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In a randomized trial involving 59 selected patients with depression, the change in depression scale scores from baseline to week 6 did not differ significantly between patients who received two doses of psilocybin and those who received daily escitalopram. Secondary outcomes generally favored psilocybin over escitalopram.

It is a basic principle of the \"psychedelic\" treatment model that the quality of the acute experience mediates long-term improvements in mental health. In the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence and magnitude 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 have negligible predictive value. Twenty patients with treatment resistant depression underwent treatment with psilocybin (two separate sessions: 10 and 25 mg psilocybin). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality of experiences in the 25 mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-type and challenging experiences, respectively. The Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) at 5 weeks served as 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), with QIDS-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. For the interaction of OBN and DED with Time (QIDS-SR as dependent variable), the main effect and the effects at each time point compared to baseline were all significant ( = 0.002 and = 0.003, respectively, for main effects), confirming our main hypothesis. Furthermore, Pearson's correlation of OBN with QIDS-SR (5 weeks) was specific compared to perceptual dimensions of the ASC ( < 0.05). This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. Future therapeutic work with psychedelics should recognize the essential importance of in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety. ISRCTN, number ISRCTN14426797, http://www.isrctn.com/ISRCTN14426797.

Proper assessment of the harms caused by the misuse of drugs can inform policy makers in health, policing, and social care. We aimed to apply multicriteria decision analysis (MCDA) modelling to a range of drug harms in the UK. Members of the Independent Scientific Committee on Drugs, including two invited specialists, met in a 1-day interactive workshop to score 20 drugs on 16 criteria: nine related to the harms that a drug produces in the individual and seven to the harms to others. Drugs were scored out of 100 points, and the criteria were weighted to indicate their relative importance. MCDA modelling showed that heroin, crack cocaine, and metamfetamine were the most harmful drugs to individuals (part scores 34, 37, and 32, respectively), whereas alcohol, heroin, and crack cocaine were the most harmful to others (46, 21, and 17, respectively). Overall, alcohol was the most harmful drug (overall harm score 72), with heroin (55) and crack cocaine (54) in second and third places. These findings lend support to previous work assessing drug harms, and show how the improved scoring and weighting approach of MCDA increases the differentiation between the most and least harmful drugs. However, the findings correlate poorly with present UK drug classification, which is not based simply on considerations of harm. Centre for Crime and Justice Studies (UK).

In this Opinion article, Nutt and colleagues examine the history of and current evidence for the dopamine theory of addiction. They argue that dopamine's role in addiction is more complicated than the role that is put forward in this theory. For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.

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.

Psychedelics including lysergic acid diethylamide (LSD) and psilocybin temporarily alter subjective experience through their neurochemical effects. Serotonin 2a (5-HT2a) receptor agonism by these compounds is associated with more diverse (entropic) brain activity. We postulate that this increase in entropy may arise in part from a flattening of the brain’s control energy landscape, which can be observed using network control theory to quantify the energy required to transition between recurrent brain states. Using brain states derived from existing functional magnetic resonance imaging (fMRI) datasets, we show that LSD and psilocybin reduce control energy required for brain state transitions compared to placebo. Furthermore, across individuals, reduction in control energy correlates with more frequent state transitions and increased entropy of brain state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors (obtained from publicly available positron emission tomography (PET) data under non-drug conditions), we demonstrate an association between the 5-HT2a receptor and reduced control energy. Our findings provide evidence that 5-HT2a receptor agonist compounds allow for more facile state transitions and more temporally diverse brain activity. More broadly, we demonstrate that receptor-informed network control theory can model the impact of neuropharmacological manipulation on brain activity dynamics. There are several models of how serotonergic psychedelic drugs affect brain activity. Here the authors use network control theory and functional MRI data to provide evidence that serotonin receptor agonists LSD and psilocybin flatten the brain’s dynamic landscape, allowing for facile state transitions and more temporally diverse brain activity.

Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD’s marked effects on the visual cortex did not significantly correlate with the drug’s other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of “ego-dissolution” and “altered meaning,” implying the importance of this particular circuit for the maintenance of “self” or “ego” and its processing of “meaning.” Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect. This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date. All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect. Psychedelic psychotherapy, therapy enhanced with psychedelic drugs such as LSD or psilocybin (the active ingredient of ‘magic mushrooms’), has been suggested to improve psychological well-being. For this reason, trials on psychedelic therapy for the treatment of depression, addiction and other conditions are ongoing. Recently, ‘microdosing’ – a way of administering psychedelics that involves taking about 10% of a recreational dose two or three times per week – has gained popularity. Unlike taking large doses of psychedelics, microdosing does not induce hallucinations, but anecdotal reports suggest that it yields similar benefits as psychedelic therapy. A key feature of modern medicine are ‘placebo control’ studies that compare two groups of patients: one that takes a drug and another that takes inactive pills, known as placebos. Crucially, neither group knows whether they are taking drug or placebo. This control ensures that observed effects are due to the drug itself and not to unrelated psychological causes. For example, in trials of mood medicines, participants often expect to feel happier, which in itself improves their mood even when taking a placebo. This is known as the placebo effect. Restrictive drug policies make placebo-controlled studies on psychedelics difficult and expensive, in particular for microdosing, which involves taking psychedelics over a longer time period. To overcome this problem, Szigeti et al. developed a new citizen-science approach, where microdosers implemented their own placebo control based on online instructions. The advantages are the low cost and the ability to recruit participants globally. The experiment was completed by 191 microdosers, making it the largest placebo-controlled study on psychedelics to-date, for a fraction of the cost of an equivalent clinical study. The trial examined whether psychedelic microdosing can improve cognitive function and psychological well-being. The team found that microdosing significantly increased a number of psychological measures, such as well-being and life satisfaction. However, participants taking placebo also improved: there were no significant differences between the two groups. The findings confirmed positive anecdotes about microdosing improving people’s moods, but at the same time show that taking empty capsules, knowing they might be microdoses, have the same benefits. This result suggests that the observed benefits are not caused by the microdose, but rather by psychological expectations. The study’s innovative ‘do-it-yourself’ approach to placebo control may serve as a template for future citizen science studies on other popular phenomena where positive expectations and social factors could play a role, such as cannabidiol (CBD) oils, nootropics and nutrition.

Psilocybin, a serotonergic psychedelic, is being increasingly researched in clinical studies for the treatment of psychiatric disorders. The relatively lengthy duration of oral psilocybin’s acute effects (4–6 h) may have pragmatic and cost-effectiveness limitations. Here, we explored the effects of intravenous (IV) N,N-Dimethyltryptamine (DMT), a closely related, but faster-acting psychedelic intervention, on mental health outcomes in healthy volunteers. Data is reported from two separate analyses: (1) A comparison of mental health-related variables 1 week after 7, 14, 18, and 20 mg of IV DMT versus IV saline placebo (n = 13) and, (2) A prospective dataset assessing effects before versus 2 weeks after 20 mg of IV DMT (n = 17). Mental health outcomes included measures of depression severity (QIDS-SR16), trait anxiety (STAI-T), Neuroticism (NEO-FFI), wellbeing (WHO-5), meaning in life (MLQ), optimism (LOT-R), and gratitude (GQ-6). In both the prospective and placebo-controlled datasets, significant improvements in scores of depression were found 1–2 weeks after DMT administration. Significant reductions in trait Neuroticism were only found for the placebo-controlled sample. Finally, changes in depression and trait anxiety correlated with acute peak experiences (assessed via ‘Oceanic Boundlessness’). While the use of two separate cohorts in pooled analysis limits the generalizability of these correlational findings, these results suggest that DMT may reduce depressive symptomatology by inducing peak experiences. The short half-life of IV DMT and its potential for flexible dosing via controlled infusions makes it an appealing candidate for psychedelic medicine. Further research in clinical samples is needed to corroborate the therapeutic potential of DMT.

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.