark was Henry Beechers
07:411955 paper the powerful placebo,
07:43in which he analyzed 15 trials and found
07:46that the rate of response to treatment
07:48with placebo is stunningly high at 35%.
07:52On a sort of parallel track from the
07:55development of placebos is just the
07:57development of comparison conditions, right?
07:59And so the RCT is sometimes dated
08:01to the 1940s with the study of
08:04streptomycin for the treatment of TB.
08:06But elements of comparison conditions
08:09appeared sporadically over at least
08:11a few centuries prior to that.
08:13Common examples James Lynch,
08:14who's seen here in a painting.
08:16This is a Scottish surgeon who published
08:19in 19 in 1753 a prospective period
08:22of trial where he tested several
08:25different common kinds of treatments
08:27for scurvy and found that surprise,
08:30those containing citrus resulted
08:31in some dramatic improvement.
08:35And loosely, controlled trials appeared
08:37increasingly on the 18th and 19th centuries,
08:40usually run by skeptics to
08:43test some dubious remedies,
08:44alternate allocation trials, and merge.
08:47And this is actually probably the most
08:50recent methodologic ancestor of RCT's.
08:51And this mostly was used in trials of
08:54treatments for preventive measures for
08:57different sorts of infectious diseases,
09:00including this commonly cited example.
09:03So this is a Danish.
09:04Position Fibiger gave diphtheria antitoxin
09:06to patients every other day in his
09:09clinic and compared outcomes from those
09:11who received it to those who did not.
09:18Concerns about selection bias
09:20and the alternate allocation
09:22model arose in about the 1930s.
09:25Max Finland, writing on some
09:27alternate allocation studies
09:28and pneumonia treatment trials,
09:30wrote that he believed that some choice
09:32might have been unconsciously exercised
09:33in selecting cases for treatment.
09:35That may be patients who are very poor
09:38or desperate might have been more,
09:40or maybe healthier,
09:41or sicker might have been put into one
09:43treatment allocation rather than another.
09:45And it wasn't until 1948 when we have this
09:48example of the Austrian Bradford Hill,
09:51who actually had the first randomized
09:53control design which introduced blinding
09:56and which ended up definitively replacing
10:00this alternate allocation method.
10:03And between then and 1970,
10:06this method gradually spread across
10:09British physicians and researchers,
10:10and then gradually into the US,
10:12where in the 1970s the FDA required
10:16that pharmaceutical companies submit
10:17RCT results with new drug applications.
10:20So this is an interesting time period,
10:23right,
10:23because it coincides almost exactly with
10:26the first wave of psychedelic research.
10:30And I think this is an important point,
10:31right?
10:32That it's not just that you know this,
10:34this this area is commonly work from
10:35this area is commonly criticized as
10:37being poorly on rigorously designed.
10:42But the reason for that was probably
10:44that these methods were not actually
10:46widely used at during that time
10:48and so some some assessments are
10:50meta analysis of studies from this
10:52time period do show that there
10:54there are some minority of studies
10:56that use randomization,
10:57blinding or rigorous outcome assessment.
11:00But these were mostly toward
11:02the end of this period,
11:03shortly before the research went
11:05dormant for about 30 years.
11:09And now we're finding
11:10ourselves in the second wave.
11:11We're surfing the 2nd wave of of
11:14all this research where, you know,
11:16places like here at Hopkins Imperial,
11:17across the pond, NYU have employed
11:19a much more rigorous study design.
11:22We've started in healthy individuals and
11:25moved gradually into clinical populations.
11:28And while we are indeed more rigorous
11:31with our outcomes assessment and design,
11:34there's still actually pretty few
11:36RCT's and many more open label studies.
11:38And RCT's have used a variety of control
11:42conditions including wait list control,
11:44a true placebo,
11:45very low dose classic psychedelics,
11:48non psychotropic active
11:49placebos like niacin or zinc.
11:52And psychotropic comparator drugs of
11:55alternative mechanisms to psychedelics,
11:58but might have some overlapping
12:00psychotropic effects.
12:00Let's be like methylphenidate,
12:04dextromethorphan.
12:04And we have some problems
12:06in the second wave still,
12:08unfortunately and so glaring.
12:10Problem number one is that subjective
12:12drug effects often lead to unblinding for
12:15both participants and research staff.
12:17And probably raters too.
12:20Even in one of the earliest
12:22papers from this era,
12:24which compared administration
12:25and methylphenidate to cell
12:27cybern and healthy participants,
12:29a good 3/4 of the participants
12:31were able to correctly identify
12:33what study arm they were in.
12:36And in a much more recent trial
12:38that reported on these results,
12:39over 90% of participants and
12:42therapists correctly guessed
12:43treatment allocation in a study of
12:46suicide in versus diphenhydramine
12:48for alcohol use disorder.
12:54And this is a problem, right,
12:56because the whole point of blinding is
12:57to limit the occurrence of conscious
12:59and unconscious bias in the conduct
13:01and interpretation of our research.
13:03And the essential aim is not met,
13:05which is to prevent identification
13:06of treatments and to all such
13:08opportunities for bias have passed.
13:10And this leads us into trouble with things
13:13like recruitment and allocation of subjects,
13:15their subsequent care,
13:16the attitudes of subjects to the treatment,
13:19the assessment endpoints,
13:20the handling of withdrawals,
13:22etcetera, etcetera, etcetera.
13:25Umm. Function on blinding,
13:26which is what happens in all these studies,
13:29can lead to no sibo effects, right?
13:31So especially if you can imagine in a
13:33design without any crossover condition,
13:35the participant with depression,
13:37severe depression that's
13:38been intractable might come.
13:39And really expect to have a high
13:42expectation for improvement for
13:43this very much hyped wonder drug.
13:45Believe and probably be quite certain
13:47that they received a placebo and
13:491st face some further demoralization
13:51or disappointment, right?
13:52So it might actually worsen
13:55or depressive symptoms.
13:56Compared to say,
13:57it's just not been in the trial at all.
13:59And nocebo effects can lead to
14:02overestimation of differences between
14:04placebo and experimental groups.
14:05And this can be compounded further
14:07by therapists and blinding, right?
14:09So you can imagine if a therapist
14:10at one of our these centers has been
14:13doing this research and they're very
14:15enthusiastic about psychedelic assisted care.
14:17Get a sense that maybe somebody did not
14:19receive so cybin or some other psychedelic,
14:21they might unwittingly or wittingly
14:24send messages or signals to them to
14:26reinforce some of the negative outcomes.
14:29Though, of course, you know,
14:30like for example, we might have,
14:31we, we know you didn't get the
14:33treatment or like we're so sorry,
14:34this is so horrible,
14:35that sort of thing.
14:38Glaring problem #2,
14:40which is where we're going to
14:42spend a little bit more time today.
14:44Secondly, assisted therapy
14:45is a hybrid intervention.
14:47It involves both a drug and
14:51psychotherapy and basically
14:52every setting and contextual
14:54factors along with psychotherapy
14:56likely make some independent
14:58contribution to symptom improvement.
15:01And sentence setting is a is a
15:02term that's kind of frequently
15:04thrown around in this area,
15:06which I'll describe in the next slide.
15:08I would argue that psychotherapy
15:10effects occur even when there
15:12is no explicit psychotherapy.
15:14Modality used like CBT or ACT or am I?
15:17And they arise just by nature
15:19of the interaction between
15:20participant and the study staff.
15:22Some of the preparation that has to happen
15:25of explaining drug effects to a person,
15:28gaining rapport with them,
15:29all of those settings are places where
15:31these kinds of effects can arise,
15:33and we'll talk more about this.
15:36And these effects are very challenging
15:38to standardize and to measure.
15:40So psychotherapy is kind of baked
15:43into the cake is my opinion here.
15:46And so sentence setting.
15:47It's is a term that's used frequently
15:48in the psychedelic sphere and
15:50refers to the psychological,
15:51environmental,
15:52and social factors that can
15:54affect the psychedelic experience.
15:55It's a term coined by Tim Leary
15:58in the early 60s.
15:59And early notions of sentence setting sort
16:02of recognize that psychedelics might act as,
16:04quote UN quote nonspecific amplifiers
16:06of the contents of the consciousness.
16:08And so the the aim was to improve
16:11the contents of the consciousness by
16:14introducing pleasing surroundings
16:15or warm interactions with with staff
16:18and other sorts of factors like that.
16:22And so preparation, expectation,
16:24environment,
16:25even broader cultural attitudes
16:26might shape acute drug effects,
16:29even some of the hype.
16:30That we're seeing,
16:31we're on psychedelics are likely
16:32changing some of the acute drug
16:33effects that we're seeing and that
16:35might affect longer term therapeutic benefit.
16:39Natalie, do you mind if I
16:40jump in with a question?
16:42I already did.
16:43So I hope you don't mind.
16:44Yeah, you go for it.
16:45Chris, I just want to comment
16:48that everything you're saying over the
16:50last two slides, which I, you know,
16:52strongly agree with about how psychotherapy
16:54is happening even if you don't mean to.
16:57And you know, how set and setting
16:59are are likely to matter.
17:00I think that's true of of
17:02of all of our interventions.
17:04I think it's acute in the case of
17:07psychedelics talking about it.
17:09And that's good.
17:10But one I hope you know,
17:13good outcome of these conversations
17:16that the psychedelics are forcing
17:18into the mainstream is to recognize
17:21the extent to which these these
17:23issues are also true with more
17:26traditional mainstream like.
17:29Treatment and and contribute to
17:31placebo control and contribute to
17:32much of the clinical improvement
17:34of our patients outside of studies
17:36for sure. Yeah, I would agree with that.
17:37I would argue though that probably
17:40psychologist therapy is a special case
17:42of an especially potent version of what
17:45normally happens in therapy happening
17:47in like a very concentrated form and
17:50we'll get into all of that about why,
17:52why I think that is.
17:54That there's a huge difference
17:56in the dose. Of psychotherapy
17:59the way that it's right piece
18:01used in psychedelic treatment.
18:04I mean people get almost 16 hours of.
18:07Psychotherapy across the course
18:09of a typical psychedelic,
18:12you know, treatment program,
18:13which is more than what most people
18:15get in an entire year, right in regular care.
18:19And I wasn't sure what the what
18:20the audience for this was.
18:21And I I've considered making an explicit
18:25slide just about like what the contents
18:26of a typical intervention looks like.
18:28But that's absolutely right that you know,
18:31I'll just briefly say that in a in a
18:33study here, for example, of depression,
18:35a person will get 8 hours of.
18:382 therapists in a room together
18:39with a patient where they'll
18:41talk at length about their life,
18:43about their problems, that sort of thing.
18:45And then of course they're there
18:47for the entirety of drug effects
18:48of one or more sessions.
18:49They're both there for next day,
18:51follow up one week, follow up monthly,
18:54long term follow-ups.
18:56That's quite a lot of therapy and people.
18:59Seem to to stick with it too.
19:02Unlike in many studies of psychotherapy
19:04where there's a lot of dropout,
19:06at least at least here,
19:07for the most part people tend to
19:09stick around for whatever reason.
19:11That
19:11does raise the question, if you like,
19:12to the extent that psychedelics
19:13are different in the terms of
19:14the the dose and the magnitude
19:16of the effects of these things,
19:17is that that because of the
19:19psychedelics or because of the dose?
19:21The answer is probably both.
19:23Hard to say, yeah. All right, so.
19:29This is a fun quote from
19:30my colleague Matt Johnson,
19:31who writes psychedelic therapy is more
19:33psychotherapy than most pharma companies
19:35and neuroscientists know how to deal with,
19:37and more pharmacology than most psycho
19:38therapists know how to deal with.
19:40So it's a kind of sneaky.
19:42Little intervention that can be kind
19:45of complicated and unlike for typical
19:47placebo-controlled RCT's for other
19:49drugs where investigators are striving
19:51to minimize those factors that are
19:54known to boost placebo response,
19:56which is especially important when
19:58the clinical target that we're
20:00looking at is known to have a
20:02very large response to placebo.
20:03That would include depression and pain which
20:07have responses in the range of 30 to 40%.
20:10So in most in most cases these are
20:12are are sort of driven down in an
20:14effort to to really understand what
20:15the actual treatment effects are,
20:17right,
20:17not any kind of placebo enhancement
20:19effects or anything like that.
20:20But those factors that boost placebo
20:23response are rife and psychedelic
20:25assisted treatment and in many cases
20:27are sort of touted to be necessary
20:30for both safety and efficacy.
20:32And so it's very hard to actually
20:34design a study especially right now
20:36when we're still in the early days
20:38to to to look at that piece meal.
20:40And in many ways,
20:42clinical trials of psychedelics tend
20:44to resemble psychotherapy research much
20:46more than the average pharma study.
20:49And an illustration I like to pull
20:51out of of those of what we know about.
20:55Contextual factors that tend to enhance
20:57placebo responses interesting study
20:59by kaptchuk and colleagues and 2008
21:01where they did a stepwise manipulation
21:04of factors known to enhance placebo effect.
21:07And they did so in A3 ARM study
21:10of people with IBS in which folks
21:13are randomized to receive either
21:14a waiting list intervention,
21:16sham acupuncture plus a limited
21:19patient practitioner relationship or
21:21sham acupuncture plus an augmented
21:24patient practitioner relationship.
21:25So.
21:26Folks ventured if they entered
21:29a sham acupuncture arm,
21:31they received 6 to 8 dummy needles
21:33that were placed over the course
21:36of about 20 minutes or so.
21:37And if you're in the limited arm of
21:40the sham acupuncture intervention,
21:42you got kind of a a cranky person
21:44who entered the room stated that
21:45they had reviewed the patient's
21:47questionnaire and quote, knew what to do.
21:49And they explained that this was a
21:51scientific study for which they've been
21:53instructed not to converse with patients.
21:55They placed the placebo needles into
21:57these fake acupuncture sites and then
21:59left the patient alone in a quiet room,
22:01after which they returned and
22:03removed the needles and left.
22:05Or people were randomized to an augmented.
22:08Practitioner relationship intervention,
22:10in which the person who was doing the
22:14intervention was instructed to incorporate
22:16at least five primary behaviors,
22:19including a warm, friendly manner.
22:22Active listening.
22:23Demonstration of empathy,
22:25communication of confidence
22:28and positive expectation.
22:3020 seconds of thoughtful silence
22:32while feeling the pulse and
22:34pondering the treatment plan.
22:35Extended conversation
22:37about history of symptoms.
22:39And eliciting the patient's own
22:40explanations of the cause and the
22:42meaning of their symptoms, right?
22:44And so this might.
22:45And finally a discussion of the
22:47impact of the symptoms on the
22:49other areas of the person's life.
22:51Which might sound familiar to you
22:53because this is basically an almost
22:55verbatim list of things that a
22:57person is supposed to be doing.
22:58If you look at the manual of any
23:00kind of psychedelic assisted
23:01therapy training program,
23:03where we're or what folks in
23:05these larger randomized controlled
23:06trials are supposed to be doing.
23:08And it might also sound familiar
23:09because these are just components
23:11of good psychotherapy,
23:12which makes it a little more confusing.
23:15And So what did catchup and colleagues find?
23:17Well,
23:18in terms of global improvement from IBS,
23:20there was a significant improvement
23:22in both of the sham acupuncture arms
23:25with more improvement in the augmented
23:27relationship or the warm relationship.
23:29Adequate relief was much higher
23:32in the augmented relationship.
23:34Symptom severity improvement was much
23:36better in that arm and quality of life,
23:40which is a favorite outcome measure.
23:42It's like all consistent therapy
23:44with significantly better, right.
23:45So I think this shows you just
23:47sort of what the power is of that
23:51warm therapeutic relationship.
23:52And so we've talked about set and
23:54setting and probably a lot of those
23:57factors that are known to enhance
23:58placebo response are present in folks
24:00that are doing psychedelic assisted
24:02therapy and paying mine to set and setting.
24:05But another kind of area that we
24:08there's sort of less talked about
24:10is what we're called common factors
24:12of psychotherapy which is.
24:14But we'll talk about for a lot
24:15of the rest of this hour,
24:17and it's something I wrote a paper
24:18about with my colleague Sandeep Nayak.
24:20That's where there's a lot more detail on
24:22some of the ideas you'll hear about today.
24:25So what is psychotherapy?
24:27Well, if we take a very broad definition,
24:31which I like to do,
24:33it's like therapy is the use
24:35of psychological methods.
24:36That is,
24:36verbal and nonverbal communication
24:38done by a socially sanctioned healer
24:41to bring relief from a sufferer.
24:43And of course,
24:44there are some exceptions to this.
24:46And you could think of, you know,
24:48like computer administrative
24:49forms of psychotherapy,
24:50which are a little different.
24:52You know,
24:52who is the socially sanctioned healer there?
24:54It's a little bit harder to say.
24:55But generally this is what I
24:57would take psychotherapy to be,
24:59and by this definition this would
25:01include various forms of religion,
25:02magical healing for both somatic
25:05and psychological ailments,
25:06including many practices that are still
25:08in use today in indigenous societies.
25:13Western psychotherapy,
25:14which is probably closer to
25:15psychotherapy as we know it,
25:17emerged in the 18th and 19th
25:19century Europe and this happened,
25:21is greater value as being placed on
25:24therapies that seem to demonstrate
25:25a logical or rational mechanism as
25:27opposed to being based in faith, right?
25:30So religious based their base
25:32like the moral therapies,
25:34moral treatments were displaced by
25:36more scientific efforts to understand
25:38and influence human behaviors or
25:40inferiority and approaches and related ways.
25:43Thank you.
25:44And today, for better or worse,
25:45we have hundreds of distinct
25:47psychotherapies that are still practiced,
25:49and a couple seem to dominate the field.
25:52But Despite that,
25:53we've largely failed to find
25:54consensus in psychotherapy about
25:56what what should make up core
25:58principles and things like that.
26:03And so how does this all work, right?
26:04So why should hundreds of different kinds
26:07of psychotherapies that all purport to
26:10work by different mechanisms all have
26:12some moderate degree of of effectiveness?
26:14You know, with rare exceptions,
26:16studies have generally failed to
26:18convincingly demonstrate superiority
26:20of 1 therapy over another.
26:22And one attempt to answer this
26:25question was posited by the gentleman
26:28Rosenzweig in 1936 who thought that
26:31perhaps it's those common factors
26:33that are shared by all therapies.
26:35Those might be mostly responsible for
26:37the efficacy we see rather than any
26:39kind of specific characteristics of
26:41this or that treatment or any kind of
26:43special theory about why this or that works.
26:46And this is expounded upon in Jerome
26:49Frank's persuasion and healing which was.
26:52An awesome book to read as a resident.
26:55A little bit humbling and kind of a hard
26:57place to start as a budding therapist,
27:00but but I think ultimately a
27:02very useful book.
27:03So this is where I sort of came across
27:06with these ideas and for the first time.
27:08And other common factors there of
27:10models have emerged since then.
27:11It's not just Jerome Franks
27:13common tractors models,
27:14also lamp olds contextual model,
27:17olinsky's process model.
27:20They all are quite similar and share sort
27:24of factors related to expectancy and the
27:27therapeutic relationship primarily but for.
27:31Structuring the the rest of my thoughts
27:32of this, I generally used room Frank's
27:35persuasion and healing common factors model.
27:37And so in an effort to understand why so
27:40many vastly different forms of therapy
27:41all seem to have at least some efficacy,
27:44Jerome Frank went off and surveyed
27:45a variety of healing traditions,
27:47including non Western ones included that
27:49they all share a handful of aspects,
27:52namely this emotionally charged
27:55healing relationship.
27:56A special healing setting.
27:59A rationale, conceptual scheme,
28:01or myth that is acceptable to the
28:04person who's receiving therapy and a
28:07ritual or procedure that is undertaken
28:10together by the sufferer and the healer.
28:13And given some of the overlap with common
28:15aspects of psychology assisted therapy,
28:16these factors might also be doing
28:18most of the heavy lifting and what
28:20we think of as set in setting
28:22in psychedelic assisted therapy.
28:24So next I'll just sort of go over some of
28:26what these are, a little bit more detail,
28:28how they might show up.
28:30Things like assisted therapy, uh,
28:33some of the evidence to support that.
28:34So the therapeutic relationship
28:36is probably the biggest and most
28:39commonly sort of cited common factor.
28:42Lots of meta analysis on this
28:44topic and one here,
28:46including data from over 30,000 patients,
28:48revealed that working alliance
28:50as measured by Working Alliance
28:52inventory was highly correlated with
28:54outcomes with an Pearsons R of .28,
28:58equivalent to Cohen's DF .57.
29:00And this didn't differ
29:02across different therapies.
29:03So working alliance was important or
29:05as important to CBT as it was to.
29:08Psychodynamic therapy.
29:11Rogerian factors of the therapists
29:13and things like empathy congruence
29:15ratings were also positively correlated
29:18with outcomes and contributed to
29:20medium effect sizes and meta analysis.
29:23Umm, and 11 factor here.
29:25It's just a note, right?
29:27Is the psychological therapy is
29:28unique in that they're usually,
29:30to date in most trials,
29:31have two therapists rather than just one.
29:33You know what what effect that
29:35might have over our benefit that
29:36might have over just one therapist?
29:37We don't really know,
29:39but it's something we could, we should,
29:41we could and should try to measure.
29:43Umm.
29:44And this is just some preliminary data
29:46from an analysis we're just starting to do,
29:50but we did take some of,
29:51we actually did take working
29:53alliance measures in our study of
29:56our waiting list controlled study
29:57for Cell 7 assisted therapy for
30:00major depressive disorder.
30:01A number of different time points
30:03and we did find that therapeutic
30:04bond scores under the working lines
30:06inventory had a moderately large
30:08correlation with the improvements
30:10in depression at one month with a
30:12correlation of .6 and a stronger bond
30:15in the final prep was also correlated.
30:19With higher ratings of mystical
30:22experiences and psychological insight.
30:24So pretty significant and it already
30:27does seem to be showing basically this
30:30is a an important factor for improvement
30:33in psychedelic assisted therapy.
30:35Of course, the end is small
30:36and this is still preliminary.
30:37We're we're taking a look at
30:39maybe some other mediating factors
30:40that might be involved here.
30:42Can I ask you a question about that?
30:43Yeah, in that
30:45previous slide.
30:46So when you that stronger bond,
30:48is that adjusted for how
30:50suggestible the person is because
30:51it seems that session is.
30:54Need to prepare people about
30:55what to expect and. Right.
30:58Mm-hmm. So these are not adjusted.
31:00We're still looking into doing that.
31:02We do have big 5 inventory and we also
31:05have like the pilot gym absorption measure
31:08that we we could use to sort of look at
31:11personality factors or suggestibility.
31:14Which is what we're working on.
31:15We're just resubmitting
31:16this abstract right now.
31:17But yeah, that's,
31:17that's a that's a good question
31:19and one that I have as well.
31:23So the healing setting, right,
31:25there's a lot of attention has been paid to
31:27sort of the unique facilities that might be
31:30needed for psychedelic assisted therapy.
31:32So in some societies, healing might occur in
31:35a temple or other kind of sacred location.
31:37And in secular forms of healing,
31:39clinicians meet patients and clinics
31:40and hospitals, places that carry what
31:43Frank called an aura of science, right.
31:45So this kind of like heavy influence
31:48that maybe this is some special
31:50place where science is done and.
31:52Might have some gravity to it.
31:54And so location can reinforce the
31:56expectation of help by symbolizing
31:57the therapist role as a healer by
32:00providing safety and confidentiality,
32:01encouraging the patient to disclose or
32:04share things they wouldn't otherwise do.
32:06And obviously this is a little bit
32:09more difficult to study on a large
32:11scale in psychotherapy and can be very,
32:13very variable.
32:14But there are a lot of smaller
32:16studies looking at tweaking individual
32:18characteristics of the treatment
32:19environment showing some, you know, mild.
32:21Significant effects there.
32:24There was one study, uh,
32:26which is a prospective survey study
32:28of naturalistic psychedelic users
32:30that found that taking psychedelics
32:31and what a person described as
32:33a therapeutic setting,
32:34so like a retreat setting or
32:36something like that,
32:37was positively associated with
32:39well-being after drug ingestion.
32:41So just a small piece of
32:42evidence suggesting or yes,
32:43the the setting is important.
32:46I'm
32:46curious whether you have thoughts about why.
32:51Eastern motives and motifs often
32:53end up in these settings like
32:56Tibetan and and not incur
32:58settings or you know why is.
33:01Has anyone looked at the
33:02difference between those?
33:06Not to my knowledge that specifically.
33:08And we've had some arguments here
33:10at Hopkins about what should and
33:12shouldn't be in the treatment room.
33:14And you know, people wanted
33:15to keep the Buddhist statue.
33:16Others really did not want
33:18the Buddhist statue.
33:19We have our little chalice, you know,
33:22another symbol that we use is,
33:24which is a holdover carryover from
33:26when this research was being done
33:28in the first wave at the Maryland
33:29State Psychiatric Institute.
33:31We have a rose in the room
33:33with every session,
33:34and before every session
33:35we talk about the roads,
33:36but with the point of the roses.
33:38We have like little little things
33:40here that we try not to keep it
33:42to obviously overtly religious.
33:44Umm.
33:44There's more more sort of like nature
33:48motifs in the setup that we have now,
33:51but that's that's a good question
33:52and one that we fight about.
33:56Umm. And then we have the rationale.
33:59Conceptual schemer, myth.
34:00And so in conjunction with the ritual.
34:02The myth is something that inspires
34:05expectations of health, right,
34:07arouses strong emotional responses
34:09from people, can enhance a sense
34:12of mastery or self efficacy,
34:13and Frank would describe rationale
34:15as a specific ingredient.
34:17So not really a common factor,
34:18but the specific details of it.
34:20But it has to be there in some form.
34:23And so in indigenous forms of healing.
34:25The myth is drawn from the
34:27cosmology of the group.
34:28In our society,
34:29the enduring source of symbolic healing
34:31power has been faith in science,
34:34right in connection with
34:35the prestigious figure.
34:35In many cases, and so long as the patient
34:38accepts the myth of the rationale,
34:39the actual contents seem less important.
34:43And this is true of psychotherapy as well,
34:45that as long as the person
34:47finds it acceptable,
34:48whatever the explanation is,
34:50then it seems to be effective.
34:53There have been a lot of studies
34:55on this about sort of trying to
34:58pick apart the specific rationale
34:59bits of the psychotherapy.
35:01And this occurs mainly in dismantling
35:03studies in which parts of the
35:05therapy are removed one by one.
35:07And this includes like critical
35:09elements of the therapy or so-called
35:10critical elements of the therapy,
35:12right.
35:13And to date this has resulted
35:15in no statistically significant
35:16change in treatment efficacy.
35:19So if you know for example try don't know
35:21psychodynamic therapy but without any.
35:23Analysis of.
35:25Some inner conflict,
35:26right?
35:26Or or some other important piece
35:28of something that you think is
35:30absolutely critical that actually
35:31doesn't seem to make a difference.
35:35She just asked, well,
35:35what is the myth or the rationale
35:37behind psychology assisted treatment?
35:39And I would argue that it's a
35:41bit of a special case because we
35:42can for patients can draw from
35:44multiple different domains, right.
35:46So on the one hand, especially now.
35:48We have a variety of biological effects
35:50that are backed by, quote UN quote,
35:53psychedelic science. Right.
35:54And so if the person is more empirically
35:57minded and more logical or rational,
35:59they might be intrigued
36:00by some of these effects.
36:02And low and behold,
36:03there's actually a like growing body of
36:05data to support all sorts of interesting.
36:09You know,
36:10objective findings about psychedelics
36:11and what they do to the brain.
36:13And there's also a variety of
36:15quite profound subjective effects
36:17that can occur that are open to
36:19the interpretation of the patient.
36:21So this can be religious experiences,
36:25psych, psychological insights,
36:26all sorts of things, right.
36:29And it's sort of,
36:30it might be the only therapy that I
36:32know that that sort of can powerfully
36:33seem to do this and this way,
36:35right,
36:35that there's multiple kinds of
36:37explanations that can be drawn.
36:40Which seems special.
36:44And then finally we have the ritual.
36:46And boy, do we have a ritual.
36:48And it's like therapy, right?
36:49This is like the big The Big Bang, right?
36:52Or sort of.
36:53There's a lot of emphasis placed on this,
36:54but the ritual is a symbolic extension
36:56of the myth or the rationale.
36:59It's usually undertaken together
37:00by the healer and the patient.
37:02And here we have an image of our special.
37:05Chalice that was gifted to the program.
37:07It's actually a copal burner,
37:09an incense burner from Mexico that
37:11was used in soil sibin ceremonies.
37:14And so this is what we actually give
37:16participants their capsule in and this is,
37:18you know, kind of a heavy,
37:21certainly not an inert part of it.
37:25And Frank notes that the method by
37:28which psychotherapy might work is
37:30by affording the patient to take
37:31A to have a an emotionally intense
37:33experience and to survive it,
37:35and thereby to strengthen their
37:38self-confidence and mastery.
37:40He writes that new experiences in
37:42therapy can enhance morale by showing
37:44patients potentially helpful alternative
37:46ways of looking at themselves,
37:48and specifically rates the more numerous
37:51and the more intense the experiential,
37:53as opposed to the purely cognitive,
37:55components of the learning.
37:56The more likely they are to produce change,
37:58it's not simply just telling somebody
38:00you should change how you think,
38:01or you should change how you
38:03deal with your mom.
38:04It's an experiential thing that can happen,
38:07right?
38:07And so in typical psychotherapy,
38:09this might mean.
38:11Engaging with some some challenges that
38:13you might have or some conflicts and
38:15really feeling out all your feelings,
38:18right?
38:19Then significantly challenging
38:22experiences and psychedelic.
38:25Subjective effects are not actually
38:26significantly associated with poor outcomes,
38:28which is something we tell
38:29participants at the outset right,
38:31that it's not a bad thing if
38:32you have a hard time,
38:34that it tends to pass,
38:35that it might be a source of
38:37some very meaningful analysis
38:38that we could do together later,
38:40or meaning making that we could do.
38:43It's worth mentioning also
38:45that the use of music,
38:46which is very commonly used in psychology,
38:49assisted therapy and could
38:51increase emotional responses,
38:53autobiographical memory recall
38:55mental imagery and so this is pretty
38:59widespread and might also contribute
39:01to the power of the ritual here.
39:04Which opens up some interesting
39:06questions about, you know,
39:07whether for someone who's
39:08suffering with depression,
39:10say,
39:10is it really the direct effect of the drug?
39:13Of some biological component of
39:15the brain that improves their mood?
39:17Or is it the patient's transformation
39:19of meetings secondary to an emotionally
39:22powerful experience, right?
39:23And further,
39:24what an emotionally salient experience
39:26caused by a drug that works by
39:29a totally different mechanism be
39:30just as effective? I don't know.
39:32My hunch is probably it would
39:33be at least somewhat effective,
39:35but we should be doing that research to
39:39answer that question, so we don't know yet.
39:41So how about?
39:42I've at least begun to sort of.
39:44Convince you of the similarities between
39:46set and setting and these common factors.
39:50But that leaves this kind of
39:52interesting connection here,
39:53right of common factors and factors that
39:55are known to enhance placebo response,
39:57which leads to an uncomfortable question
39:59that makes every therapist very upset,
40:02which is is psychotherapy placebo?
40:06And this is a bit of a hot take by
40:07Kirshen colleagues at highlights and
40:09this is probably actually more of
40:11a semantic problem arising from the
40:13medical roots of the term placebo.
40:15So we'll see.
40:16Was very well defined in medicine
40:18where it emerged, right?
40:20But it's less coherent in the
40:22context of psychotherapy.
40:23Look, here's rights of the placebo effect.
40:25And medicine is produced by
40:26factors other than the physical
40:28properties of the treatment.
40:29But the effect of psychotherapy is,
40:32by definition of the term,
40:33psychotherapy produced by something
40:35other than the physical properties
40:37of a treatment. Therefore.
40:38Met by the medical definition of placebo,
40:41the effects of psychotherapy or
40:43absofacto placebo effects and
40:45psychotherapy is absofacto placebos.
40:46And therapists hate this,
40:48they don't like it,
40:49but it's fine because it's probably
40:51just a category error, right?
40:52The psychotherapy is a non physical
40:55intervention by definition.
40:56We know that it is indeed
40:58effective for the treatment of
41:00many different health issues.
41:02And Kirsten colleagues try to help
41:04us along and encourage us to think
41:07of psychotherapy not as placebo,
41:09just because that makes no sense,
41:10but instead as active psychological
41:13ingredients that are necessary
41:16for adequate treatment.
41:18And for conceptual clarity,
41:19it's best to consider placebo
41:22effects or the patient's own belief
41:24separately from effects related to
41:26therapeutic interactions with staff,
41:28which is hard to disentangle but probably
41:31for the better if we can do it right,
41:33because patients can improve in a
41:34clinical trial or in or in clinical
41:36care from the number of things
41:38was actual treatment effects,
41:39which is what we're most interested in,
41:41in an RCT. Spontaneous healing, right?
41:44So this is often controlled for.
41:46It could be controlled for like a
41:48waiting list controlled design.
41:50So this is healing that would
41:51or would not have occurred,
41:51would have occurred whether
41:53without city participation,
41:55improvement directly related
41:56to belief in the treatment,
41:58what we normally think of as placebo effects.
41:59And then here is what we're talking
42:02about with psychotherapy effects
42:03improvement from interaction with
42:04the study team or aspects of the
42:07study often considered together
42:08but are probably separate things.
42:14And some caveats, all this pessimism,
42:15I think, you know,
42:16a lot of times when I give a talk like this,
42:18people think that I'm suggesting that
42:20psychedelics are entirely placebo.
42:21And there are some people who believe that.
42:23I don't believe that.
42:24And the reasons I don't believe
42:25that is because we've demonstrated,
42:27I think at this point pretty convincingly
42:29in animal models that there is at
42:31least some biological mechanism
42:33and we're sort of getting more more
42:35evidence in human models as well.
42:38And the effect sizes are way larger in our
42:41psychologist therapy studies than usual.
42:43Typical trials for psychotherapy
42:45for depression, for example.
42:48And further,
42:49I think even if psychedelics work
42:51by merely enhancing the placebo
42:53or the expectancy,
42:54this is probably still a powerful
42:57clinical tool that we shouldn't overlook.
43:00You know,
43:01whether the subjective effects
43:03of psychedelics are necessary
43:04for therapeutic efficacy remains
43:06a matter of debate,
43:07and I know of some interesting
43:09studies plan to take a look at that.
43:11You know whether memory for
43:13the experience has anything to
43:14do with clinical benefit.
43:16I would guess that it does.
43:19And we know that psychedelics can
43:20produce meaningful experiences
43:21even in the absence of any kind of
43:24therapeutic relationship where people
43:25use psychedelics on their own all the time.
43:30Here's a little artificial
43:32intelligence art break.
43:33This is randomized
43:34placebo-controlled trial,
43:35the style of Remedios Varo.
43:37I thought it was pretty cool.
43:41Umm, just a couple slides here to
43:44highlight that contextual factors in
43:46psychotherapy can be potent even when
43:48there is probable unblinding, right?
43:51So this is from Carhartt,
43:52Harris and colleagues study
43:54comparing escitalopram,
43:566 weeks vegetale Apram +2 Shamsul Sibin
44:01sessions are very low dose sessions to
44:04two high dose sessions plus six weeks
44:06of fake or placebo escitalopram, right.
44:09So and you'll see this in many studies.
44:11There is a compared to baseline,
44:13both treatment arms tend to have a pretty
44:17dramatic decrease between baseline
44:19and the first follow up time point.
44:22So it's not just the silicide,
44:23but it's working.
44:24I think this might be an approximation of
44:26of what those contextual factors might be.
44:31Same same is true.
44:33This is from Mike Bogenschutz's cell
44:34cybern for alcohol use disorder study.
44:37So both treatment arms seem to
44:38have some substantial improvement
44:40in heavy drinking days,
44:41right from around 50% to
44:44about 20% in both groups,
44:46regardless of whether they
44:48got sober or diphenhydramine.
44:54This is like another Dolly AI break here.
44:56Psychedelic scientist fighting
44:57on the Internet. We like that.
45:02So what do we do to reduce confounds
45:06in psychedelic clinical trials?
45:09Ways forward, right.
45:10So there are a number of things
45:12we could and should be doing.
45:13First, we probably should be
45:15measuring contextual factors very
45:17carefully in all of our studies so
45:18we can do this with a number of
45:20instruments that already exist.
45:21We have the Working Alliance inventory,
45:23which is what I described for our
45:26our current study here credibility
45:28and expectancy questionnaire.
45:30Both of these come out of psychotherapy
45:33research and are used primarily
45:35psychotherapy tools and more recent tools,
45:38the Stanford expectations of treatment scale,
45:41which can be used for both psychotherapy.
45:44Or other kinds of interventions
45:46like even surgery or medication,
45:48and some might actually be a little
45:50bit better suited to psychedelic
45:51assisted therapy.
45:52Probably we need new and better instruments
45:54that are more specific to psychedelics.
45:56We're working on some here,
45:58and I've seen a growing number of
46:00these being being published recently,
46:02so I think this is a move in
46:04the right direction.
46:06We should assess blinding efficacy
46:09so there is a recent preprint of
46:11a new instrument on a measure of
46:14blinding efficacy and blinding should
46:15ideally be assessed among everybody
46:18involved in this study participants,
46:20Raiders and staff.
46:21There's just a screenshot of
46:23the new measure from spaghetti,
46:25which notably only asks about binding
46:28of the participant and doesn't include
46:30any blinding questions of the staff.
46:32So.
46:32Probably this isn't this isn't
46:34a perfect instrument.
46:35We might need more more work here.
46:40We need to figure out what some convincing
46:43comparator drugs might be, right?
46:45With that caveat that I mentioned earlier,
46:47that it's possible that a very convincing
46:49act of drug would be just as therapeutic if
46:52the way that this all works is by producing
46:55this very emotionally powerful experience.
46:57But we do need better,
46:59better research and you know,
47:00some some drugs have been
47:03suggested as possible.
47:05Possible good candidates here,
47:06probably like THC is is an interesting one.
47:08Dextromethorphan has been studied before.
47:12Probably some dose finding studies to
47:14determine what it what a comparable
47:16dose of THC might be to to fool someone
47:18doing it they got solbin and vice versa.
47:23And we want to avoid study designs
47:26that are most vulnerable to biases.
47:28And we can heed lessons from
47:30psychotherapy research.
47:31So, for example,
47:32horse race trials comparing like
47:341 psychotherapy to another have
47:36largely proven kind of useless,
47:38that they don't really reliably or
47:40convincingly demonstrate that one
47:41therapy is better than another.
47:43So I think this is most applicable to.
47:45You know, someone who might want want
47:47to answer the question of what's better,
47:49act or CBT or something,
47:52or psychodynamic therapy and in
47:54conjunction with psychedelics.
47:55And probably my guess is that we
47:58wouldn't actually find very much
47:59useful information there. To date.
48:02So the most common designs that we've
48:04seen in psychedelics are open label design,
48:06delayed treatment, waiting list,
48:08control, crossover.
48:11Parallel groups of triple sebo.
48:13All of these are problematic for the
48:15reasons we've talked about today, right?
48:16When there's functional unblinding,
48:19we may as well not have blinded at all.
48:22But there are some designs that
48:23could help us understand a little
48:25bit better what the actual treatment
48:27effects of psychedelics are then.
48:29This is covered in great detail in
48:32this excellent paper by Muthukumar
48:35Swami published in 2021 about blinding
48:38and expectancy in psychedelic trials.
48:40And so, one suggestion.
48:41It's the parallel design with an
48:43active comparator where you have
48:44where you can sort of compare the
48:47group that believes that they got
48:48the active drug correctly versus
48:51incorrectly and use that figure to
48:54quantify the actual treatment effect.
48:58So that's that's sort of what happens there.
49:02Enrichment, factorial design.
49:03So these have been proposed by
49:05Card Harris and colleagues, right,
49:07where you can kind of where one factor
49:09is the drug versus placebo and the other
49:12factor is environmental enrichment.
49:13So it could be a more interesting room,
49:16different or more engaging music,
49:19more engaging therapists that sort of thing.
49:22And so this is a pretty,
49:24pretty good design could be could lead
49:25to some interesting work I think, but.
49:28Probably would do well to again take some
49:31lessons from the psychotherapy research
49:33and focus on those factors that are
49:35known to to heavily influence treatment
49:38effects like the therapeutic report.
49:43Pretreatment designs have been brought up,
49:44so this would be using something
49:47like ketanserin versus placebo.
49:50Before administering a dose of the drug.
49:52Again this this does sort of run into that
49:54same problem with unblinding potentially,
49:56but but everybody in the study
49:58would be getting solsiden and so.
50:00Theoretically,
50:01maybe that would be less of an issue,
50:03but, and these are just a couple
50:05of the suggestions by Kumar Swami,
50:08should check out this paper. Umm.
50:11And just to sort of close this actually was,
50:14this came up just a few days ago.
50:16I think this is,
50:17well time for this talk, right.
50:18So a lot of you might have seen
50:20this notice information from NIH
50:22on considerations for research
50:24involving psychedelics and related
50:26compounds is just two days ago.
50:28And weirdly for the human studies section,
50:31they didn't write what their
50:32high priority items were,
50:34they wrote with their low
50:35priority items were.
50:36And so they were saying that they're
50:38low priority items were studies that
50:40lacked rigorous and reproducible.
50:42Assessment of the integrity of the
50:44blind for everyone involved patients,
50:46therapists and Raiders.
50:48Studies that lacked rigorous and reproducible
50:51assessment of expectancy effects.
50:53And studies that involve the use of
50:55some sort of adjunctive therapy that
50:58don't operationalize the therapy and
51:00assess the delivery of that therapy.
51:02So and I may just be on board with a
51:05lot of what we've talked about today.
51:08So just, yeah, some conclusions.
51:10There's a lot of overlap between
51:12set and setting common factors,
51:14and that may complicate the
51:16assessment of placebo effects in
51:18psychedelic therapy research.
51:20RCT's with psychedelics often
51:21resemble psychotherapy trials more
51:23than they do pharmacotherapy trials,
51:26which complicates things and
51:29frustrates everybody.
51:30But measurement and experimental
51:32manipulation of those common factors,
51:34namely the therapeutic
51:35relationship expectancy effects,
51:37may help us tease out those actual
51:40treatment effects from those of
51:42the psychedelics themselves.
51:45And an important so this is
51:47back to John Haygarth question,
51:49the beginning of this talk. Right.
51:50So he's the guy who did that Perkins
51:52tractor research where he wrote
51:53that you know an important lesson in
51:55physics is to be learned that that's
51:56wonderful and powerful influence
51:58of the passions of the mind upon
51:59the state and disorder of the body.
52:01And this is too often overlooked.
52:03It's closing quote for us to to ponder
52:06because I do think it's pretty remarkable,
52:09right that like well what if all
52:11this is just a placebo effect of
52:13some sort you know it's still.
52:14Still, pretty remarkable thing that we
52:17can have such powerful treatment effects.
52:20Uh, so I'll close it there.
52:22Leave it open to a couple questions in
52:24the few minutes that we have remaining.
52:26Thanks for your attention this afternoon.
52:34Thank you, Natalie. That was great.
52:35A really thoughtful. Dive and survey
52:38into this this complicated landscape.
52:42We do have time for a few questions.
52:44People can raise hands or just speak up.
52:51Natalie, you you talked about
52:52Frank's framework for the
52:54common factors of psychotherapy.
52:55I've actually purchased his book
52:56on Amazon during this lecture,
52:58so I hope you get it of that, but.
53:03Badly. But you talked about controlling
53:05for expectancy effects and alliance
53:08and how that's been should be done in
53:11this field and has been done in some
53:13of the better psychotherapy research.
53:16But how about the other components?
53:17How about the myth and the ritual?
53:21Yes, I think.
53:23There I think I saw somebody recently
53:25published on this wasn't maybe.
53:27I don't know if it was a formal instrument,
53:28but I think it would be.
53:30And we're working on something like this too.
53:32An instrument to look at what
53:33a person's beliefs are about
53:36psychedelic assisted therapy.
53:37Just psychedelics in general with their
53:39knowledge is how they know all that stuff.
53:41Is it from reading stuff in the media,
53:43from first hand conversations with
53:45with people that they know. Umm.
53:47And what they believe the the the
53:50mechanisms are by which psychedelics work?
53:53And are they more of a empirical?
53:56A logical person who really likes
53:58the scientific literature on this,
53:59or they're more of a spiritual person
54:01who thinks they're going to get some,
54:03you know, sort of resolution
54:05here on the spiritual level.
54:06Are they looking for some kind of insight,
54:10revelation of some sort, right.
54:14And I think and looking into that probably
54:16also for the therapists themselves is
54:18going to be interesting too, because.
54:19As much as we want to sort of
54:21standardize and control what
54:23happens in therapy, we can't. Umm.
54:27Which is a frustrating aspect of
54:29psychotherapy research is that
54:30what what we do in psychotherapy
54:32research is often not actually what
54:33happens in in real world clinics,
54:35and it's often much more eclectic.
54:39So try as we might,
54:39it's it is kind of hard to actually
54:41standardize for it at the end of the day.
54:42But along what therapists are doing.
54:49And I I wonder, I mean,
54:50you can imagine if people are studying,
54:51you know, young yen and alias,
54:52SIS versus classical analysis versus
54:55CBT versus ACT, but, you know,
54:57and finding no enormous differences
54:59in what you call horse race trials.
55:02But all of those things have a myth, right?
55:04All of those things and
55:05things have a framework.
55:06The therapist explains the framework.
55:07Yet most of the time,
55:08patient may or may not buy into it.
55:10It'd be interesting to look,
55:11even leaving the psychedelics aside,
55:12it'd be interesting to look
55:14not at what the myth is.
55:15But at how much the patient buys into
55:18it is the independent factor to see
55:20if that moderates treatment effect.
55:22Has anyone attempted to do that?
55:23It would be very hard to do and
55:25it require you to engage multiple
55:27myths in the same study,
55:28which most investigators are
55:29going to be disinclined to do.
55:32That's my knowledge.
55:32We haven't done that.
55:34I mean I could just tell you
55:36like anecdotally in some of the
55:38studies here where there is less.
55:40Rigorous, they're less rigorous guidelines
55:42that what we're actually supposed to say.
55:45Like I, I often will engage like,
55:47well, how do you think this works?
55:49Like why do you think this works?
55:50And get them to tell me.
55:51And I'm sure that leads to some kind of,
55:54you know, working together on
55:55this explanatory model that the
55:57person has and then focusing on
55:59that during the rest of therapy.
56:01Like I have to that has to happen.
56:03And that happens in my normal
56:05clinical practice too, right?
56:06It's something we spend a lot of
56:08time on this patients explaining
56:09and understanding why or why not
56:11they they why they don't think a
56:12treatment is going to work for them.
56:15Super hard to study.
56:16I mean, maybe.
56:17This is a question for, you know, big data
56:21machine learning analyzing transcripts of.
56:24Prep and follow up sessions.
56:27I don't know all that much about it but.
56:30We've got somebody who
56:31could solve that question.
56:36Natalie highly, Jerry
56:39said you you should be getting
56:40some royalties because I also
56:42purchased the book during this time.
56:44So yeah, they should do
56:46like an Amazon affiliate.
56:49But, but with that being said,
56:51you know, there are ways of you know,
56:53breaking down expectancy
56:55expectation and actually close you.
56:58Luana Colloca does a lot of research.
57:00I don't know University
57:01of Maryland really more.
57:05Placebo is her thing but as you as
57:07you would say placebo means different
57:09things to a lot of different people.
57:11And you know she looks at the
57:13nonspecific or the non pharmacologic
57:14effects and pain mainly.
57:16But you know this is the word we even use.
57:18How we use expectation and expectancy
57:20are really two different words that
57:22we use at the but in the field
57:24expectation is kind of this pre held
57:26belief of what you're going to get.
57:29Expectancy is actually the physiologic state.
57:32Of being in that point.
57:33So you can measure some of those
57:35things with expectancy and a lot of
57:37the work that she's done for pain
57:39actually suggests that the biggest
57:41component is actually conditioning.
57:43Not, not what we would think,
57:44but it's having a previous experience and
57:46that I think goes you were saying it's,
57:48it's not.
57:49It's not the cognitive part of it,
57:51it's actually haven't experienced
57:53that before.
57:54So the other classic example they
57:56always use is if you've been taking
57:58ibuprofen for the last 30 years,
57:59every time you have a headache
58:01and your headache gets better,
58:02the next time you take any pill,
58:04you just expect your headache
58:05is going to get better.
58:06And and the actual physiologic
58:08change that you have,
58:09where there's evidence that there's
58:11actually increases in some cytochromes,
58:13I mean in some cytokines and things,
58:16after you take the placebo pill,
58:18that's the expectancy.
58:20Physiologic response.
58:21So I mean,
58:23it's a really.
58:24Powerful way of looking at this
58:27and with ketamine one of the.
58:29There are ways that people have
58:31done is to try to block the ketamine
58:33response by using specific things
58:35and it's been hard to do that.
58:37But the one study that may you
58:39know it's a tiny study but using
58:42now trek zone you know is the one
58:45set at the Stanford group did
58:47that you know has to be repeated
58:48but did seem to show it.
58:50Umm.
58:51Is interesting because that's also what's
58:53been shown to show a lot of the placebo.
58:54It can block placebo response.
58:57Yeah, yeah, it's important clarification
58:59and I I'm familiar with with that person.
59:01I think it was been meaning
59:03to reach out for many months.
59:04That's probably the reason to do.
59:08Yeah, that the fields are overlap,
59:10although not not as directly
59:11as we may think initially.
59:16Natalie, I wonder if I could
59:17ask you a question.
59:18Am I really enjoyed your talking?
59:20It is fun to be reminded of the Frank
59:22I was taught by a Hopkins trained
59:24psychiatrist and medical school in Red
59:26Reddit as a fourth year medical student.
59:28And one thing that I remember from that work
59:31was the focus on state dependent belief.
59:35And in particular, you know,
59:37there's a story in that work that
59:39stood out to me about, as I recall it,
59:43someone who was sort of fired up.
59:46About the idea that shamanism is
59:48fake and this person travels to some
59:51area where there's a lot of shamans
59:54and in order to prove that it's fake
59:56enrolls in training to sort of become
59:59a shaman himself and ultimately
01:00:01becomes the best of all the shamans.
01:00:04And the the develops a specific technique
01:00:06and and and then there's another story
01:00:09about sort of some people on the way
01:00:12to a tent revival and three people
01:00:14are going to car and one person.
01:00:16Who's most strongly sort of against it
01:00:19is the person who becomes born again.
01:00:23And the take away, as I recall,
01:00:25is that people who are sort of in
01:00:28an activated state of belief or
01:00:31disbelief are the ones most changeable.
01:00:33And so I'm thinking about some of the
01:00:36psychiatric disorders that we work on.
01:00:38Some of them have more steady
01:00:41states of mood or of belief,
01:00:44and some have more fluctuating.
01:00:46States, I'm,
01:00:47I'm particularly interested in
01:00:49borderline personality disorder and
01:00:51I I heard you say if I understood
01:00:53that you were on eating disorders,
01:00:54which I think might share some
01:00:56sort of fluctuation in symptoms
01:00:58more than some of the disorders
01:01:00that have already been studied.
01:01:02And so I'm curious about what you think
01:01:06about the importance of state symptoms
01:01:09or state mood at the time of a treatment?
01:01:13And how you think about that in terms
01:01:16of both placebo and also the the
01:01:18effects of psychedelics in general.
01:01:22One thing I'm remembering is
01:01:23something that is now in a file
01:01:26drawer that I worked on as a postdoc
01:01:28where we have this questionnaire we
01:01:30asked participants the morning of.
01:01:32So they're sitting there waiting
01:01:34to get so suddenly asking are
01:01:36you how preoccupied are you?
01:01:38How, how good are you feeling about today?
01:01:40How how much you know hesitation do you have?
01:01:44Today, I think there's three
01:01:46questions and we're trying to see
01:01:47if we could use those single item
01:01:49measures somehow to correlate to like.
01:01:51The magnitude of mystical
01:01:52effects or meaningful effects,
01:01:54and there wasn't really
01:01:55anything significant there.
01:01:57You know, if State moved over the
01:01:59last week or over the last day heading
01:02:02into the infusion impact on mood
01:02:04change for people with depression.
01:02:07Umm. I don't know. I mean, we do.
01:02:10And I'm not sure we have.
01:02:13The right data points like data from
01:02:15data points to answer that question.
01:02:17I mean they're all depressed
01:02:18for the most part, you know,
01:02:20like they're like they're depressed
01:02:23probably or they should be.
01:02:25So, so I'm not totally sure the one,
01:02:27the one thing from that analysis we did
01:02:29though was that being preoccupied with
01:02:32something else was almost significant
01:02:34and maybe if we had some additional,
01:02:36you know, data points to look at,
01:02:38it could have been significant.
01:02:39But otherwise, you know feeling
01:02:40good or bad about the session,
01:02:42they didn't have much of a difference and.
01:02:45Speaking more anecdotally about.
01:02:48You know, folks who come to our studies
01:02:51and are are not religious or spiritual.
01:02:54It's always hard for me to predict
01:02:55who's going to have that, like,
01:02:56big mystical transformative
01:02:58experience where like,
01:02:59I kind of like this person's
01:03:00never going to have it.
01:03:01And then.
01:03:02Lo and behold,
01:03:03this like diehard atheist has this
01:03:07weird ontological shock experience.
01:03:10Struggles to contextualize it afterward,
01:03:13might poopoo it afterward,
01:03:14but at the end of the day I also feel
01:03:17that it was like totally valid and real.
01:03:20Interesting to work with,
01:03:21but I like just anecdotally,
01:03:22I don't think we can prescribe
01:03:24and be able to predict like who
01:03:26is more prone to those kinds of.
01:03:28Mystical types of effects.
01:03:30Those are interesting questions,
01:03:31but yeah, I think that's there's,
01:03:33I think there's a couple of people
01:03:35who are planning to look at this from
01:03:37borderline personality disorder.
01:03:38Umm.
01:03:39I've heard of like some cases
01:03:43from other studies.
01:03:44Where there were patients who might have
01:03:47met criteria or like almost met criteria.
01:03:49So it was again a very small number of cases,
01:03:51but they tended not to do great.
01:03:54And this one person I'm thinking
01:03:56of in particular even had.
01:03:58Their long-term therapist as one
01:04:00of their facilitators in that case.
01:04:02And then we've had a very hard
01:04:04time during the session and we're
01:04:05dropping out of the study.
01:04:07So I I'm, I would be,
01:04:08I would worry a little bit about
01:04:09that because it seems like even
01:04:11with an established relationship,
01:04:12people can have poor outcomes.
01:04:17We are at an even a little past time and I
01:04:19want to be respectful of everyone's time.
01:04:21People are starting to to have
01:04:23to duck out for other things,
01:04:24but I'm sure we could thank you deep waters
01:04:27and we could discuss for a long time.
01:04:29So Natalie, this has been great.
01:04:31Thank you so much for joining us.