Long-COVID symptoms improved after MDMA and psilocybin therapy: A case report.

Key Clinical Message: Long-COVID syndrome lacks effective holistic treatment options. We present a case of a 41-year-old fully vaccinated female with Long-COVID syndrome who obtained significant symptomatic relief after self-medicating with psilocybin and MDMA. Abstract: Long-COVID, a syndrome persisting after the acute phase of coronavirus disease 2019 (COVID-19), lacks effective holistic treatment options. We present a case of a 41-year-old fully vaccinated female with Long-COVID syndrome who obtained significant symptomatic relief by self-prescribing psilocybin and MDMA. Future research is needed to assess safety and efficacy.

Chronic pain as an emergent property of a complex system and the potential roles of psychedelic therapies.

Despite research advances and urgent calls by national and global health organizations, clinical outcomes for millions of people suffering with chronic pain remain poor. We suggest bringing the lens of complexity science to this problem, conceptualizing chronic pain as an emergent property of a complex biopsychosocial system. We frame pain-related physiology, neuroscience, developmental psychology, learning, and epigenetics as components and mini-systems that interact together and with changing socioenvironmental conditions, as an overarching complex system that gives rise to the emergent phenomenon of chronic pain. We postulate that the behavior of complex systems may help to explain persistence of chronic pain despite current treatments. From this perspective, chronic pain may benefit from therapies that can be both disruptive and adaptive at higher orders within the complex system. We explore psychedelic-assisted therapies and how these may overlap with and complement mindfulness-based approaches to this end. Both mindfulness and psychedelic therapies have been shown to have transdiagnostic value, due in part to disruptive effects on rigid cognitive, emotional, and behavioral patterns as well their ability to promote neuroplasticity. Psychedelic therapies may hold unique promise for the management of chronic pain.

High-frequency spinal cord stimulation (10 kHz) alters sensory function and nerve fiber density in painful diabetic neuropathy: a pilot prospective open-label study.

OBJECTIVE: Spinal cord stimulation at 10 kHz has provided effective pain relief and improved function in painful diabetic peripheral neuropathy. This study aims to confirm the clinical outcomes for 10-kHz spinal cord stimulation treatment of painful diabetic peripheral neuropathy and explore its impact on objective quantitative measures of nerve pathology and function. METHODS: This single-academic center, prospective, open-label, observational study examined the pain relief success of 10-kHz spinal cord stimulation in patients >18 years of age with diabetic peripheral neuropathy. Patients underwent skin biopsies to measure intra-epidermal nerve fiber densities and corneal confocal microscopy measurements before implantation and at the 3-, 6-, and 12-month follow-up visits. Numerical rating scale for pain, visual analog scale, neuropathy pain scale, Short Form-36, and Neuropen (pin prick and monofilament) assessments were also conducted. RESULTS: Eight patients met the criteria and were enrolled in the study. A successful trial was achieved in 7 subjects, and 6 completed the study. Significant pain relief (P < .001) was achieved at all follow-up visits. Neurological assessments showed reduced numbers of "absent" responses and increased "normal" responses from baseline to 12 months. Both proximal and distal intra-epidermal nerve fiber densities were higher at 12 months than at baseline (P < .01). Confocal microscopy measurements showed a steady increase in nerve density from baseline (188.8% increase at 12 months; P = .029). CONCLUSIONS: We observed pain relief and improvements in sensory function after stimulation that were accompanied by increases in lower-limb intra-epidermal nerve fiber density and corneal nerve density. Further evaluation with a blinded and controlled study is needed to confirm the preliminary findings in this study.

Deep-learning-based biomarker of spinal cartilage endplate health using ultra-short echo time magnetic resonance imaging.

Background: T2* relaxation times in the spinal cartilage endplate (CEP) measured using ultra-short echo time magnetic resonance imaging (UTE MRI) reflect aspects of biochemical composition that influence the CEP's permeability to nutrients. Deficits in CEP composition measured using T2* biomarkers from UTE MRI are associated with more severe intervertebral disc degeneration in patients with chronic low back pain (cLBP). The goal of this study was to develop an objective, accurate, and efficient deep-learning-based method for calculating biomarkers of CEP health using UTE images. Methods: Multi-echo UTE MRI of the lumbar spine was acquired from a prospectively enrolled cross-sectional and consecutive cohort of 83 subjects spanning a wide range of ages and cLBP-related conditions. CEPs from the L4-S1 levels were manually segmented on 6,972 UTE images and used to train neural networks utilizing the u-net architecture. CEP segmentations and mean CEP T2* values derived from manually- and model-generated segmentations were compared using Dice scores, sensitivity, specificity, Bland-Altman, and receiver-operator characteristic (ROC) analysis. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated and related to model performance. Results: Compared with manual CEP segmentations, model-generated segmentations achieved sensitives of 0.80-0.91, specificities of 0.99, Dice scores of 0.77-0.85, area under the receiver-operating characteristic curve values of 0.99, and precision-recall (PR) AUC values of 0.56-0.77, depending on spinal level and sagittal image position. Mean CEP T2* values and principal CEP angles derived from the model-predicted segmentations had low bias in an unseen test dataset (T2* bias =0.33±2.37 ms, angle bias =0.36±2.65°). To simulate a hypothetical clinical scenario, the predicted segmentations were used to stratify CEPs into high, medium, and low T2* groups. Group predictions had diagnostic sensitivities of 0.77-0.86 and specificities of 0.86-0.95. Model performance was positively associated with image SNR and CNR. Conclusions: The trained deep learning models enable accurate, automated CEP segmentations and T2* biomarker computations that are statistically similar to those from manual segmentations. These models address limitations with inefficiency and subjectivity associated with manual methods. Such techniques could be used to elucidate the role of CEP composition in disc degeneration etiology and guide emerging therapies for cLBP.

Narrative review of current neuromodulation modalities for spinal cord injury.

Neuromodulation is a developing field of medicine that includes a vast array of minimally invasive and non-invasive therapies including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation (VNS), peripheral nerve stimulation, and spinal cord stimulation (SCS). Although the current literature surrounding the use of neuromodulation in managing chronic pain is abundant, there is an insufficient amount of evidence specifically regarding neuromodulation in patients with spinal cord injury (SCI). Given the pain and functional deficits that these patients face, that are not amenable to other forms conservative therapy, the purpose of this narrative review is to examine and assess the use of various neuromodulation modalities to manage pain and restore function in the SCI population. Currently, high-frequency spinal cord stimulation (HF-SCS) and burst spinal cord stimulation (B-SCS) have been shown to have the most promising effect in improving pain intensity and frequency. Additionally, dorsal root ganglion stimulation (DRG-S) and TMS have been shown to effectively increase motor responses and improve limb strength. Although these modalities carry the potential to enhance overall functionality and improve a patient's degree of disability, there is a lack of long-term, randomized-controlled trials in the current space. Additional research is warranted to further support the clinical use of these emerging modalities to provide improved pain management, increased level of function, and ultimately an overall better quality of life in the SCI population.

Microdosing psilocybin for chronic pain: a case series.

ABSTRACT: Psychedelic serotonergic agonists such as psilocybin have recently been shown to produce sustained benefit in refractory depression, end of life anxiety, and addiction when administered in hallucinogenic doses and coupled with psychotherapy. Although it has been suggested that similar high-dose protocols may help chronic pain conditions, there are few published clinical trials of psychedelics for pain. The use of these agents in subpsychedelic doses for chronic pain management has received even less attention. This case series details the experiences of 3 individuals who have used low-dose psilocybin to manage chronic neuropathic pain. Although the nature and etiology of each patient's pain vary, they share a common experience, including inefficacy of current therapeutics and decreased quality of life. Through self-administration of psilocybin, these patients have achieved robust pain relief with decreased reliance on traditional analgesic medications. Despite varying preparations and uncertain potencies, the analgesic effects for all 3 patients occurred at doses without a psychedelic experience and with minimal cognitive or somatic adverse effects. Furthermore, the efficacy of pain relief and, in some cases, the duration of the effect were magnified when coupled with functional exercise. In addition, in 1 case, repeated dosing seemed to produce increased relief, suggesting a possible long-term plasticity-mediated effect. These commonalities highlight psilocybin's therapeutic potential in the treatment of chronic pain that warrants further investigation.

The Use of Psychedelics in the Treatment of Medical Conditions: An Analysis of Currently Registered Psychedelics Studies in the American Drug Trial Registry.

Although early therapeutic research on psychedelics dates back to the 1940s, this field of investigation was met with many cultural and legal challenges in the 1970s. Over the past two decades, clinical trials using psychedelics have resumed. Therefore, the goal of this study was to (1) better characterize the recent uptrend in psychedelics in clinical trials and (2) identify areas where potentially new clinical trials could be initiated to help in the treatment of widely prevalent medical disorders. A systematic search was conducted on the clinicaltrials.gov database for all registered clinical trials examining the use of psychedelic drugs and was both qualitatively and quantitatively assessed. Analysis of recent studies registered in clinicaltrials.gov was performed using Pearson's correlation coefficient testing. Statistical analysis and visualization were performed using R software. In totality, 105 clinical trials met this study's inclusion criteria. The recent uptrend in registered clinical trials studying psychedelics (p = 0.002) was similar to the uptrend in total registered clinical trials in the registry (p < 0.001). All trials took place from 2007 to 2020, with 77.1% of studies starting in 2017 or later. A majority of clinical trials were in phase 1 (53.3%) or phase 2 (25.7%). Common disorders treated include substance addiction, post-traumatic stress disorder, and major depressive disorder. Potential research gaps include studying psychedelics as a potential option for symptomatic treatment during opioid tapering. There appears to be a recent uptrend in registered clinical trials studying psychedelics, which is similar to the recent increase in overall trials registered. Potentially, more studies could be performed to evaluate the potential of psychedelics for symptomatic treatment during opioid tapering and depression refractory to selective serotonin reuptake inhibitors.

Peripheral Nerve Stimulation for Chronic Pain and Migraine: A Review.

Interventional pain procedures offer treatments for chronic pain conditions refractory to conservative measures. Neuromodulation, including peripheral nerve stimulation (PNS), applies electrical stimuli to neural structures to treat pain. Here we review the literature on PNS for various chronic pain conditions including neuropathic pain, postamputation pain, musculoskeletal pain, migraine, and pelvic pain.

The minimally conscious state: an analysis of current clinical trials registered in ClinicalTrials.gov.

The minimally conscious state (MCS) is a disorder of consciousness described in recent years for patients who have behavioral responses to stimuli that do not meet the classification of chronic vegetative state (CVS) or coma. This distinction is valuable in clinical practice, as minimally conscious patients may require different treatments and may have different long-term outcomes when compared to vegetative states or coma. In this report, we analyzed the ClinicalTrials.gov database to systematically assess all clinical trials regarding MCS. The database was queried using the term "minimally conscious state" in the "condition or disease" search parameter. Of the studies identified, those that had suspended, terminated, or otherwise unknown statuses were excluded. In total, 41 studies were analyzed. The included studies were initiated between 2008 and 2020, with the majority (63%) beginning in 2015 or later. Of the primary intervention modalities included, 15 (37%) evaluated stimulation modalities such as transcranial magnetic stimulation, transcranial direct current stimulation, implantable neurostimulation, vagus nerve stimulation, focused ultrasound and median nerve stimulation. Additionally, 5 (12%) used some form of behavioral therapy. A total of 4 (10%) studies involved pharmaceutical intervention, including dopamine agonists, analgesics and sedatives. Finally, 4 (10%) studies sought to determine the validity of current diagnostic methods and systems used to assess the status of patients in MCSs. Since the definition and criteria for CVS and MCS have been established, these two conditions remain closely associated despite evidence of different patient outcomes and treatment options. Many clinical trials are underway assessing interventions with stimulation. However, the trials are lacking with respect to diagnostic methods and pharmaceutical treatment.

The impact of nociplastic pain features on the response to physical therapy in patients with primary myofascial pain.

BACKGROUND: Myofascial pain is a common, but poorly understood multifactorial condition. OBJECTIVE: This study analyzed how the degree of central sensitization (nociplastic pain) can impact the response to physical therapy for patients with myofascial pain. METHODS: This prospective, observational cohort study compared pain phenotyping and functional measures in 30 participants with non-acute neck/shoulder girdle primary myofascial pain following 3-months of physical therapy. The Fibromyalgia Survey Questionnaire Score served as a surrogate of central sensitization. RESULTS: All participants demonstrated some benefit from physical therapy; however, those with moderate levels of nociplastic pain features were less likely to have clinically significant improvements on the Neck Disability Index, PEG score, or pain catastrophizing measures. Those with higher levels of nociplastic pain had a similar chance of showing improvement as those with lower levels, except regarding catastrophizing. Significant improvements were independent of the type or amount of therapy received. CONCLUSION: The degree of nociplastic pain in patients with myofascial pain appears to be inversely related to improvements from a peripherally based treatment. This is not to say that individuals with moderate to higher levels of nociplastic pain do not benefit from physical therapy, but they proportionally benefit less.

Widespread Pressure Delivered by a Weighted Blanket Reduces Chronic Pain: A Randomized Controlled Trial.

Pleasant sensation is an underexplored avenue for modulation of chronic pain. Deeper pressure is perceived as pleasant and calming, and can improve sleep. Although pressure can reduce acute pain, its effect on chronic pain is poorly characterized. The current remote, double-blind, randomized controlled trial tested the hypothesis that wearing a heavy weighted blanket - providing widespread pressure to the body - relative to a light weighted blanket would reduce ratings of chronic pain, mediated by improvements in anxiety and sleep. Ninety-four adults with chronic pain were randomized to wear a 15-lb. (heavy) or 5-lb. (light) weighted blanket during a brief trial and overnight for one week. Measures of anxiety and chronic pain were collected pre- and post-intervention, and ratings of pain intensity, anxiety, and sleep were collected daily. After controlling for expectations and trait anxiety, the heavy weighted blanket produced significantly greater reductions in broad perceptions of chronic pain than the light weighted blanket (Cohen's f = .19, CI [-1.97, -.91]). This effect was stronger in individuals with high trait anxiety (P = .02). However, weighted blankets did not alter pain intensity ratings. Pain reductions were not mediated by anxiety or sleep. Given that the heavy weighted blanket was associated with greater modulation of affective versus sensory aspects of chronic pain, we propose that the observed reductions are due to interoceptive and social/affective effects of deeper pressure. Overall, we demonstrate that widespread pressure from a weighted blanket can reduce the severity of chronic pain, offering an accessible, home-based tool for chronic pain. The study purpose, targeted condition, study design, and primary and secondary outcomes were pre-registered in ClinicalTrials.gov (NCT04447885: "Weighted Blankets and Chronic Pain"). PERSPECTIVE: This randomized-controlled trial showed that a 15-lb weighted blanket produced significantly greater reductions in broad perceptions of chronic pain relative to a 5-lb weighted blanket, particularly in highly anxious individuals. These findings are relevant to patients and providers seeking home-based, nondrug therapies for chronic pain relief.

Predicting Risk of Sport-Related Concussion in Collegiate Athletes and Military Cadets: A Machine Learning Approach Using Baseline Data from the CARE Consortium Study.

OBJECTIVE: To develop a predictive model for sport-related concussion in collegiate athletes and military service academy cadets using baseline data collecting during the pre-participation examination. METHODS: Baseline assessments were performed in 15,682 participants from 21 US academic institutions and military service academies participating in the CARE Consortium Study during the 2015-2016 academic year. Participants were monitored for sport-related concussion during the subsequent season. 176 baseline covariates mapped to 957 binary features were used as input into a support vector machine model with the goal of learning to stratify participants according to their risk for sport-related concussion. Performance was evaluated in terms of area under the receiver operating characteristic curve (AUROC) on a held-out test set. Model inputs significantly associated with either increased or decreased risk were identified. RESULTS: 595 participants (3.79%) sustained a concussion during the study period. The predictive model achieved an AUROC of 0.73 (95% confidence interval 0.70-0.76), with variable performance across sports. Features with significant positive and negative associations with subsequent sport-related concussion were identified. CONCLUSION(S): This predictive model using only baseline data identified athletes and cadets who would go on to sustain sport-related concussion with comparable accuracy to many existing concussion assessment tools for identifying concussion. Furthermore, this study provides insight into potential concussion risk and protective factors.

Psychosocial characteristics of candidates for implantable pain devices: validation of an assessment model.

Aim: To provide a detailed profile of Veteran and community patients with chronic pain who completed preprocedural psychological evaluations for implantable pain devices. Patients & methods: A total of 157 candidates completed a preimplantable pain device evaluation between June 2018 and October 2019 with a pain psychologist that included a structured interview, elicitation of patient-centered goals for the implantable device, and psychometric testing. Results: Candidates demonstrated moderate to high rates of sleep impairment (73%), depressive symptoms (62%), anxiety symptoms (61%), pain catastrophizing (37%), cognitive impairment screen (30%) and somatic symptoms (24%). Conclusion: Candidates for implantable pain devices report high rates of mood, sleep and cognitive impairment, reinforcing the value of preprocedural psychological evaluations.

Chronic pain and psychedelics: a review and proposed mechanism of action.

The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT2A) receptor agonism, to 'reset' areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT2A activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.

A revised psychosocial assessment model for implantable pain devices to improve their evidence basis and consensus with updated pain management guidelines.

Although psychosocial evaluations for implantable pain devices have been consensus recommendations since the 1990s, there is an inconsistent support regarding their ability to identify suitable pain device candidates or to predict clinical outcomes. With the emergence of evidence-based practices and the recent release of pain management guidelines emphasizing functional improvements and safety, the disparity between the recommendations for implantable pain device psychosocial evaluations and the evidence supporting them has only grown. In this special report, we describe a revised model for conducting psychosocial evaluations among implantable pain device candidates. This model includes changes to increase the evidence-basis of the psychosocial evaluations, incorporate patient-centered care standards and harmonize the evaluation structure with the most current pain management guidelines.

Identification of canonical neural events during continuous gameplay of an 8-bit style video game.

Cognitive neuroscience suffers from a unique and pervasive problem of generalizability. Since neural findings are often interpreted in the context of a specific manipulation during a carefully controlled task, it is hard to transfer knowledge from one task to another. In this report we address problems of generalizability with two methodological advancements. First, we aimed to transcend status quo experimental procedures with a continuous, engaging task environment. To this end, we created a novel 8-bit style continuous space shooter video game that elicits a multitude of goal-oriented events, such as crashing into a wall or blowing up an enemy with a missile. Second, we aimed to objectively define the psychological significance of these events. To achieve this aim, we used pattern classification of EEG data to derive predictive weights from carefully controlled pre-game exemplar events (oddball target detection and gambling wins and losses) and transferred those weights to EEG activities during video game events. All major goal-oriented events (crashes into the wall, crashes into an enemy, missile hit on an enemy) had a significant between-task transfer bias towards oddball target weights in the time range of the canonical P3, indicating the presence of similar salience detection processes. Missile hits on an enemy were specifically identified as gambling wins, confirming the hypothesis that this goal-oriented event was appetitive. These findings suggest that it is possible to identify the contribution of canonical neural activities during otherwise ambiguous and uncontrolled task performance.