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When it comes to studying neural plasticity and psychedelics, the numerous and diverse neuroscientific fields converging on the topic provide unique insight into a complex picture. This editorial will describe the major ways in which the known effects of psychedelics on plasticity are being studied. We lay out strengths of different techniques and the major gaps and room for future research, particularly in the translation of pre-clinical studies to human research.

Neuroplasticity is essential to learning and memory in the brain; it has therefore also been implicated in numerous neurological and psychiatric disorders, making measuring the state of neuroplasticity of foremost importance to clinical neuroscience. Long-term potentiation (LTP) is a key mechanism of neuroplasticity and has been studied extensively, and invasively in non-human animals. Translation to human application largely relies on the validation of non-invasive measures of LTP. The current study presents a generative thalamocortical computational model of visual cortex for investigating and replicating interlaminar connectivity changes using non-invasive EEG recording of humans. The model is combined with a commonly used visual sensory LTP paradigm and fit to the empirical EEG data using dynamic causal modelling. The thalamocortical model demonstrated remarkable accuracy recapitulating post-tetanus changes seen in invasive research, including increased excitatory connectivity from thalamus to layer IV and from layer IV to II/III, established major sites of LTP in visual cortex. These findings provide justification for the implementation of the presented thalamocortical model for ERP research, including to provide increased detail on the nature of changes that underlie LTP induced in visual cortex. Future applications include translating rodent findings to non-invasive research in humans concerning deficits to LTP that may underlie neurological and psychiatric disease.

Background Microdosing psychedelics is a phenomenon with claimed cognitive benefits that are relatively untested clinically. Pre-clinically, psychedelics have demonstrated enhancing effects on neuroplasticity, which cannot be measured directly in humans, but may be indexed by non-invasive electroencephalography (EEG) paradigms. This study used a visual long-term potentiation (LTP) EEG paradigm to test the effects of microdosed lysergic acid diethylamide (LSD) on neural plasticity, both acutely while on the drug and cumulatively after microdosing every third day for six weeks. Healthy adult males ( n  = 80) completed the visual LTP paradigm at baseline, 2.5 h following a dose of 10 µg of LSD or inactive placebo, and 6 weeks later after taking 14 repeated microdoses. Visually induced LTP was used as indirect index of neural plasticity. Surface level event-related potential (ERPs) based analyses are presented alongside dynamic causal modelling of the source localised data using a generative thalamocortical model (TCM) of visual cortex to elucidate underlying synaptic circuitry. Results Event-related potential (ERP) analyses of N1b and P2 components did not show evidence of changes in visually induced LTP by LSD either acutely or after 6 weeks of regular dosing. However modelling the complete timecourse of the ERP with the TCM demonstrated changes in laminar connectivity in primary visual cortex. This primarily included changes to self-gain and inhibitory input parameters acutely. Layer 2/3 to layer 5 excitatory connectivity was also different between LSD and placebo groups. After regular dosing only excitatory input from layer 2/3 into layer 5 and inhibitory input into layer 4 were different between groups. Conclusions Without modulation of the ERPs it is difficult to relate the findings to other studies visually inducing LTP. It also indicates the classic peak analysis may not be sensitive enough to demonstrate evidence for changes in LTP plasticity in humans at such low doses. The TCM provides a more sensitive approach to assessing changes to plasticity as differences in plasticity mediated laminar connectivity were found between the LSD and placebo groups. Trial registration:  ANZCTR registration number ACTRN12621000436875; Registered 16/04/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 .

Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine's ability to alter local coupling mediated by NMDA, AMPA and GABA-A.

Background Regular ingestion of sub-hallucinogenic doses of psychedelics, referred to as “microdosing”, has gained increasing popularity and attention in the press and in online forums, with reported benefits across multiple cognitive and emotional domains. Rigorously controlled studies to date, however, have been limited in scope and have failed to produce results comparable to those reported in the grey literature. Methods Eighty healthy male participants will receive 14 doses of placebo or 10 μg lysergic acid diethylamide orally every 3rd day over a 6-week treatment protocol. A battery of personality, creativity, mood, cognition, and EEG plasticity measures, as well as resting-state fMRI imaging, will be administered at baseline and at the end of the protocol. Creativity, mood, and plasticity measures will additionally be assessed in the acute phase of the first dose. Daily functioning will be monitored with questionnaires and a wearable sleep and activity tracker. Discussion This study will rigorously examine the claims presented in the microdosing grey literature by pairing a comparable dosing protocol with objective measures. Potential therapeutic implications include future clinical trials to investigate microdosed psychedelics as a standalone treatment or as an augmentation of psychotherapy in the treatment of depression, addiction, eating disorders, obsessive-compulsive disorders, and palliative care. Trial registration ACTRN12621000436875 . Registered on 19 February 2021

Revealing the acute cortical pharmacodynamics of an antidepressant dose of ketamine in humans with depression is key to determining the specific mechanism(s) of action for alleviating symptoms. While the downstream effects are characterised by increases in plasticity and reductions in depressive symptoms—it is the acute response in the brain that triggers this cascade of events. Computational modelling of cortical interlaminar and cortico-cortical connectivity and receptor dynamics provide the opportunity to interrogate this question using human electroencephalography (EEG) data recorded during a ketamine infusion. Here, resting-state EEG was recorded in a group of 30 patients with major depressive disorder (MDD) at baseline and during a 0.44 mg/kg ketamine dose comprising a bolus and infusion. Fronto-parietal connectivity was assessed using dynamic causal modelling to fit a thalamocortical model to hierarchically connected nodes in the medial prefrontal cortex and superior parietal lobule. We found a significant increase in parietal-to-frontal AMPA-mediated connectivity and a significant decrease in the frontal GABA time constant. Both parameter changes were correlated across participants with the antidepressant response to ketamine. Changes to the NMDA receptor time constant and inhibitory intraneuronal input into superficial pyramidal cells did not survive correction for multiple comparisons and were not correlated with the antidepressant response. These results provide evidence that the antidepressant effects of ketamine may be mediated by acute fronto-parietal connectivity and GABA receptor dynamics. Furthermore, it supports the large body of literature suggesting the acute mechanism underlying ketamine’s antidepressant properties is related to GABA-A and AMPA receptors rather than NMDA receptor antagonism.

Long-term potentiation (LTP) is a form of neuroplasticity commonly implicated in mechanistic models of learning and memory. Acute exercise can boost LTP in the motor cortex, and is associated with a shift in excitation/inhibition (E:I) balance, but whether this extends to other regions such as the visual cortex is unknown. We investigated the effect of a preceding bout of exercise on LTP induction and the E:I balance in the visual cortex using electroencephalography (EEG). Young adults (N = 20, mean age = 24.20) engaged in 20 min of high-intensity interval training (HIIT) exercise and rest across two counterbalanced sessions. LTP was induced using a high frequency presentation of a visual stimulus; a “visual tetanus”. Established EEG markers of visual LTP, the N1b and P2 component of the visual evoked potential, and an EEG-derived measure of the E:I balance, the aperiodic exponent, were measured before and after the visual tetanus. As expected, there was a potentiation of the N1b following the visual tetanus, with specificity to the tetanised stimulus, and a non-specific potentiation of the P2. These effects were not sensitive to a preceding bout of exercise. However, the E:I balance showed a late shift towards inhibition following the visual tetanus. A preceding bout of exercise resulted in specificity of this E:I balance shift to the tetanised stimulus, that was not seen following rest. This novel finding suggests a possible exercise-induced tuning of the visual cortex to stimulus details following LTP induction.

Microdosing psychedelic drugs at a level below the threshold to induce hallucinations is an increasingly common lifestyle practice. However, the effects of microdosing on sleep have not been previously reported. Here, we report results from a Phase 1 randomized controlled trial in which 80 healthy adult male volunteers received a 6-week course of either LSD (10 µg) or placebo with doses self-administered every third day. Participants used a commercially available sleep/activity tracker for the duration of the trial. Data from 3231 nights of sleep showed that on the night after microdosing, participants in the LSD group slept an extra 24.3 min per night (95% Confidence Interval 10.3–38.3 min) compared to placebo—with no reductions of sleep observed on the dosing day itself. There were no changes in the proportion of time spent in various sleep stages or in participant physical activity. These results show a clear modification of the physiological sleep requirements in healthy male volunteers who microdose LSD. The clear, clinically significant changes in objective measurements of sleep observed are difficult to explain as a placebo effect. Trial registration: Australian New Zealand Clinical Trials Registry: A randomized, double-blind, placebo-controlled trial of repeated microdoses of lysergic acid diethylamide (LSD) in healthy volunteers; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381476 ; ACTRN12621000436875.

Background Major depressive disorder (MDD) is a leading cause of disability worldwide. The current treatments are ineffective in approximately one-third of patients, resulting in a large economic burden and reduced quality of life for a significant proportion of the global population. There is considerable evidence that increased inflammation may distinguish a sub-type of MDD, and there are no validated diagnostic tools or treatments for neuroinflammation in MDD patients. The current study aims to explore the potential role of low-dose naltrexone (LDN), a drug with purported anti-inflammatory properties in the central nervous system, as an adjunctive treatment in patients with MDD. Methods/design This double-blind placebo-controlled hybrid parallel arm study enables the exploration of peripheral and central inflammatory markers with LDN as an approach to investigate inflammation as a pathophysiological contributor to MDD. Eligible participants with MDD ( n = 48) will be stratified into the high and low inflammatory groups according to the levels of high-sensitivity C-reactive protein (hs-CRP) and then randomized to receive LDN or placebo for an initial 12 weeks, followed by a further 12 weeks during which all participants will receive LDN. The primary outcome measure will be the Montgomery-Åsberg Depression Rating Scale (MADRS) administered at baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 14 weeks, 16 weeks, 20 weeks, and 24 weeks, to assess the effectiveness of the anti-depressant response. The secondary outcomes include the use of MRI techniques including quantitative magnetization transfer (qMT), echo-planar spectroscopic imaging (EPSI), and diffusion-weighted imaging (DWI) to help to elucidate the neurobiological mechanism of LDN, and the inflammatory mechanisms in action in MDD. Electroencephalography, blood samples, cognitive tasks, and additional questionnaires will also be used to determine if there is a specific profile of symptoms in individuals with inflammatory MDD. Healthy participants ( n = 24) will be recruited for baseline outcome measures only, to enable comparison with patients with MDD. Discussion This trial contributes to the literature on inflammation in MDD, including the understanding of the pathophysiology and efficacy of anti-inflammatory treatments. The investigation of inflammatory mechanisms in MDD is an important first step in the development of biomarkers to classify patient sub-groups, increase the accuracy of diagnosis, and tailor the approach to patients in clinical practice. This study may provide evidence of the benefit of LDN for the groups in whom conventional anti-depressants are ineffective and lead the way for translation into clinical practice. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12622000881730 . Registered on 21 June 2022

Background: Depressive disorders affect approximately 280 million globally, with many finding treatments ineffective or limited by side effects. Growing evidence suggests that psychedelic therapies may help alleviate depressive symptoms. Among these, lysergic acid diethylamide (LSD) microdosing shows promise for major depressive disorder (MDD). However, research on LSD microdosing in clinical populations remains limited. Objectives: This study aimed to understand the experiences of individuals participating in an open-label trial of LSD microdosing for MDD. Design: Open-label pilot trial in target population (MDD; phase IIa). Methods: Seventeen participants with MDD completed an 8-week LSD microdosing regimen, dosing twice weekly. Following the intervention, participants underwent semi-structured interviews regarding their experiences. Data were analysed using thematic analysis. Results: Themes were grouped into five categories: enhanced self-determination, increased connectedness, improved cognitive processing, better emotional well-being, and negative effects. Conclusion: Reported effects appeared to reinforce one another; that is, self-determination led to feeling more connected, which enhanced cognitive processing and ultimately improved emotional well-being and reduced depressive symptoms. However, this effect was not universal; some individuals reported negative effects or no significant improvement from microdosing LSD. This variability may be due to individual differences in response, insufficient dosage, or the treatment’s lack of effectiveness for some individuals. The presence of side effects highlights the need for a careful titration protocol, while the lack of symptom improvement in some cases reinforces that microdosing is not a guaranteed solution, and expectations should remain realistic. The absence of a placebo control represents a key limitation as it precludes attribution of observed changes specifically to LSD. Trial registration: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385758). Plain language summary Depression affects millions of people worldwide, and many find that current treatments either don’t work or have unwanted side effects. Recent research suggests that psychedelic substances, like LSD, may help improve mood when used carefully small amounts. This practice is known as LSD microdosing. Despite growing interest, there is very little controlled research on how LSD microdosing affects people with depression. In this study, we invited 17 adults with depression to take very low doses of LSD twice a week for eight weeks. After the study, we asked them about their experiences to understand how microdosing affected them. Participants reported a range of experiences. Many described feeling more motivated to engage in daily activities, a stronger sense of connection with others, clearer thinking, new personal insights, and overall improvements in emotional well-being. The improvements participants described often seemed to build on each other—for example, feeling more connected encouraged them to take part in more activities, which then helped them feel mentally clearer and emotionally better. However, not everyone benefited. Some participants reported negative experiences or no noticeable improvement, suggesting that microdosing may not work for everyone. The study also did not include a placebo comparison, so it is unclear whether the changes were due specifically to LSD. Overall, these findings suggest that LSD microdosing may offer some people with depression new ways to feel more connected, motivated, and emotionally balanced. At the same time, careful monitoring is important due to potential side effects, and expectations should remain realistic.