Preventing Overdoses Involving Stimulants: The POINTS Study Protocol.

Background: In recent years, overdoses involving illicit cocaine, methamphetamine, and other stimulants have increased in the U.S. The unintentional consumption of stimulants containing illicit fentanyl is a major risk factor for overdoses, particularly in Massachusetts and Rhode Island. Understanding the drug use patterns and strategies used by people who use stimulants (PWUS) to prevent overdose is necessary to identify risk and protective factors for stimulant-involved overdoses. Mixed-methods research with people who distribute drugs (PWDD) can also provide critical information into the mechanisms through which fentanyl may enter the stimulant supply, and the testing of drug samples can further triangulate PWUS and PWDD perspectives regarding the potency and adulteration of the drug supply. These epidemiological methods can inform collaborative intervention development efforts with community leaders to identify feasible, acceptable, and scalable strategies to prevent fatal and non-fatal overdoses in high-risk communities. Methods: Our overall objective is to reduce stimulant and opioid-involved overdoses in regions disproportionately affected by the overdose epidemic. To meet this long-term objective, we employ a multi-pronged approach to identify risk and protective factors for unintentional stimulant and opioid-involved overdoses among PWUS, and use these findings to develop a package of locally tailored intervention strategies that can be swiftly implemented to prevent overdoses. Specifically, this study aims to [1] Carry out mixed-methods research with incarcerated and non-incarcerated people who use or distribute illicit stimulants to identify risk and protective factors for stimulant and opioid-involved overdoses; [2] Conduct drug checking to examine the presence and relative quantity of fentanyl and other adulterants in the stimulant supply; and [3] Convene a series of working groups with community stakeholders involved in primary and secondary overdose prevention in Massachusetts and Rhode Island to contextualize our mixed-methods findings and identify multilevel intervention strategies to prevent stimulant-involved overdoses. Discussion: Completion of this study will yield a rich understanding of the social epidemiology of stimulant and opioid-involved overdoses in addition to community-derived intervention strategies that can be readily implemented and scaled to prevent such overdoses in two states disproportionately impacted by the opioid and overdose crises: Massachusetts and Rhode Island.

Implementation and Uptake of the Massachusetts Drug Supply Data Stream: A Statewide Public Health-Public Safety Partnership Drug Checking Program.

CONTEXT: The illicit drug supply is rapidly evolving. Equally important to gathering drug supply data for monitoring is timely sharing of information with people who use drugs, the providers who care for them, law enforcement partners, and public health stakeholders so that efforts to avoid harmful substances, take preventive actions, and better target interventions can occur. PROGRAM: The Massachusetts Drug Supply Data Stream (MADDS) is the country's first statewide community drug checking program. Founded on public health-public safety partnerships, MADDS collects remnant drug packaging and paraphernalia with residue from people who use drugs and noncriminal samples from partnering police departments. MADDS tests samples using simultaneous immunoassay fentanyl test strips, Fourier-transform infrared spectrometry (FTIR), and off-site laboratory testing by gas chromatography-mass spectrometry (GC/MS). Results are accessible to community programs and municipalities, while trend analyses inform public health for cross-site alerts and informational bulletins. IMPLEMENTATION: MADDS was launched statewide in 2020 and rapidly expanded to a multisite program. Program staff approached communities and met with municipal police and community partners to secure written agreements to host drug checking. Community partners designed sample collection consistent with their pandemic era workflows. Consultations with stakeholders gathered feedback on design and deliverables. EVALUATION: The program tests sample donations on-site from community agencies and police departments, incorporates review by a medical toxicologist for health and safety concerns, crafts stakeholder-specific communications, and disseminates English, Spanish, and Portuguese language materials. For 2020, a total of 427 samples were tested, of which 47.1% were positive for fentanyl. By early 2021, MADDS detected shifts in cocaine purity, alerted communities of a new toxic fentanyl analogue and a synthetic cannabinoid contaminant, and confirmed the increase of xylazine (a veterinary sedative) in Massachusetts. DISCUSSION: Community drug checking programs can be collaboratively designed with public health and public safety to generate critical health and safety information for people who use drugs and the communities where they live.

Classic Psychedelic Coadministration with Lithium, but Not Lamotrigine, is Associated with Seizures: An Analysis of Online Psychedelic Experience Reports.

INTRODUCTION: Psychedelics show promise in treating unipolar depression, though patients with bipolar disorder have been excluded from recent psychedelic trials. There is limited information on the use of classic psychedelics (e. g., LSD or psilocybin) in individuals using mood stabilizers to treat bipolar disorder. This is important to know, as individuals with bipolar depression may attempt to treat themselves with psychedelics while on a mood stabilizer, particularly given enthusiastic media reports of the efficacy of psilocybin for depression. METHODS: This study analyzed reports of classic psychedelics administered with mood stabilizers from 3 websites (Erowid.org, Shroomery.org, and Reddit.com). RESULTS: Strikingly, 47% of 62 lithium plus psychedelic reports involved seizures, and an additional 18% resulted in bad trips while none of 34 lamotrigine reports did. Further, 39% of lithium reports involved medical attention. Most of the lamotrigine reports (65%) but few (8%) of the lithium reports were judged to not affect the psychedelic experience. DISCUSSION: Although further research is needed, we provisionally conclude that psychedelic use may pose a significant seizure risk for patients on lithium.

Cessation and reduction in alcohol consumption and misuse after psychedelic use.

BACKGROUND: Meta-analysis of randomized studies using lysergic acid diethylamide (LSD) for alcohol use disorder (AUD) showed large, significant effects for LSD efficacy compared to control conditions. Clinical studies suggest potential anti-addiction effects of LSD and mechanistically-related classic psychedelics for alcohol and other substance use disorders. AIMS: To supplement clinical studies, reports of psychedelic use in naturalistic settings can provide further data regarding potential effects of psychedelics on alcohol use. METHODS: An anonymous online survey of individuals with prior AUD reporting cessation or reduction in alcohol use following psychedelic use in non-clinical settings. RESULTS: 343 respondents, mostly White (89%), males (78%), in the USA (60%) completed the survey. Participants reported seven years of problematic alcohol use on average before the psychedelic experience to which they attributed reduced alcohol consumption, with 72% meeting retrospective criteria for severe AUD. Most reported taking a moderate or high dose of LSD (38%) or psilocybin (36%), followed by significant reduction in alcohol consumption. After the psychedelic experience 83% no longer met AUD criteria. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced alcohol misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with a greater reduction in alcohol consumption, controlling for prior alcohol consumption and related distress. CONCLUSIONS: Although results cannot demonstrate causality, they suggest that naturalistic psychedelic use may lead to cessation or reduction in problematic alcohol use, supporting further investigation of psychedelic-assisted treatment for AUD.

Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports.

The real or perceived proximity to death often results in a non-ordinary state of consciousness characterized by phenomenological features such as the perception of leaving the body boundaries, feelings of peace, bliss and timelessness, life review, the sensation of traveling through a tunnel and an irreversible threshold. Near-death experiences (NDEs) are comparable among individuals of different cultures, suggesting an underlying neurobiological mechanism. Anecdotal accounts of the similarity between NDEs and certain drug-induced altered states of consciousness prompted us to perform a large-scale comparative analysis of these experiences. After assessing the semantic similarity between ≈15,000 reports linked to the use of 165 psychoactive substances and 625 NDE narratives, we determined that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine consistently resulted in reports most similar to those associated with NDEs. Ketamine was followed by Salvia divinorum (a plant containing a potent and selective κ receptor agonist) and a series of serotonergic psychedelics, including the endogenous serotonin 2A receptor agonist N,N-Dimethyltryptamine (DMT). This similarity was driven by semantic concepts related to consciousness of the self and the environment, but also by those associated with the therapeutic, ceremonial and religious aspects of drug use. Our analysis sheds light on the long-standing link between certain drugs and the experience of "dying", suggests that ketamine could be used as a safe and reversible experimental model for NDE phenomenology, and supports the speculation that endogenous NMDA antagonists with neuroprotective properties may be released in the proximity of death.

Persisting Reductions in Cannabis, Opioid, and Stimulant Misuse After Naturalistic Psychedelic Use: An Online Survey.

BACKGROUND: Observational data and preliminary studies suggest serotonin 2A agonist psychedelics may hold potential in treating a variety of substance use disorders (SUDs), including opioid use disorder (OUD). AIMS: The study aim was to describe and analyze self-reported cases in which naturalistic psychedelic use was followed by cessation or reduction in other substance use. METHODS: An anonymous online survey of individuals reporting cessation or reduction in cannabis, opioid, or stimulant use following psychedelic use in non-clinical settings. RESULTS: Four hundred forty-four respondents, mostly in the USA (67%) completed the survey. Participants reported 4.5 years of problematic substance use on average before the psychedelic experience to which they attributed a reduction in drug consumption, with 79% meeting retrospective criteria for severe SUD. Most reported taking a moderate or high dose of LSD (43%) or psilocybin-containing mushrooms (29%), followed by significant reduction in drug consumption. Before the psychedelic experience 96% met SUD criteria, whereas only 27% met SUD criteria afterward. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced substance misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with greater reduction in drug consumption. CONCLUSIONS: While these cross-sectional and self-report methods cannot determine whether psychedelics caused changes in drug use, results suggest the potential that psychedelics cause reductions in problematic substance use, and support additional clinical research on psychedelic-assisted treatment for SUD.

The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines.

Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user ("set") and the surroundings ("setting"). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics. The diversity of subjective effects elicited by different compounds has been attributed to the variables of "set" and "setting," to the binding affinities for other 5-HT receptor subtypes, and to the heterogeneity of transduction pathways initiated by conformational receptor states as they interact with different ligands ("functional selectivity"). Here we investigate the complementary (i.e., not mutually exclusive) possibility that such variety is also related to the binding affinity for a range of neurotransmitters and monoamine transporters including (but not limited to) 5-HT receptors. Building on two independent binding affinity datasets (compared to "in silico" estimates) in combination with natural language processing tools applied to a large repository of reports of psychedelic experiences (Erowid's Experience Vaults), we obtained preliminary evidence supporting that the similarity between the binding affinity profiles of psychoactive substituted phenethylamines and tryptamines is correlated with the semantic similarity of the associated reports. We also showed that the highest correlation was achieved by considering the combined binding affinity for the 5-HT, dopamine (DA), glutamate, muscarinic and opioid receptors and for the Ca+ channel. Applying dimensionality reduction techniques to the reports, we linked the compounds, receptors, transporters and the Ca+ channel to distinct fingerprints of the reported subjective effects. To the extent that the existing binding affinity data is based on a low number of displacement curves that requires further replication, our analysis produced preliminary evidence consistent with the involvement of different binding sites in the reported subjective effects elicited by psychedelics. Beyond the study of this particular class of drugs, we provide a methodological framework to explore the relationship between the binding affinity profiles and the reported subjective effects of other psychoactive compounds.

Corrigendum: The Experience Elicited by Hallucinogens Presents the Highest Similarity to Dreaming within a Large Database of Psychoactive Substance Reports.

[This corrects the article on p. 7 in vol. 12, PMID: 29403350.].

The Experience Elicited by Hallucinogens Presents the Highest Similarity to Dreaming within a Large Database of Psychoactive Substance Reports.

Ever since the modern rediscovery of psychedelic substances by Western society, several authors have independently proposed that their effects bear a high resemblance to the dreams and dreamlike experiences occurring naturally during the sleep-wake cycle. Recent studies in humans have provided neurophysiological evidence supporting this hypothesis. However, a rigorous comparative analysis of the phenomenology ("what it feels like" to experience these states) is currently lacking. We investigated the semantic similarity between a large number of subjective reports of psychoactive substances and reports of high/low lucidity dreams, and found that the highest-ranking substance in terms of the similarity to high lucidity dreams was the serotonergic psychedelic lysergic acid diethylamide (LSD), whereas the highest-ranking in terms of the similarity to dreams of low lucidity were plants of the Datura genus, rich in deliriant tropane alkaloids. Conversely, sedatives, stimulants, antipsychotics, and antidepressants comprised most of the lowest-ranking substances. An analysis of the most frequent words in the subjective reports of dreams and hallucinogens revealed that terms associated with perception ("see," "visual," "face," "reality," "color"), emotion ("fear"), setting ("outside," "inside," "street," "front," "behind") and relatives ("mom," "dad," "brother," "parent," "family") were the most prevalent across both experiences. In summary, we applied novel quantitative analyses to a large volume of empirical data to confirm the hypothesis that, among all psychoactive substances, hallucinogen drugs elicit experiences with the highest semantic similarity to those of dreams. Our results and the associated methodological developments open the way to study the comparative phenomenology of different altered states of consciousness and its relationship with non-invasive measurements of brain physiology.

Comparative Analysis of Opioid Queries on Erowid.org: An Opportunity to Advance Harm Reduction.

BACKGROUND: Many individuals who use opioids turn to online resources to gather information on effects, availability, and safety. OBJECTIVE: Describe opioid index page views on Erowid.org to assess trends in public interest in particular opioids. METHODS: Retrospective analysis of Erowid.org site traffic was performed to identify unique average daily visits to opioid pages. All data was normalized to that of visits to the heroin index page. Average daily visits to the index pages of each of 6 commonly abused opioids were assessed during the period of 2009 to 2015. Similarly, visits to 15 distinct opioid index pages at 5 time points (July, October 2014 and Jan, April, and July 2015) were described. RESULTS: From 2009 to 2015 a decrease in the number of page visits versus heroin (1.00) occurred for hydrocodone (0.87 to 0.59, -32%), oxycodone (1.38 to 0.99, -28%), and morphine (0.26 to 0.25, -6%). Increases in page visits compared to heroin occurred for fentanyl (0.18 to 0.47, +157%), tramadol (0.43 to 0.88, +106%), hydromorphone (0.19 to 0.24, +29%), and oxymorphone (0.11 to 0.13, +18%). Indexed to heroin (1.00) average opioid page visit frequencies from July 2014 to July 2015 were highest for oxycodone (1.02) and tramadol (0.81). Conclusion/Importance: Oxycodone and tramadol represent the greatest number of Erowid.org opioid page visits compared to heroin. The largest increase in visits over the study periods was for fentanyl and tramadol. The relationship of page visits on Erowid.org creates a unique opportunity for real-time evaluation of emerging drug trends and epidemiological study.

Experiences of Kratom Users: A Qualitative Analysis.

Kratom (Mitragyna speciosa) is a psychoactive plant that has been used since at least 1836 in folk medicine in Southeast Asian countries. More recently, kratom has become widely available in the West and is used for both recreational and medicinal purposes. There has, however, been little scientific research into the short- and long-term effects of kratom in humans, and much of the information available is anecdotal. To supplement the increasing scientific understanding of kratom's pharmacology and research into its effects in animals, we report the results of a qualitative analysis of first-hand descriptions of human kratom use that were submitted to, and published by, a psychoactive substance information website (Erowid.org). Themes that emerged from these experience reports indicate that kratom may be useful for analgesia, mood elevation, anxiety reduction, and may aid opioid withdrawal management. Negative response themes also emerged, indicating potential problems and unfavorable "side" effects, especially stomach upset and vomiting. Based on our analyses, we present preliminary hypotheses for future examination in controlled, quantitative studies of kratom.

Use patterns and self-reported effects of Salvia divinorum: an internet-based survey.

BACKGROUND: There is growing use of Salvia divinorum (SD), a psychoactive plant that produces hallucinogen-like effects through a kappa opioid receptor (KOR) mechanism. Little is known about KOR agonist effects in humans and about users of SD. OBJECTIVES: To characterize the reasons, methods, and reported consequences of SD use. METHODS: Individuals reading SD-related pages of a drug-information website were invited to anonymously complete an online questionnaire if they had used SD. RESULTS: Participants (N=500) were 92.6% male and 23.4 ± 8.7 (mean ± s.d.) years old. They had used a median of six times (range 1-250). 80.6% probably or definitely would use SD again. Most participants (92.6%) typically smoked or vaporized SD product. When smoked, the drug's main effects were estimated to last 14.1 ± 12.8 (range 0.5-120) minutes. When asked to compare SD effects to other methods of altering consciousness, the most common answer was that SD was unique (38.4%). 25.8% reported persisting (≥ 24 h) positive effects (often described as increased sense of well-being) on at least one occasion. 4.4% reported persisting negative effects (most often anxiety). CONCLUSIONS: SD is typically smoked, acute effects are brief, and persistent adverse effects are uncommon. In addition to acute hallucinogenic effects, SD may produce subacute increases in subjective well-being. Such a subacute effect would be unusual for a drug that is used non-medically, as withdrawal from other drugs typically either does not affect mood or causes dysphoria. Findings from this convenience sample should be confirmed and extended using surveys of random samples and controlled clinical studies.