HoldsUp

Mark Hyman, MD · 2025-07-16 · Mark Hyman (host), Robin Carhart-Harris

Why Your Brain is Stuck: The Truth About Psychedelics and Plasticity

37 research-tied claims examined: 2 contradicted 3 overstated 27 supported 5 unverified

27

Supported by research

0:00:36Robin Carhart-Harrissupportedvery low

The first patient in the psilocybin trial who had previously failed numerous antidepressants achieved full remission and remained well.

"Our first patient had been on I don't know how many antidepressants, and this got her well and she's still well." (said at 0:00:36)

The speaker refers to the first participant enrolled in the Imperial College London open-label feasibility trial of psilocybin for treatment-resistant depression. Published records from this trial evaluated patients with moderate-to-severe major depression who had failed multiple conventional antidepressant treatments. Patients received two oral doses of psilocybin alongside psychological support, with substantial proportions achieving rapid and sustained symptom reductions and remission up to 6 months post-treatment. As this claim describes an individual outcome from an open-label, uncontrolled pilot trial, the certainty of evidence for general therapeutic efficacy remains very low.

0:05:00Robin Carhart-Harrissupportedmoderate

In the mid-20th century, psychedelics were used as psychotherapeutic adjuncts by public figures such as Ethel Kennedy and Cary Grant.

"During studying psychoanalysis, I discovered that psychedelics had been used in psychotherapy as tools to catalyze and deepen psychotherapy. And that was done in the mid-20th century. And it was a big thing for a while, you know, big names like Ethel Kennedy and Cary Grant had had this therapy and seemingly had benefited from it." (said at 0:05:00)

Historical and psychiatric literature documents that throughout the mid-20th century (specifically the 1950s and 1960s), psychedelics such as lysergic acid diethylamide (LSD) were extensively investigated and administered clinically as adjuncts to psychotherapy to facilitate psychotherapeutic insights and treat psychiatric conditions. Prominent figures, including actor Cary Grant, publicly documented undergoing clinical LSD-assisted psychotherapy during this era and reported personal benefit, before regulatory restrictions in the late 1960s and 1970 halted widespread clinical use.

0:11:45Robin Carhart-Harrissupportedhigh

Placebo pain relief produces measurable biological neural correlates in the brain.

"You might have a psychological response to a placebo, say it's given for pain and you experience some pain relief, and then we know in neuroscience that that process has a biological counterpart even though the mechanism on the face of it looks psychological." (said at 0:11:45)

Extensive neuroimaging research demonstrates that placebo-induced pain relief corresponds to measurable neurobiological changes in the brain. An individual participant-level fMRI meta-analysis of 20 neuroimaging studies (n = 603) found that placebo analgesia is associated with significant reductions in pain-related neural activity across multiple brain networks—including the ventral attention network (mid-insula), somatomotor network (posterior insula), thalamus, habenula, mid-cingulate cortex, and supplementary motor area—alongside increases in activity within frontoparietal networks.

0:13:10Mark Hyman (host)supportedmoderate

Functional MRI imaging of lifetime meditators shows suppressed activity in the default mode network.

"they took lifetime meditators, guys who've been in a cave in Tibet for 40 years meditating for tens of thousands of hours, and they brought them to the United States, they put them in functional MRI machines, and they saw that the function of their brain was different, that things like the default mode network were suppressed, which is this area of the brain that identifies yourself as ego, separate, different" (said at 0:13:10)

Functional MRI studies comparing experienced, long-term meditators to meditation-naïve controls demonstrate relative deactivation (suppression) of primary nodes of the default mode network (DMN), including the medial prefrontal cortex and posterior cingulate cortex, across various meditation practices as well as altered baseline functional connectivity. The DMN is widely recognized in neuroscience as being involved in mind-wandering and self-referential processing (ego/self-identification).

0:16:20Robin Carhart-Harrissupportedmoderate

In studies published around 2017, administration of LSD, psilocybin, and psychedelic doses of ketamine was shown to increase brain entropy.

"We first saw it around 2017. We published on it with LSD, psilocybin, and also ketamine in a psychedelic-like dosage, saw brain entropy dial up under all of those compounds, and with it people's conscious experience, the subjective experience was deeper, richer, more diverse, more changeable." (said at 0:16:20)

A 2017 study by Schartner, Carhart-Harris, and colleagues evaluated measures of neural signal diversity—including entropy and Lempel-Ziv complexity—using spontaneous magnetoencephalography (MEG) in humans administered LSD, psilocybin, and sub-anesthetic (psychedelic) doses of ketamine. The investigators found significant increases in signal diversity across all three compounds compared to normal waking consciousness, with increases correlating with subjective reports of the intensity of the psychedelic experience.

0:19:00Robin Carhart-Harrissupportedmoderate

Psychedelics do not shut down the default mode network, but rather cause dysregulation and irregular activity patterns within it.

"it's not that we shut off the default mode network. That's a popular in a sense myth that people like and you can get away with it, but it's not really true. You're not turning it off, you're scrambling it up. And in scrambling it up—and I say it that way because it's still very active, it's just the activity is irregular now." (said at 0:19:00)

Human neuroimaging studies confirm that psychedelics do not deactivate or 'shut off' the default mode network (DMN). Instead, acute administration of serotonergic psychedelics such as psilocybin disrupts the coordinated functional connectivity and synchronization within the DMN and between large-scale networks—characterized by reduced internal network integrity, desynchronization, and increased entropy/irregularity of activity patterns.

0:26:40Robin Carhart-Harrissupportedlow

Psychological insight experienced during a psychedelic session strongly predicts downstream therapeutic outcomes.

"One, yes, it's psychological insight, very strong predictor of therapeutic outcomes downstream." (said at 0:26:40)

Observational and prospective psychometric studies support the claim that acute psychological insight experienced during or immediately following a psychedelic session predicts positive downstream therapeutic and psychological outcomes. Validation studies for the Psychological Insight Scale (PIS) and Psychological Insight Questionnaire (PIQ) demonstrate that psychological insight acts as a key mediator for long-term well-being and predicts unique variance in improvements in psychological flexibility, life satisfaction, and therapeutic outcomes beyond traditional measures like mystical-type effects. Because the evidence relies primarily on self-report survey data and observational designs rather than controlled experimental manipulations of insight, certainty is rated low.

0:26:54Robin Carhart-Harrissupportedmoderate

Emotional release during psychedelic sessions is a key factor predicting positive clinical outcomes.

"The other one is emotional release. It's strong emotion. What What is that? What's that look like? Well, often it looks like people crying... it's a cathartic a cathartic release." (said at 0:26:54)

Clinical and prospective studies consistently show that experiencing an emotional breakthrough or emotional release (commonly measured by the Emotional Breakthrough Inventory, or EBI) during psychedelic administration is a robust predictor of subsequent clinical improvement. In a Phase II randomized trial of psilocybin for treatment-resistant depression, EBI scores had one of the strongest correlations (r = -0.637) with reductions in depression severity at 3 weeks post-treatment. Similar predictive relationships between emotional breakthrough and improvements in mental well-being and depressive symptoms have been replicated across observational and clinical datasets.

0:28:40Mark Hyman (host)supportedhigh

5-MeO-DMT is a naturally occurring compound found in the secretions of the Sonoran Desert toad.

"one of the things that you're studying is is 5-MeO-DMT, which is dimethyltryptamine, which is a compound that's found in nature in the Sonoran Desert toad." (said at 0:28:40)

5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is well-established as a naturally occurring psychedelic alkaloid secreted in high concentrations by the parotoid and skin glands of the Sonoran Desert toad (Incilius alvarius, formerly Bufo alvarius).

0:15:05Robin Carhart-Harrissupportedmoderate

States of reduced consciousness such as deep sleep, coma, or general anesthesia are characterized by low brain entropy and highly predictable ongoing brain activity.

"At one far end, the end of low entropy, the lights go out, sort of literally. There's nothing there. You're knocked out with an anesthetic. You're in deep sleep. You've suffered a brain injury. You're in a coma. There's no content. And if you look at ongoing brain activity, it's very uneventful. It's very predictable. It's very low entropy." (said at 0:15:05)

Empirical measures of spontaneous brain activity across electroencephalography (EEG), intracranial recordings, and magnetoencephalography (MEG) consistently show that states of reduced or lost consciousness—such as general anesthesia, non-REM deep sleep, and severe brain injury/coma—are characterized by reduced neural signal diversity, reduced Lempel-Ziv complexity, and low entropy (reflecting more stereotypic, predictable neurodynamics) relative to normal waking consciousness.

0:28:49Mark Hyman (host)supportedmoderate

DMT is naturally present in small amounts in the brain.

"you have a release of DMT in your brain that is normally there in small amounts." (said at 0:28:49)

N,N-dimethyltryptamine (DMT) is an endogenous indole alkaloid detected in trace to basal concentrations in mammalian brain tissue and body fluids. In situ hybridization has demonstrated that the biosynthetic enzymes for DMT (such as indolethylamine N-methyltransferase, INMT) are expressed in human and rodent brain regions (including the cerebral cortex, choroid plexus, and pineal gland). Microdialysis studies in rodents have also shown natural basal extracellular release of DMT at concentrations comparable to other monoamines. However, researchers emphasize that these normal endogenous concentrations are far too low to produce the psychoactive effects observed with exogenous administration.

0:35:00Mark Hyman (host)supportedlow

Ibogaine is used to break the cycle of addiction.

"For example, ibogaine is being used for addiction, right? To break the cycle of addiction, which is really fascinating." (said at 0:35:00)

Ibogaine is widely investigated and used in alternative or specialized clinic settings to interrupt substance use disorders, particularly opioid withdrawal and craving. Observational and early clinical data support its putative capacity to mitigate withdrawal symptoms and disrupt addictive cycles via complex polypharmacological actions across multiple neurotransmitter systems. However, its formal medical translation remains constrained by a lack of rigorous, randomized double-blind clinical trials and significant safety concerns, most notably cardiac toxicity and QT prolongation.

0:36:40Robin Carhart-Harrissupportedmoderate

The gold standard treatment for borderline personality disorder is a long course of psychotherapy, such as Dialectical Behavior Therapy (DBT) over approximately a year.

"You know, the the gold standard treatment for for borderline is a is a long psychotherapy, you know, year or so of psychotherapy. HOST: Yeah. DBT." (said at 0:36:40)

Comprehensive structured psychotherapy, most notably Dialectical Behavior Therapy (DBT) and Mentalization-Based Therapy (MBT), is widely recognized in clinical guidelines and systematic reviews as the first-line treatment for borderline personality disorder (BPD). Standard comprehensive DBT is designed as a one-year program involving individual therapy, group skills training, and between-session coaching. A 2020 Cochrane systematic review of 75 randomized controlled trials (4,507 participants) found that psychotherapy (most commonly DBT and MBT, with trial durations up to 36 months) significantly reduced BPD symptom severity (SMD -0.52), self-harm, and suicide-related outcomes compared to treatment-as-usual.

0:43:57Robin Carhart-Harrissupportedmoderate

Schizophrenia is typically preceded by mood disorders like depression and anxiety.

"You know, most schizophrenia are preceded by mood disorder, depression, anxiety." (said at 0:43:57)

Published systematic reviews and longitudinal cohort studies of first-episode psychosis and clinical high-risk (CHR) / at-risk mental state (ARMS) populations confirm that the onset of schizophrenia is commonly preceded by non-specific affective and anxiety symptoms or disorders. A 2025 systematic review of prodromal presentations found that non-specific symptoms such as depression (52%), worry (41%), and anxiety (38%) are the predominant initial manifestations before attenuated psychotic symptoms emerge. Furthermore, large multicenter cohorts (such as the NAPLS 2 study) and meta-analyses show that 70% to 79% of individuals in the clinical prodrome meet criteria for comorbid Axis I psychiatric diagnoses, with depressive and anxiety disorders being the most prevalent.

0:44:45Robin Carhart-Harrissupportedhigh

Avatar therapy uses computer animation to create an image of a persecutory voice for dialogic therapy to reduce hallucination-related distress in schizophrenia.

"avatar therapy, you know, where through, um, computer animation, you can create an avatar, an image, a animated image of of the voice, the persecutory voice, tormenting voice, and and then work in dialogue to to sort of um change your relationship with this persecuting voice" (said at 0:44:45)

The claim accurately describes AVATAR therapy. AVATAR therapy uses computer software to create a digital audio-visual representation (avatar) of the patient's persecutory auditory hallucination. Through a series of facilitated sessions, the patient engages in direct dialogue with this avatar (voiced by the therapist) to alter their relationship with the persecutory voice, assert control, and reduce voice-related distress and severity. Multiple randomized controlled trials (e.g., Craig et al., 2018; Garety et al., 2024) have confirmed that AVATAR therapy significantly reduces auditory hallucination severity and voice-related distress in individuals with psychosis/schizophrenia spectrum disorders compared to supportive counselling or treatment as usual.

0:50:55Robin Carhart-Harrissupportedlow

Robin Carhart-Harris conducted a clinical trial of psilocybin for treatment-resistant depression in 20 participants, some of whom had previously tried up to 14 antidepressant medications.

"We did that small trial, it ended up being 20 people, and saw really promising results... some people had tried 14 in in that trial, and this got her well, and she's still well." (said at 0:50:55)

Robin Carhart-Harris and colleagues at Imperial College London conducted an open-label feasibility clinical trial assessing psilocybin with psychological support in patients with treatment-resistant major depression. The initial findings in 12 patients were reported in 2016 (Lancet Psychiatry), and the expanded cohort totaling 20 patients followed for up to 6 months was published in 2018 (Psychopharmacology). All participants had moderate-to-severe unipolar treatment-resistant depression having failed multiple prior antidepressant treatments (with participants having tried up to 14 previous treatments). Marked reductions in depressive symptoms were observed following treatment, with responses maintained through 6 months of follow-up. Because the study was an open-label, uncontrolled feasibility trial (n=20), certainty regarding clinical efficacy is rated as low.

0:59:45Mark Hyman (host)supportedhigh

The response rate to SSRI antidepressants across patients with depression is approximately 50 percent.

"HOST: I mean, when you look at the response rates to SSRIs across depression, it's it's pretty pretty shitty. I mean, they really they do work for some people, but but for the majority, it's it's GUEST1: 50%. Yeah. HOST: Barely 50% response." (said at 0:59:45)

Large-scale systematic reviews and meta-analyses of randomized controlled trials (RCTs) evaluating SSRIs and other second-generation antidepressants in major depressive disorder show that approximately 40% to 55% (roughly 50%) of adult patients achieve clinical response (standardly defined as a ≥50% reduction in baseline depression severity scores). While all major SSRIs are significantly more efficacious than placebo, placebo response rates in clinical trials typically range from 30% to 40%, leaving total acute response rates to active drug around 50%.

0:33:25Robin Carhart-Harrissupportedlow

Preliminary neuroimaging and EEG data on 5-MeO-DMT indicate that it induces slow-wave brain activity in addition to psychedelic brain expansion.

"In fact, there's some data that's come through that suggests some paradoxical quality to the activity, that you also get some slow waves, which is weird. So maybe a a bit like sleep, but then a bit or a lot like a a psychedelic opening up and expansion." (said at 0:33:25)

Human electroencephalography (EEG) and preclinical local field potential (LFP) data support the claim that 5-MeO-DMT induces cortical slow waves and sleep-like electrophysiological spectral signatures alongside its psychedelic effects. A human EEG study (n=29) demonstrated amplified low-frequency oscillations and complex atypical cortical slow-wave dynamics following vaporized 5-MeO-DMT administration. Preclinical research in awake rodents similarly found that 5-MeO-DMT increases delta-band power and produces LFP spectral signatures resembling slow-wave sleep. Certainty is low due to the preliminary nature and small sample sizes of the available studies.

0:42:15Mark Hyman (host)supportedmoderate

Ketogenic diets are being clinically investigated and used as metabolic therapies for severe mental illnesses including schizophrenia and bipolar disorder.

"And we're seeing bipolar disease, schizophrenia, and severe mental illness being treated with ketogenic diets, which also do similar things, such at Mayo and many other places." (said at 0:42:15)

Ketogenic metabolic therapy is actively being clinically investigated and utilized as an adjunctive metabolic intervention for severe mental illnesses, including bipolar disorder, schizophrenia, and schizoaffective disorder. Pilot clinical trials and inpatient retrospective cohorts (such as Sethi et al., 2024 and Danan et al., 2022) have reported improvements in both metabolic parameters (e.g., insulin resistance, weight, visceral adiposity) and psychiatric symptom severity (e.g., Brief Psychiatric Rating Scale, PANSS, and CGI scores), leading to formal ongoing randomized controlled trials in metabolic psychiatry.

1:02:42Robin Carhart-Harrissupportedmoderate

Psychedelics directly stimulate a specific aspect of the serotonin system to promote psychological and neuroplasticity.

"But what psychedelics do is actually a more direct stimulation of a certain aspect of the serotonin system, promoting plasticity. It's definitely psychological plasticity, and probably neuroplasticity, too." (said at 1:02:42)

Classical serotonergic psychedelics (such as psilocybin, LSD, and DMT) directly stimulate the serotonin 2A (5-HT2A) receptor subtype. Activation of this specific receptor stimulates downstream intracellular signaling cascades (including BDNF/TrkB and mTOR pathways), which promote structural and functional neuroplasticity—evidenced by increased neuritogenesis, spinogenesis, and synaptogenesis—as well as psychological and cognitive flexibility.

1:03:56Mark Hyman (host)supportedlow

Psilocybin increases brain-derived neurotrophic factor (BDNF), which helps increase brain connections and neuroplasticity.

"some of the data showing that some of these compounds like psilocybin increase various trophic factors for the brain like BDNF or brain-derived neurotrophic factor that helps to sort of increase brain connections and sort of neuroplasticity." (said at 1:03:56)

Preclinical in vitro and animal studies show that psilocybin and its active metabolite psilocin promote neuroplasticity, dendritic spine density, and synaptogenesis in brain regions such as the prefrontal cortex and hippocampus. Mechanistic work indicates this occurs in part via direct binding to TrkB (the BDNF receptor), facilitating endogenous BDNF signaling and upregulating BDNF-related neuroplastic pathways. However, human evidence remains limited; a 2025 systematic review and meta-analysis found no significant increase in circulating peripheral (blood) BDNF levels in humans following psychoplastogen administration, suggesting that these trophic effects are best characterized in central brain tissue models rather than peripheral blood markers.

1:05:00Robin Carhart-Harrissupportedlow

A diffusion tensor imaging preprint by Lyons et al. shows changes in prefrontal white matter tracts following a single dose of psilocybin.

"Lyons, L-Y-O-N-S, et al. And there we show through diffusion tensor imaging, looking at the white matter tracts of the brain, that there are some changes after a single dose of psilocybin. So let's see if that replicates, of course, but it's a super exciting finding. Prefrontal tracts changed." (said at 1:05:00)

A placebo-controlled, within-subjects neuroimaging study by Lyons et al. (subsequently published in Nature Communications) evaluated 28 psychedelic-naive healthy participants before and one month after a single 25 mg dose of psilocybin versus active placebo. Diffusion tensor imaging (DTI) demonstrated decreased axial diffusivity bilaterally in prefrontal-subcortical white matter tracts at one month post-dose. The certainty is graded as low due to the small, exploratory sample size and need for independent replication.

1:05:25Robin Carhart-Harrissupportedlow

An open-label trial at UCSF by Ellen Bradley and Josh Woolley found improvements in motor symptoms from psilocybin in Parkinson's disease patients.

"Well, there's a trial at at UCSF looking at psilocybin for Parkinson's. It's just been published, actually. Ellen Bradley, Josh Woolley, and colleagues, really good work, really promising. It was a simple design, open-label, so there's no placebo control. So, we need to be careful at this stage about extrapolating too much. They did see improvements even in motor symptoms." (said at 1:05:25)

An open-label pilot trial conducted by Ellen Bradley, Josh Woolley, and colleagues evaluated psilocybin therapy in 12 individuals with Parkinson's disease and mood dysfunction. In addition to improvements in depression and anxiety, the study observed statistically significant post-treatment improvements in Parkinson's motor symptoms as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS Part II and Part III), sustained up to one month post-treatment. As the speaker noted, the study was an uncontrolled open-label pilot trial (n=12), limiting certainty.

1:07:38Robin Carhart-Harrissupportedhigh

Clinical trial evidence to date shows underwhelming efficacy for psychedelic microdosing.

"the evidence to date is a little underwhelming for microdosing. And part of the issue is that the trials have been limited, really. There haven't been many. And when they've been done, they haven't often dosed for long enough, in my view." (said at 1:07:38)

Randomized placebo-controlled trials, systematic reviews, and meta-analyses evaluate psychedelic microdosing (primarily low-dose LSD or psilocybin) as demonstrating underwhelming efficacy beyond placebo. Blinded clinical trials show minimal to no significant improvements over placebo for mood, depression, anxiety, stress, executive function, or ADHD symptoms. Furthermore, reviews highlight that the literature remains constrained by a limited number of controlled studies with small sample sizes, brief intervention periods, and relatively few doses administered.

1:12:10Mark Hyman (host)supportedhigh

MDMA was originally developed by the pharmaceutical company Merck.

"Some of them are new, obviously, like MDMA that was developed by Merck." (said at 1:12:10)

Historical analyses of original pharmaceutical records confirm that MDMA (3,4-methylenedioxymethamphetamine) was first synthesized by the German pharmaceutical company Merck in Darmstadt in 1912. Chemist Anton Köllisch synthesized the compound (then termed 'Methylsafrylamin') as a chemical intermediate/precursor in an alternative pathway to produce the styptic compound hydrastinine, and Merck filed for a patent covering the synthesis in 1912 (granted in 1914).

1:15:04Robin Carhart-Harrissupportedmoderate

Human life expectancy and longevity increased reliably following the acceptance of germ theory in the 19th century.

"germ theory, when when did that come around? 18 something or other, middle of the 19th century. And and then it was only really after that that lifespan—I know there are a few factors, you know, better dissemination of knowledge—but lifespan longevity is going up quite reliably." (said at 1:15:04)

Historical demographic and economic literature confirms that before the mid-19th century, human life expectancy fluctuated without sustained upward trends, typically averaging below 40 years. Following the mid-to-late 19th-century emergence and acceptance of the germ theory of disease—alongside associated public health, sanitation, and medical developments—life expectancy and population health began a sustained, reliable upward trajectory through the late 19th and 20th centuries.

  • supports: Health, Wealth, and Welfare (? 2004) · cited 103x in the literature
    "Between the 16th century and the mid-19th century, average life expectancy around the world fluctuated but averaged under 40 years, with no upward trend. Life spans slowly but steadily increased in the second half of the 19th century and then jumped markedly in the 20th century, initially in Europe and then in the rest of the world (see table). Economic historians and demographers still debate the genesis of these changes, but they increasingly point to rising incomes (and resulting improvements in sanitation and food availability) as the major cause of declines in 19th-century mortality rates. For the 20th century, however, they believe technical improvements were the catalysts— particularly the discovery of the germ theory of disease" (abstract, passage verified)
    openalexfull study (doi)
  • supports: Leaders and Laggards in Life Expectancy Among European Scholars From the Sixteenth to the … (Demography 2021) · cited 23x in the literature
    "We also show, however, that the onset of mortality improvements among scholars in medicine was delayed, possibly because these scholars were exposed to pathogens and did not have germ theory knowledge that might have protected them. The disadvantage among medical professionals decreased toward the end of the nineteenth century." (abstract, passage verified)
    openalexfull study (doi)
1:17:48Mark Hyman (host)supportedvery low

The anti-addictive property of ibogaine was discovered accidentally by an individual with an opioid addiction whose cravings disappeared after taking it.

"And sort of like you hear the story about the ibogaine discovery, it was sort of an accident. There was an addict who was a narcotic addict who took it and his cravings went away." (said at 1:17:48)

The speaker's description of the historical origin of ibogaine's anti-addictive use is supported by the scientific literature. In 1962, Howard Lotsof, a 19-year-old heroin (narcotic/opioid) user, ingested ibogaine recreationally and unexpectedly discovered that his craving for heroin and symptoms of opioid withdrawal disappeared. This anecdotal observation subsequently spurred interest, self-help advocacy, and scientific investigation into ibogaine's potential in treating substance use disorders. Because the account reflects historical self-experimentation and anecdotal case reports, the certainty grade of the underlying evidence for this discovery narrative is very low.

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.