Publications
237 results found
Carhart-Harris RL, 2019, How do psychedelics work?, Curr Opin Psychiatry, Vol: 32, Pages: 16-21
PURPOSE OF REVIEW: Psychedelics are reawakening interest from psychiatry, cognitive neuroscience and the general public with impressive outcomes in small-scale clinical trials, intriguing human brain imaging work and high-impact journalism. RECENT FINDINGS: This brief opinion piece offers a perspective on how psychedelics work in the brain that may help contextualize these developments. It attempts to link various scales of action, from the molecular (serotonin 2A receptor agonism) through to the anatomical and functional (heightened plasticity) and up to the dynamic (increased brain entropy), systems level (network disintegration and desegregation) and experiential. SUMMARY: It is proposed that psychedelics initiate a cascade of neurobiological changes that manifest at multiple scales and ultimately culminate in the relaxation of high-level beliefs. The purpose of psychedelic therapy is to harness the opportunity afforded by this belief-relaxation to achieve a healthy revision of pathological beliefs.
Moroz M, Carhart-Harris RL, 2018, Employing synergistic interactions of virtual reality and psychedelics in neuropsychopharmacology
The increased prevalence of various psychiatric disorders continue to concern [54], [71], [96]. Promising results are starting to emerge from recent experimental interventions employing VR [32], [81], and psychedelics [14], [69] individually. We propose that for certain pathologies researchers need not bother themselves as to which medium offers greater hope. Instead, we hypothesize that the most effective interventions shall necessarily come from a composite approach utilizing both.Traditional medicine adopts similar such synergistic strategies. Combining codeine and acetaminophen increases the analgesic effect. While research into the therapeutic effects of novel interventions using VR and psychedelics, independent of one another, is still in its infancy, we believe that the increased utility of a dual approach justifies closer examination without delay. We posit three main benefits from this integrated intervention. Increases in the efficacy of each individual paradigm due to synergistic coupling, and increases in specificity due to the ability to tailor bespoke therapies for particular individuals and groups, are achieved directly. Such increases in efficacy consequently lead to the third benefit of allowing a therapeutic effect to be achieved while using lower doses of a given psychedelic compound [19].
Haijen ECHM, Kaelen M, Roseman L, et al., 2018, Predicting responses to psychedelics: a prospective study, Frontiers in Pharmacology, Vol: 9, ISSN: 1663-9812
Responses to psychedelics are notoriously difficult to predict, yet significant work is currently underway to assess their therapeutic potential and the level of interest in psychedelics among the general public appears to be increasing. We aimed to collect prospective data in order to improve our ability to predict acute- and longer-term responses to psychedelics. Individuals who planned to take a psychedelic through their own initiative participated in an online survey (www.psychedelicsurvey.com). Traits and variables relating to set, setting and the acute psychedelic experience were measured at five different time points before and after the experience. Principle component and regression methods were used to analyse the data. Sample sizes for the five time points included N= 654, N= 535, N= 379, N= 315, and N= 212 respectively. Psychological well-being was increased two weeks after a psychedelic experience and remained at this level after four weeks. This increase was larger for individuals who scored higher for a ‘mystical-type experience’, and smaller for those who scored higher for ‘challenging experience’. Having ‘clear intentions’ for the experience was conducive to mystical-type experiences. Having a positive ‘set’, as well as having the experience with intentions related to ‘recreation’, were both found to decrease the likelihood of having a challenging experience. The trait ‘absorption’ and higher drug doses promoted both mystical-type and challenging experiences. When comparing different types of variables, traits variables seemed to explain most variance in the change in well-being after a psychedelic experience. These results confirm the importance of extra-pharmacological factors in determining responses to a psychedelic. We view this study as an early step towards the development of empirical guidelines that can evolve and improve iteratively with the ultimate purpose of guiding
Roseman L, Demetriou L, Wall M, et al., 2018, Increased amygdala responses to emotional faces after psilocybin for treatment-resistant depression, Neuropharmacology, Vol: 142, Pages: 263-269, ISSN: 0028-3908
Recent evidence indicates that psilocybin with psychological support may be effective for treating depression. Some studies have found that patients with depression show heightened amygdala responses to fearful faces and there is reliable evidence that treatment with SSRIs attenuates amygdala responses (Ma, 2015). We hypothesised that amygdala responses to emotional faces would be altered post-treatment with psilocybin. In this open-label study, 20 individuals diagnosed with moderate to severe, treatment-resistant depression, underwent two separate dosing sessions with psilocybin. Psychological support was provided before, during and after these sessions and 19 completed fMRI scans one week prior to the first session and one day after the second and last. Neutral, fearful and happy faces were presented in the scanner and analyses focused on the amygdala. Group results revealed rapid and enduring improvements in depressive symptoms post psilocybin. Increased responses to fearful and happy faces were observed in the right amygdala post-treatment, and right amygdala increases to fearful versus neutral faces were predictive of clinical improvements at 1-week. Psilocybin with psychological support was associated with increased amygdala responses to emotional stimuli, an opposite effect to previous findings with SSRIs. This suggests fundamental differences in these treatments’ therapeutic actions, with SSRIs mitigating negative emotions and psilocybin allowing patients to confront and work through them. Based on the present results, we propose that psilocybin with psychological support is a treatment approach that potentially revives emotional responsiveness in depression, enabling patients to reconnect with their emotions.
Erritzoe D, Roseman L, Nour MM, et al., 2018, Effects of psilocybin therapy on personality structure, Acta Psychiatrica Scandinavica, Vol: 138, Pages: 368-378, ISSN: 1600-0447
ObjectiveTo explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment‐resistant depression (TRD).MethodTwenty patients with moderate or severe, unipolar, TRD received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. Personality was assessed at baseline and at 3‐month follow‐up using the Revised NEO Personality Inventory (NEO‐PI‐R), the subjective psilocybin experience with Altered State of Consciousness (ASC) scale, and depressive symptoms with QIDS‐SR16.ResultsNeuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO‐PI‐R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend‐level increases, and Agreeableness did not change.ConclusionOur observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy. This needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.
Carhart-Harris RL, 2018, The entropic brain - revisited, NEUROPHARMACOLOGY, Vol: 142, Pages: 167-178, ISSN: 0028-3908
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- Citations: 174
Lyons T, Carhart-Harris RL, 2018, More realistic forecasting of future life events after psilocybin for treatment-resistant depression, Frontiers in Psychology, Vol: 9, ISSN: 1664-1078
Background: Evidence suggests that classical psychedelics can promote enduring changes in personality, attitudes and optimism, as well as improvements in mental health outcomes.Aim: To investigate the effects of a composite intervention, involving psilocybin, on pessimism biases in patients with treatment-resistant depression (TRD).Methods: Patients with TRD (n = 15) and matched, untreated non-depressed controls (n = 15) performed the Prediction Of Future Life Events (POFLE) task. The POFLE task requires participants to predict the likelihood of certain life events occurring within a 30-day period, after which the actual rate of event occurrence is reported; this gives an index of potential pessimism versus optimism bias. Psilocybin was administered in two oral dosing sessions (10 and 25 mg) one week apart. Main outcome measures were collected at baseline and one week after the second dosing session.Results: Patients showed a significant pessimism bias at baseline [t(14) = -3.260, p = 0.006; 95% CI (-0.16, -0.03), g = 1.1] which was related to the severity of their depressive symptoms (rs = -0.55, p = 0.017). One week after psilocybin treatment, this bias was significantly decreased [t(14) = -2.714, p = 0.017; 95% CI (-0.21, -0.02), g = 0.7] and depressive symptoms were greatly improved [t(14) = 7.900, p < 0.001; 95% CI (16.17, 28.23), g = 1.9]; moreover, the magnitude of change in both variables was significantly correlated (r = -0.57, p = 0.014). Importantly, post treatment, patients became significantly more accurate at predicting the occurrence of future life events [t(14) = 1.857, p = 0.042; 95% CI (-0.01, 0.12), g = 0.6] whereas no such change was observed in the control subjects.Conclusion: These findings suggest that psilocybin with psychological support might correct pessimism biases in TRD, enabling a more positive and accurate outlook.
Deco G, Cruzat J, Cabral J, et al., 2018, Whole-brain multimodal neuroimaging model using serotonin receptor maps explains non-linear functional effects of LSD, Current Biology, Vol: 28, Pages: 3065-3074.E6, ISSN: 0960-9822
Understanding the underlying mechanisms of the human brain in health and disease will require models with necessary and sufficient details to explain how function emerges from the underlying anatomy and is shaped by neuromodulation. Here, we provide such a detailed causal explanation using a whole-brain model integrating multimodal imaging in healthy human participants undergoing manipulation of the serotonin system. Specifically, we combined anatomical data from diffusion magnetic resonance imaging (dMRI) and functional magnetic resonance imaging (fMRI) with neurotransmitter data obtained with positron emission tomography (PET) of the detailed serotonin 2A receptor (5-HT2AR) density map. This allowed us to model the resting state (with and without concurrent music listening) and mechanistically explain the functional effects of 5-HT2AR stimulation with lysergic acid diethylamide (LSD) on healthy participants. The whole-brain model used a dynamical mean-field quantitative description of populations of excitatory and inhibitory neurons as well as the associated synaptic dynamics, where the neuronal gain function of the model is modulated by the 5-HT2AR density. The model identified the causative mechanisms for the non-linear interactions between the neuronal and neurotransmitter system, which are uniquely linked to (1) the underlying anatomical connectivity, (2) the modulation by the specific brainwide distribution of neurotransmitter receptor density, and (3) the non-linear interactions between the two. Taking neuromodulatory activity into account when modeling global brain dynamics will lead to novel insights into human brain function in health and disease and opens exciting possibilities for drug discovery and design in neuropsychiatric disorders.
Carhart-Harris RL, 2018, Serotonin, psychedelics and psychiatry, World Psychiatry, Vol: 17, Pages: 358-359, ISSN: 1723-8617
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- Citations: 25
Millière R, Carhart-Harris RL, Roseman L, et al., 2018, Psychedelics, meditation, and self-consciousness, Frontiers in Psychology, Vol: 9, Pages: 1-29, ISSN: 1664-1078
In recent years, the scientific study of meditation and psychedelic drugs has seen remarkable developments. The increased focus on meditation in cognitive neuroscience has led to a cross-cultural classification of standard meditation styles validated by functional and structural neuroanatomical data. Meanwhile, the renaissance of psychedelic research has shed light on the neurophysiology of altered states of consciousness induced by classical psychedelics, such as psilocybin and LSD, whose effects are mainly mediated by agonism of serotonin receptors. Few attempts have been made at bridging these two domains of inquiry, despite intriguing evidence of overlap between the phenomenology and neurophysiology of meditation practice and psychedelic states. In particular, many contemplative traditions explicitly aim at dissolving the sense of self by eliciting altered states of consciousness through meditation, while classical psychedelics are known to produce significant disruptions of self-consciousness, a phenomenon known as drug-induced ego dissolution. In this article, we discuss available evidence regarding convergences and differences between phenomenological and neurophysiological data on meditation practice and psychedelic drug-induced states, with a particular emphasis on alterations of self-experience. While both meditation and psychedelics may disrupt self-consciousness and underlying neural processes, we emphasize that neither meditation nor psychedelic states can be conceived as simple, uniform categories. Moreover, we suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that “self-loss,” far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-
Timmermann C, Timmermann Slater C, Roseman L, et al., 2018, DMT models the near-death experience, Frontiers in Psychology, Vol: 9, ISSN: 1664-1078
Near-death experiences (NDEs) are complex subjective experiences, which have been previously associated with the psychedelic experience and more specifically with the experience induced by the potent serotonergic, N,N-Dimethyltryptamine (DMT). Potential similarities between both subjective states have been noted previously, including the subjective feeling of transcending one’s body and entering an alternative realm, perceiving and communicating with sentient ‘entities’ and themes related to death and dying. In this within-subjects placebo-controled study we aimed to test the similarities between the DMT state and NDEs, by administering DMT and placebo to 13 healthy participants, who then completed a validated and widely used measure of NDEs. Results revealed significant increases in phenomenological features associated with the NDE, following DMT administration compared to placebo. Also, we found significant relationships between the NDE scores and DMT-induced ego-dissolution and mystical-type experiences, as well as a significant association between NDE scores and baseline trait ‘absorption’ and delusional ideation measured at baseline. Furthermore, we found a significant overlap in nearly all of the NDE phenomenological features when comparing DMT-induced NDEs with a matched group of ‘actual’ NDE experiencers. These results reveal a striking similarity between these states that warrants further investigation.
Carhart-Harris RL, Roseman L, Haijen E, et al., 2018, Psychedelics and the essential importance of context, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 32, Pages: 725-731, ISSN: 0269-8811
Lyons T, Carhart-Harris RL, 2018, Increased nature relatedness and decreased authoritarian political views after psilocybin for treatment-resistant depression, Journal of Psychopharmacology, Vol: 32, Pages: 811-819, ISSN: 1461-7285
Rationale:Previous research suggests that classical psychedelic compounds can induce lasting changes in personality traits, attitudes and beliefs in both healthy subjects and patient populations.Aim:Here we sought to investigate the effects of psilocybin on nature relatedness and libertarian–authoritarian political perspective in patients with treatment-resistant depression (TRD).Methods:This open-label pilot study with a mixed-model design studied the effects of psilocybin on measures of nature relatedness and libertarian–authoritarian political perspective in patients with moderate to severe TRD (n=7) versus age-matched non-treated healthy control subjects (n=7). Psilocybin was administered in two oral dosing sessions (10 mg and 25 mg) 1 week apart. Main outcome measures were collected 1 week and 7–12 months after the second dosing session. Nature relatedness and libertarian–authoritarian political perspective were assessed using the Nature Relatedness Scale (NR-6) and Political Perspective Questionnaire (PPQ-5), respectively.Results:Nature relatedness significantly increased (t(6)=−4.242, p=0.003) and authoritarianism significantly decreased (t(6)=2.120, p=0.039) for the patients 1 week after the dosing sessions. At 7–12 months post-dosing, nature relatedness remained significantly increased (t(5)=−2.707, p=0.021) and authoritarianism remained decreased at trend level (t(5)=−1.811, p=0.065). No differences were found on either measure for the non-treated healthy control subjects.Conclusions:This pilot study suggests that psilocybin with psychological support might produce lasting changes in attitudes and beliefs. Although it would be premature to infer causality from this small study, the possibility of drug-induced changes in belief systems seems sufficiently intriguing and timely to deserve further investigation.
Gabay AS, Carhart-Harris RL, Mazibuko N, et al., 2018, Psilocybin and MDMA reduce costly punishment in the Ultimatum Game, SCIENTIFIC REPORTS, Vol: 8, ISSN: 2045-2322
Disruptions in social decision-making are becoming evident in many psychiatric conditions. These are studied using paradigms investigating the psychological mechanisms underlying interpersonal interactions, such as the Ultimatum Game (UG). Rejection behaviour in the UG represents altruistic punishment – the costly punishment of norm violators – but the mechanisms underlying it require clarification. To investigate the psychopharmacology of UG behaviour, we carried out two studies with healthy participants, employing serotonergic agonists: psilocybin (open-label, within-participant design, N = 19) and 3,4-methylenedioxymethamphetamine (MDMA; placebo-controlled, double-blind, crossover design, N = 20). We found that both MDMA and psilocybin reduced rejection of unfair offers (odds ratio: 0.57 and 0.42, respectively). The reduction in rejection rate following MDMA was associated with increased prosociality (R2 = 0.26, p = 0.025). In the MDMA study, we investigated third-party decision-making and proposer behaviour. MDMA did not reduce rejection in the third-party condition, but produced an increase in the amount offered to others (Cohen’s d = 0.82). We argue that these compounds altered participants’ conceptualisation of ‘social reward’, placing more emphasis on the direct relationship with interacting partners. With these compounds showing efficacy in drug-assisted psychotherapy, these studies are an important step in the further characterisation of their psychological effects.
Carrillo F, Sigman M, Fernandez Slezak D, et al., 2018, Natural speech algorithm applied to baseline interview data can predict which patients will respond to psilocybin for treatment-resistant depression, JOURNAL OF AFFECTIVE DISORDERS, Vol: 230, Pages: 84-86, ISSN: 0165-0327
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- Citations: 28
Kaelen M, Giribaldi B, Raine J, et al., 2018, Correction to: The hidden therapist: evidence for a central role of music in psychedelic therapy., Psychopharmacology, Vol: 235, Pages: 1623-1623, ISSN: 0033-3158
The article The hidden therapist: evidence for a central role of music in psychedelic therapy, written by Mendel Kaelen, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, Robin Carhart-Harris, was originally published electronically on the publisher's internet portal.
Kaelen M, Giribaldi B, Raine J, et al., 2018, The hidden therapist: evidence for a central role of music in psychedelic therapy, PSYCHOPHARMACOLOGY, Vol: 235, Pages: 505-519, ISSN: 0033-3158
RationaleRecent studies have supported the safety and efficacy of psychedelic therapy for mood disorders and addiction. Music is considered an important component in the treatment model, but little empirical research has been done to examine the magnitude and nature of its therapeutic role.ObjectivesThe present study assessed the influence of music on the acute experience and clinical outcomes of psychedelic therapy.MethodsSemi-structured interviews inquired about the different ways in which music influenced the experience of 19 patients undergoing psychedelic therapy with psilocybin for treatment-resistant depression. Interpretative phenomenological analysis was applied to the interview data to identify salient themes. In addition, ratings were given for each patient for the extent to which they expressed “liking,” “resonance” (the music being experienced as “harmonious” with the emotional state of the listener), and “openness” (acceptance of the music-evoked experience).ResultsAnalyses of the interviews revealed that the music had both “welcome” and “unwelcome” influences on patients’ subjective experiences. Welcome influences included the evocation of personally meaningful and therapeutically useful emotion and mental imagery, a sense of guidance, openness, and the promotion of calm and a sense of safety. Conversely, unwelcome influences included the evocation of unpleasant emotion and imagery, a sense of being misguided and resistance. Correlation analyses showed that patients’ experience of the music was associated with the occurrence of “mystical experiences” and “insightfulness.” Crucially, the nature of the music experience was significantly predictive of reductions in depression 1 week after psilocybin, whereas general drug intensity was not.ConclusionsThis study indicates that music plays a central therapeutic function in psychedelic therapy.
Carhart-Harris RL, Erritzoe D, Haijen E, et al., 2018, Psychedelics and connectedness, PSYCHOPHARMACOLOGY, Vol: 235, Pages: 547-550, ISSN: 0033-3158
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- Citations: 118
Roseman L, Nutt DJ, Carhart-Harris RL, 2018, Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression, Frontiers in Pharmacology, Vol: 8, ISSN: 1663-9812
Introduction: It is a basic principle of the ‘psychedelic’ treatment model that the quality of the acute experience mediateslong-term improvements in mental health. In the present paper we sought to test this using data from a clinical trial assessingpsilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence andmagnitude of Oceanic Boundlessness (OBN) (sharing features with mystical-type experience) and Dread of Ego Dissolution (DED)(similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would not.Material and Methods: Twenty patients with treatment resistant depression underwent treatment with psilocybin (two separatesessions: 10mg and 25mg psilocybin). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality ofexperiences in the 25mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-typeand challenging experiences, respectively. The Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) at 5 weeks servedas the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments,thus confounding inferences. In a repeated measure ANOVA, Time was the within-subject factor (independent variable), withQIDS-SR as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. OBN and DED were independent variables.OBN-by-time and DED-by-time interactions were the primary outcomes of interest.Results: For the interaction of OBN and DED with Time (QIDS-SR as dependent variable), the main effect and the effects at each timepoint compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our mainhypothesis. Furthermore, Pearson’s correlation of OBN with QIDS-SR (5 weeks) was specific compared to perceptual dimensions ofthe ASC (p < 0.05).Discussion: This repo
Atasoy S, Vohryzek J, Deco G, et al., 2018, Common neural signatures of psychedelics: Frequency-specific energy changes and repertoire expansion revealed using connectome-harmonic decomposition., Pages: 97-120
The search for the universal laws of human brain function is still on-going but progress is being made. Here we describe the novel concepts of connectome harmonics and connectome-harmonic decomposition, which can be used to characterize the brain activity associated with any mental state. We use this new frequency-specific language to describe the brain activity elicited by psilocybin and LSD and find remarkably similar effects in terms of increases in total energy and power, as well as frequency-specific energy changes and repertoire expansion. In addition, we find enhanced signatures of criticality suggesting that the brain dynamics tune toward criticality in both psychedelic elicited states. Overall, our findings provide new evidence for the remarkable ability of psychedelics to change the spatiotemporal dynamics of the human brain.
Atasoy S, Roseman L, Kaelen M, et al., 2017, Connectome-harmonic decomposition of human brain activity reveals dynamical repertoire re-organization under LSD, Scientific Reports, Vol: 7, ISSN: 2045-2322
Recent studies have started to elucidate the effects of lysergic acid diethylamide (LSD) on the human brain but the underlying dynamics are not yet fully understood. Here we used ’connectome-harmonic decomposition’, a novel method to investigate the dynamical changes in brain states. We found that LSD alters the energy and the power of individual harmonic brain states in a frequency-selective manner. Remarkably, this leads to an expansion of the repertoire of active brain states, suggestive of a general re-organization of brain dynamics given the non-random increase in co-activation across frequencies. Interestingly, the frequency distribution of the active repertoire of brain states under LSD closely follows power-laws indicating a re-organization of the dynamics at the edge of criticality. Beyond the present findings, these methods open up for a better understanding of the complex brain dynamics in health and disease.
Carhart-Harris RL, Bolstridge M, Day CMJ, et al., 2017, Psilocybin with psychological support for treatment-resistant depression: six-month follow-up, Psychopharmacology, Vol: 235, Pages: 399-408, ISSN: 0033-3158
RATIONALE: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. OBJECTIVES: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. METHODS: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. RESULTS: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. CONCLUSIONS: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
Timmermann C, Spriggs MJ, Kaelen M, et al., 2017, LSD modulates effective connectivity and neural adaptation mechanisms in an auditory oddball paradigm., Neuropharmacology, ISSN: 0028-3908
Under the predictive coding framework, perceptual learning and inference are dependent on the interaction between top-down predictions and bottom-up sensory signals both between and within regions in a network. However, how such feedback and feedforward connections are modulated in the state induced by lysergic acid diethylamide (LSD) is poorly understood. In this study, an auditory oddball paradigm was presented to healthy participants (16 males, 4 female) under LSD and placebo, and brain activity was recorded using magnetoencephalography (MEG). Scalp level Event Related Fields (ERF) revealed reduced neural adaptation to familiar stimuli, and a blunted neural 'surprise' response to novel stimuli in the LSD condition. Dynamic causal modelling revealed that both the presentation of novel stimuli and LSD modulate backward extrinsic connectivity within a task-activated fronto-temporal network, as well as intrinsic connectivity in the primary auditory cortex. These findings show consistencies with those of previous studies of schizophrenia and ketamine but also studies of reduced consciousness - suggesting that rather than being a marker of conscious level per se, backward connectivity may index modulations of perceptual learning common to a variety of altered states of consciousness, perhaps united by a shared altered sensitivity to environmental stimuli. Since recent evidence suggests that the psychedelic state may correspond to a heightened 'level' of consciousness with respect to the normal waking state, our data warrant a re-examination of the top-down hypotheses of conscious level and suggest that several altered states may feature this specific biophysical effector.
Stroud JB, Freeman TP, Leech R, et al., 2017, Psilocybin with psychological support improves emotional face recognition in treatment-resistant depression, Psychopharmacology, Vol: 235, Pages: 459-466, ISSN: 0033-3158
RATIONALE: Depressed patients robustly exhibit affective biases in emotional processing which are altered by SSRIs and predict clinical outcome. OBJECTIVES: The objective of this study is to investigate whether psilocybin, recently shown to rapidly improve mood in treatment-resistant depression (TRD), alters patients' emotional processing biases. METHODS: Seventeen patients with treatment-resistant depression completed a dynamic emotional face recognition task at baseline and 1 month later after two doses of psilocybin with psychological support. Sixteen controls completed the emotional recognition task over the same time frame but did not receive psilocybin. RESULTS: We found evidence for a group × time interaction on speed of emotion recognition (p = .035). At baseline, patients were slower at recognising facial emotions compared with controls (p < .001). After psilocybin, this difference was remediated (p = .208). Emotion recognition was faster at follow-up compared with baseline in patients (p = .004, d = .876) but not controls (p = .263, d = .302). In patients, this change was significantly correlated with a reduction in anhedonia over the same time period (r = .640, p = .010). CONCLUSIONS: Psilocybin with psychological support appears to improve processing of emotional faces in treatment-resistant depression, and this correlates with reduced anhedonia. Placebo-controlled studies are warranted to follow up these preliminary findings.
Carhart-Harris RL, Roseman L, Bolstridge M, et al., 2017, Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms, Scientific Reports, Vol: 7, ISSN: 2045-2322
Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.
Watts R, Day C, Krzanowski J, et al., 2017, Patients' Accounts of Increased "Connectedness" and "Acceptance" After Psilocybin for Treatment-Resistant Depression, JOURNAL OF HUMANISTIC PSYCHOLOGY, Vol: 57, Pages: 520-564, ISSN: 0022-1678
Carhart-Harris RL, Nutt D, 2017, Serotonin and brain function: a tale of two receptors, Journal of Psychopharmacology, Vol: 31, Pages: 1091-1120, ISSN: 1461-7285
Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.
Carhart-Harris R, Lawton G, 2017, Trip advisor, NEW SCIENTIST, Vol: 235, Pages: 42-43, ISSN: 0262-4079
Erritzoe D, Nutt DJ, Carhart-Harris R, 2017, Concerns regarding conclusions made about LSD-treatments, HISTORY OF PSYCHIATRY, Vol: 28, Pages: 257-258, ISSN: 0957-154X
Carhart-Harris RL, Goodwin GM, 2017, The therapeutic potential of psychedelic drugs: past, present and future, Neuropsychopharmacology, Vol: 42, Pages: 2105-2113, ISSN: 1740-634X
Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.
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