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Welcome to Psylo's Neuroscience Newsletter - June Edition!
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The Placebo Response: Mind Over Matter
In medical research, few phenomena are as fascinating and perplexing as the placebo response, where patients experience real symptom improvements after receiving treatments with no active therapeutic ingredients. Placebos are effective across various conditions, can be measured, predicted, socially transmitted, and can even be pharmacologically blocked. Remarkably, the placebo effect extends to surgeries, with a systematic review finding that sham surgeries led to improvements in 74% of the trials, and were comparable to actual surgery in half of the cases.
Variability and Specificity
The placebo response varies significantly across conditions. For example, a recent study found that placebo effects were largest in trials for alcohol use disorder, depression and generalized anxiety disorder, and smaller in trials for obsessive-compulsive disorder, insomnia, and schizophrenia. Larger placebo responses were associated with more recency, younger participants, more trial sites, larger sample sizes, increased baseline severity, and larger active treatment effect sizes.
Perceived cost, appearance, and administration context also impact the placebo response. For example, expensive placebos tend to work better than cheaper ones, more invasive placebos like injections are more effective than simple sugar pills, and the color and description of placebo pills can affect their efficacy. Clinical trial design factors such as trial duration and randomization ratio also impact the placebo response. Longer trials with frequent check-ins enhance patient expectations and reinforce the placebo effect. Additionally, unbalanced randomization, where patients are more likely to receive active treatment, often results in stronger placebo responses due to heightened patient expectations.
Open-Label Placebos and the Nocebo Effect
Placebos can be effective even when patients know they are taking them. These open-label placebos have shown efficacy in treating menopausal hot flashes, seasonal allergies, ADHD, and major depression. Conversely, negative expectations or beliefs about treatments can lead to worsening symptoms or the onset of new symptoms without any active treatment involved, a phenomenon known as the nocebo effect.
Mechanisms of the Placebo Effect
The placebo response is driven by neurobiological and psychological factors, including natural symptom improvement (regression to the mean), positive expectations, confirmation bias, and conditioning (associating treatments with relief). The ritual of taking medication, the clinical environment, and interactions with healthcare providers also enhance the perception of improvement.
For example, a study on asthma found that patients reported similar symptom improvements from the active drug (albuterol), a placebo, and sham acupuncture, but only albuterol improved the objective measure of airflow. This highlights that while placebos can influence symptom perception, they can't always address the disease pathophysiology.
Nonetheless, placebos can induce physiological changes, affecting autonomic, neuroendocrine, and immune responses, and neurobiology. For example, in a study [preprint] of pain, where a placebo cream reduced pain, MRI scans showed the placebo to alter the emotional response to pain rather than the pain itself. Placebos release opioids (endorphins) in the brain and the placebo response can be blocked by the opioid antagonist naloxone (e.g. Narcan). Additionally, the placebo response in Parkinson's disease has been linked to dopamine release, demonstrating real biological effects and potential therapeutic benefits.
Placebo Response in Depression Trials
The placebo response in depression trials can be substantial and complicate the assessment of new treatments. Placebo responses are influenced by patient expectations, therapeutic alliances, and the clinical environment. Neuroimaging studies show that placebo effects in depression involve changes in brain activity related to mood regulation and reward processing, mimicking those of active treatments. Recent evidence suggests placebos may stimulate neuroplasticity, causing physiological changes similar to active treatments. This underscores the importance of considering the placebo effect in accurately assessing new antidepressant therapies.
Conclusion
The placebo response, showing real symptom improvements without active ingredients, highlights the complexity of factors involved in patient care. Its variability across conditions and influence on clinical trials highlight the need for careful consideration in accurately assessing new therapies. Furthermore, leveraging the placebo effect could significantly improve patient outcomes.
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Clinical Research
- Brain Circuit Scores Define Depression and Anxiety Biotypes | The study identified six distinct biotypes of depression and anxiety using machine learning, each with specific brain circuit dysfunctions and different responses to pharmacological and behavioral treatments. It involved task-free and task-evoked fMRI data from 801 unmedicated participants with depression and anxiety, and 137 healthy controls. Nat Med
- Extended-Release Ketamine for Depression | Extended-release ketamine tablets (180 mg) significantly reduced depression symptoms compared to placebo, with minimal side effects, in phase 2 randomized, placebo-controlled clinical trial of 231 patients in the open-label phase and 168 in the double-blind phase. Nat Med
- Check out Psychedelic Alpha’s detailed commentary on this study highlighting how its unique study characteristics may overestimate treatment effects and potentially limit real-world use.
- Placebo Effects in nine Psychiatric Disorders | A meta-analysis of 90 high-quality RCTs with 9985 participants found significant symptom improvements with placebo across nine psychiatric disorders, with the greatest improvements occurring in major depressive disorder and generalized anxiety disorder. Panic disorder, ADHD, PTSD, social phobia, and mania showed moderate improvements, while OCD and schizophrenia had smaller placebo effects. JAMA Psychiatry
- Brain Structures Predict Depression Treatment Response | The study identified two patterns of neuroanatomical characteristics in patients with major depressive disorder (MDD), with one dimension showing significant improvement with SSRI treatment but not placebo and the other showing similar responses to both SSRI and placebo. This case-control study of MRI data (N=1,384) highlights the potential for neuroimaging-based markers to predict treatment responses in MDD. Nat Ment Health
- How Psychedelics Induce Visual Imagery | This study examined how psilocybin affects the brain to create visual images with eyes closed, using a double-blind, randomized, placebo-controlled, cross-over fMRI study (N=24). Psilocybin increased self-control in visual regions and enhanced communication from higher-level to lower-level visual areas, leading to vivid visual imagery. Mol Psychiatry
- Ethics Framework for Psychedelic Therapy | This consensus statement, involving 27 multidisciplinary experts, identified 20 points of consensus across 5 ethical issues: reparations and reciprocity, equity, and respect; informed consent; professional boundaries and physical touch; personal experience; and gatekeeping. JAMA Netw Open
- Attitudes Towards Psychedelics in Australia | Forty-three percent of Australians, with support higher among those with mental illness or prior psychedelic experience, support the medical legalization of psychedelics but have concerns about their safety, found a cross-sectional survey (N=502). Aust N Z J Psychiatry
- Psychedelics Distort Memory Familiarity at Encoding | Psychedelics, Psilocybin and 2C-B, impaired the encoding of recollection and familiarity, leading to increased false familiarity, especially for emotional stimuli; a double-blind, placebo-controlled, within-subjects study of healthy (N=20). Biol Psychiatry Cogn Neurosci Neuroimaging
- Lessons from Cannabis for Psychedelics Regulation | The study identifies parallels between cannabis and psychedelics legalization, emphasizing the need for rigorous clinical research, minimizing for-profit influence, and coordinated regulation to avoid recreational markets masked as medical use. Addiction
- Global Psychedelic Use Patterns | A survey of 6379 adults across 85 countries found that psilocybin, LSD, and MDMA were the most used psychedelics, with significant regional differences in usage patterns and motivations. Infrequent, life-enhancing use was common, with a preference for legal, quality-controlled sources. Int J Drug Policy
- Serotonin's Role in OCD's Brain Network | A computational model of the prefrontal cortex analyzing the effects of serotonin and dopamine receptors on network dynamics suggests reduced serotonin levels can lead to increased brain activity and stability in certain brain networks, potentially contributing to the symptoms of OCD. Cereb Cortex
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Preclinical Research
- Effects of Psilocybe Mushroom Tryptamines on Rats |Comparing baeocystin, norbaeocystin, and aeruginascin with psilocybin. Norbaeocystin improved antidepressant-like outcomes in rats without causing hallucinations. Br J Pharmaco
- Psilocin’s Effects on Stress Response| Psilocin increased activity in the brain's stress center, the hypothalamic paraventricular nucleus (PVN), and reduced threat-responding behavior in rats without impairing long-term stress response. Nat Commun
- Ibogaine Causes Heart Damage in Rats | The study investigated the cardiotoxic effects of ibogaine in rats, finding dose-dependent heart necrosis without consistent changes in oxidative stress markers. Int J Mol Sci
- Ketamine's Impact on Brain Waste Removal | Ketamine caused cognitive impairment in mice by increasing 5-HT2C receptor expression, which led to ΔFosb accumulation, reduced Aqp4 expression and glymphatic system dysfunction. Biomed Pharmacother
- Iboga Alkaloids Relieve Pain via 5-HT2A | Non-hallucinogenic iboga alkaloids alleviated neuropathic and visceral pain in mice through 5-HT2A receptor activation. Biomed Pharmacother
- 5-HT3’s Role in Anxiety | NP65-deficient mice model anxiety, which results from disrupted serotonin and 5-HT3 receptor activity in the dorsal raphe nucleus-hippocampus pathway. Increasing TPH2, a key enzyme for serotonin production, or administering serotonin or the 5-HT3 agonist SR57227A in the hippocampus alleviated anxiety-like behaviors in these mice. Acta Pharmacol Sin
- 5-HT6 Antagonists Protect Astrocytes | A potent and selective 5-HT6 receptor antagonist demonstrated cytoprotective effects in astrocytes in vitro. Eur J Med Chem
- 5-HT2A Agonism’s Effects on Neural Circuits | DOI, a 5-HT2A agonist, caused persistent desynchronization in the medial prefrontal cortex (mPFC) of mice, with decreased low-frequency power and increased gamma power, impacting cortical activity during active and rest periods. This disruption may explain the long-lasting effects of psychedelics on neural plasticity and their therapeutic potential. Neuropharmacology
- Non-5-HT2A Receptors Modulate Head Twitch Response | The 5-HT2C and 5-HT1A receptors are implicated in the biphasic dose-response curves of head twitch response (HTR) and locomotor activity induced by 5-HT2A agonist DOM in mice, with different mechanisms modulating these effects. Psychopharmacology (Berl)
- Social Isolation Alters 5-HT3 Expression | Social isolation in rats led to reduced sociability and changes in the expression of the genes, including decreased 5-HT3 receptor expression, in the medial prefrontal cortex (mPFC). Cells
- 5-HT7 Agonists Promote Neuron Growth | New 5-HT7 receptor agonists showed neuroprotective effects and stimulated neurite outgrowth (which are essential for forming neuronal connections) in human neuroblastoma cells, indicating their potential for therapeutic applications. Neurochem Res
- 5-HT4 Agonist Reduces Parkinson's Medicine Side Effect | L-DOPA, used to treat Parkinson's disease, often causes burdensome uncontrollable jerky movements known as L-DOPA-induced dyskinesia. Agonism of the 5-HT4 receptor reduced this side effect without affecting L-DOPA's beneficial effects and enhanced cAMP-PKA pathway activation in striatopallidal neurons, which are crucial for motor control. Neurobiol Dis
- Neuroplastogen Reduces Heroin-Seeking Behavior | DM506, a novel neuroplastogen, reduced cue-induced heroin-seeking behavior in male rats and inhibited tonic GABA currents in the prelimbic cortex, suggesting its potential as a therapeutic agent for opioid use disorder. Neurochem Int
- LSD's Effects on Brain Activity | LSD induced a dose-dependent decrease in brain activity in rats – particularly in the primary olfactory system, prefrontal cortex, thalamus, and hippocampus, with enhanced connectivity between the thalamus and sensorimotor cortices and cerebellar nuclei. Brain Commun
- Psychedelic’s Impact on Brain Connectivity | Both psilocybin and Salvinorin-A caused changes in brain connectivity, with psilocybin affecting thalamo-cortical networks dependent on 5HT2A receptor activation and both substances leading to acute desynchronization relative to the default mode network; and fMRI study of nonhuman primates. ACS Chem Neurosci
- 5-HT2A Receptors Reduce Seizure-Induced Death | The incidence of seizure-induced respiratory arrest was significantly reduced by the 5-HT2A receptor agonist TCB-2 in DBA/1 mice, but not by agonists of 5-HT1A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT7 receptors. PLoS One
- [Preprint] Classifying Psychedelics by Brain Imaging | This study developed a method to classify different psychoactive drugs based on brain-wide imaging of cellular c-Fos expression and machine learning, achieving 67% accuracy. Drugs studied included: psilocybin, ketamine, 5-MeO-DMT, 6-fluoro-DET, MDMA, acute fluoxetine, chronic fluoxetine, and saline vehicle. bioRxiv
- [Preprint] Psilocybin Alters Rat Brain Connectivity | A single dose of psilocybin induced both acute and persistent changes in metabolic connectivity within rat brain networks that are related to compulsions and anxiety. Preprint
- [Preprint] 5-HT2A Receptors and Head-Twitch Response | Activation of 5-HT2A receptor-expressing neurons in the PFC was not sufficient to produce head-twitch response (HTR) in the absence of an agonist, but was necessary for the HTR induced by 5-HT2A agonist DOI in a sex-dependent manner. bioRxiv
- [Preprint] Psilocybin Reduces Heroin-Seeking | Psilocybin reduced cue-induced heroin-seeking behavior and modulated inflammatory gene expression in the prefrontal cortex of male rats. bioRxiv
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Reviews and Commentaries
- Beyond The Serotonin Deficit Hypothesis: Communicating A Neuroplasticity Framework of Major Depressive Disorder | This review critiques the traditional serotonin deficit hypothesis for major depressive disorder (MDD) and proposes a neuroplasticity framework that incorporates both traditional and innovative treatments to address the disease's complexity. Mol Psychiatry
- Paradigm Shift Required for Translational Research on The Brain | This review discusses the evolution and future of biomedical brain research, emphasizing the necessity of interdisciplinary collaboration and advanced methodologies to enhance translational outcomes. Exp Mol Med
- Phytoconstituents Targeting the Serotonin 5-HT3 Receptor: Promising Therapeutic Strategies for Neurological Disorders | This review explores the potential of plant-derived phytoconstituents targeting the 5-HT3 receptor as therapeutic agents for various neurological disorders, highlighting their mechanisms and the need for more comprehensive research to establish their efficacy and safety. ACS Pharmacol Transl Sci
- Serotonergic Neuromodulation of Synaptic Plasticity | This review explores how serotonin modulates synaptic plasticity, affecting cognitive, emotional, and behavioral functions, emphasizing its impact across various structures like the hippocampus, amygdala, and prefrontal cortex. Neuropharmacology
- Commentary On Darke et al.: Expanded Psychedelic Access Requires New Safety Monitoring Systems | This commentary discusses the need for new safety monitoring systems as psychedelic use expands, highlighting that despite the low incidence of psychedelic-related deaths, increasing use demands enhanced safety protocols and frameworks to prevent potential harms. Addiction
- Emerging Therapeutic Potential of Fluoxetine on Cognitive Decline in Alzheimer's Disease: Systematic Review | This systematic review explores the potential of fluoxetine in treating cognitive decline in Alzheimer's disease, highlighting its neuroprotective mechanisms in preclinical models and suggesting promising therapeutic avenues pending further clinical validation. Int J Mol Sci
- Allosteric Modulators of Serotonin Receptors: A Medicinal Chemistry Survey | This review discusses the potential of allosteric modulators of serotonin receptors as safer alternatives to orthosteric ligands, highlighting natural and synthetic compounds, and their implications for treating conditions like schizophrenia, depression, migraines, and obesity. Pharmaceuticals (Basel)
- Increasing Psychopharmacology Clinical Trial Success Rates with Digital Measures and Biomarkers: Future Methods | This review explores how digital measures and biomarkers can address diagnostic heterogeneity, subjective endpoints, and high placebo response rates in psychiatric clinical trials, offering potential solutions to improve drug development success. NPP—Digital Psychiatry and Neuroscience
- Do Classic Psychedelics Increase the Risk of Seizures? A Scoping Review | This review explores existing literature to determine if classic psychedelics increase the risk of seizures, suggesting that in the absence of other substances, these risks are not heightened, though comprehensive data is still lacking. Eur Neuropsychopharmacol
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Clinical Trials Update
A round-up of the latest registered clinical trials investigating psychedelics:
- Esketamine (continuous infusion) | Prolonged Disorders of Consciousness (N=80) | Effects of Esketamine on Consciousness-related Brain Network Characteristics in Patients With Prolonged Disorders of Consciousness - NCT06473285
- Ketamine and i-CBT | Major Depressive Disorder and Suicide (N=110) | Integrated Internet-Based Cognitive Behavioural Therapy (i-CBT) and Intravenous Ketamine for Suicidality in Treatment-Resistant Depression: A Randomized, Midazolam-Controlled Clinical Trial - NCT06480500
- Psilocybin | Functional Impairment Due to Psychiatric Symptoms (N=50) | Safety, Feasibility, and Tolerability of Psilocybin Treatment for Individuals With Functional Impairment Related to Mood, Anxiety, Trauma and/or Addiction Symptoms: An Open-label Proof-of-concept Study - NCT06442423
- Psilocybin | Migraine (N=50) | Mechanistic Studies of Psilocybin in Headache Disorders - NCT06464367
- Psilocybin Microdosing | Healthy Volunteers (N=20) | Safety for Home Administration of Microdose Psilocybin Use - NCT06450210
- Psilocybin-assisted therapy | Alcohol Use Disorder (N=90) | A Multi-centre, Double-blinded, Placebo-controlled, Randomised, Phase II Clinical Trial for Psilocybin-assisted Therapy for Alcohol Use Disorder - NCT06444243
- Psilocybin-assisted Therapy | Depression in Parkinson's Disease (N=60) | The Efficacy of Psilocybin Therapy for Depression in Parkinson's Disease - NCT06455293
- Psychedelic-assisted group program | First responders (N=32) | Assessing the Feasibility of a Custom Psychedelic-assisted Group Program on Mental and Physical Health in First Responders - NCT06471959
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Psylo is incredibly proud to be featured alongside some of the most well-funded and innovative startups focused on neuroplastogens (what we used to call next-generation psychedelics) in an article published in Nature Biotechnology and Scientific American.
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Psylo's US trip: why the psychedelics startup is keeping one foot in Australia as it expands stateside - Capital Brief, June 24
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Dr Dilara Bahceci (Head of Communications) attended the Interdisciplinary Conference on Psychedelic Research (ICPR) meeting in the Netherlands and spoke on a panel titled, “Lessons learned from Ketamine”.
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