A tale of two copies: Evolutionary trajectories of moth pheromone receptors.

Pheromone communication is an essential component of reproductive isolation in animals. As such, evolution of pheromone signaling can be linked to speciation. For example, the evolution of sex pheromones is thought to have played a major role in the diversification of moths. In the crop pests Spodoptera littoralis and S. litura, the major component of the sex pheromone blend is (Z,E)-9,11-tetradecadienyl acetate, which is lacking in other Spodoptera species. It indicates that a major shift occurred in their common ancestor. It has been shown recently in S. littoralis that this compound is detected with high specificity by an atypical pheromone receptor, named SlitOR5. Here, we studied its evolutionary history through functional characterization of receptors from different Spodoptera species. SlitOR5 orthologs in S. exigua and S. frugiperda exhibited a broad tuning to several pheromone compounds. We evidenced a duplication of OR5 in a common ancestor of S. littoralis and S. litura and found that in these two species, one duplicate is also broadly tuned while the other is specific to (Z,E)-9,11-tetradecadienyl acetate. By using ancestral gene resurrection, we confirmed that this narrow tuning evolved only in one of the two copies issued from the OR5 duplication. Finally, we identified eight amino acid positions in the binding pocket of these receptors whose evolution has been responsible for narrowing the response spectrum to a single ligand. The evolution of OR5 is a clear case of subfunctionalization that could have had a determinant impact in the speciation process in Spodoptera species.

Cannabis Significantly Reduces the Use of Prescription Opioids and Improves Quality of Life in Authorized Patients: Results of a Large Prospective Study.

OBJECTIVES: This article presents findings from a large prospective examination of Canadian medical cannabis patients, with a focus on the impacts of cannabis on prescription opioid use and quality of life over a 6-month period. METHODS: The Tilray Observational Patient Study took place at 21 medical clinics throughout Canada. This analysis includes 1,145 patients who had at least one postbaseline visit, with follow-up at 1, 3, and 6 months. Instruments included a comprehensive cannabis use inventory, the World Health Organization Quality of Life Short Form (WHOQOL-BREF), and a detailed prescription drug questionnaire. RESULTS: Participants were 57.6% female, with a median age of 52 years. Baseline opioid use was reported by 28% of participants, dropping to 11% at 6 months. Daily opioid use went from 152 mg morphine milligram equivalent (MME) at baseline to 32.2 mg MME at 6 months, a 78% reduction in mean opioid dosage. Similar reductions were also seen in the other four primary prescription drug classes identified by participants, and statistically significant improvements were reported in all four domains of the WHOQOL-BREF. CONCLUSIONS: This study provides an individual-level perspective of cannabis substitution for opioids and other prescription drugs, as well as associated improvement in quality of life over 6 months. The high rate of cannabis use for chronic pain and the subsequent reductions in opioid use suggest that cannabis may play a harm reduction role in the opioid overdose crisis, potentially improving the quality of life of patients and overall public health.

Light-Weight Portable Electroantennography Device as a Future Field-Based Tool for Applied Chemical Ecology.

Portable electroantennograms (pEAG) can further our understanding of odor plume dynamics and complement laboratory-based electroantennogram tools. pEAG's can help to address important questions such as the influence of plume structure on insect behavior, the active space of semiochemical-baited traps, and the impact of biotic and abiotic factors on this active space. Challenges associated with pEAGs include their miniaturization and sensitivity, confounding environmental odors, and processing of data. Here, we describe a pEAG built with modern engineering hardware and techniques that is portable in being both light in weight (516 g) and smaller (12 × 12 × 8 cm, volume 1152 cm3) than earlier models. It is able to incorporate insects of a range of sizes (4 to 30 mm antennal length), has wireless communication (communication range of 600 m urban, 10 km line of sight), a stand-alone power supply, and uses both antennae of the test insect. We report normalized antennal responses from Epiphyas postvittana in a dose response experiment where our pEAG compared favorably with traditional laboratory EAG equipment for this species. Dose-response comparisons between E. postvittana, Agrotis ipsilon, and Lymantria dispar dispar showed mean detection limits from a pheromone source dose of 100, 100, and 1 ng, respectively, for our pEAG. This pEAG should allow future real-time analysis of EAG responses in the field in research on how insects interact with odor plumes and the factors that influence the active space of semiochemical-baited traps.

Moth olfactory receptor neurons adjust their encoding efficiency to temporal statistics of pheromone fluctuations.

The efficient coding hypothesis predicts that sensory neurons adjust their coding resources to optimally represent the stimulus statistics of their environment. To test this prediction in the moth olfactory system, we have developed a stimulation protocol that mimics the natural temporal structure within a turbulent pheromone plume. We report that responses of antennal olfactory receptor neurons to pheromone encounters follow the temporal fluctuations in such a way that the most frequent stimulus timescales are encoded with maximum accuracy. We also observe that the average coding precision of the neurons adjusted to the stimulus-timescale statistics at a given distance from the pheromone source is higher than if the same encoding model is applied at a shorter, non-matching, distance. Finally, the coding accuracy profile and the stimulus-timescale distribution are related in the manner predicted by the information theory for the many-to-one convergence scenario of the moth peripheral sensory system.

Medical cannabis patterns of use and substitution for opioids & other pharmaceutical drugs, alcohol, tobacco, and illicit substances; results from a cross-sectional survey of authorized patients.

BACKGROUND: A 239-question cross-sectional survey was sent out via email in January 2017 to gather comprehensive information on cannabis use from Canadian medical cannabis patients registered with a federally authorized licensed cannabis producer, resulting in 2032 complete surveys. METHODS: The survey gathered detailed demographic data and comprehensive information on patient patterns of medical cannabis use, including questions assessing the self-reported impact of cannabis on the use of prescription drugs, illicit substances, alcohol, and tobacco. RESULTS: Participants were 62.6% male (n = 1271) and 91% Caucasian (n = 1839). The mean age was 40 years old, and pain and mental health conditions accounted for 83.7% of all respondents (n = 1700). Then, 74.6% of respondents reported daily cannabis use (n = 1515) and mean amount used per day was 1.5 g. The most commonly cited substitution was for prescription drugs (69.1%, n = 953), followed by alcohol (44.5%, n = 515), tobacco (31.1%, n = 406), and illicit substances (26.6%, n = 136). Opioid medications accounted for 35.3% of all prescription drug substitution (n = 610), followed by antidepressants (21.5%, n = 371). Of the 610 mentions of specific opioid medications, patients report total cessation of use of 59.3% (n = 362). CONCLUSIONS: This study offers a unique perspective by focusing on the use of a standardized, government-regulated source of medical cannabis by patients registered in Canada's federal medical cannabis program. The findings provide a granular view of patient patterns of medical cannabis use, and the subsequent self-reported impacts on the use of opioids, alcohol, and other substances, adding to a growing body of academic research suggesting that increased regulated access to medical and recreational cannabis can result in a reduction in the use of and subsequent harms associated with opioids, alcohol, tobacco, and other substances.

Comparison of Chemoreceptive Abilities of the Hydrothermal Shrimp Mirocaris fortunata and the Coastal Shrimp Palaemon elegans.

Chemoreception might play an important role for endemic shrimp that inhabit deep and dark hydrothermal vents to find food sources and to locate active edifices that release specific chemicals. We compared the chemosensory abilities of the hydrothermal shrimp Mirocaris fortunata and the coastal related species, Palaemon elegans. The detection of diverse ecologically relevant chemical stimuli by the antennal appendages was measured with electroantennography. The 2 species can detect food-related odor and sulfide, a short-distance stimulus, via both their antennae and antennules. Neither iron nor manganese, considered as long-distance stimuli, was detected by the antennal appendages. Investigation of the ultrastructure of aesthetasc sensilla revealed no specific features of the hydrothermal species regarding innervation by olfactory sensory neurons. Pore-like structures occurring in the aesthetasc cuticle and dense bacterial covering seem to be unique to hydrothermal species, but their potential link to chemoreception remains elusive.

Olfactory coding in the turbulent realm.

Long-distance olfactory search behaviors depend on odor detection dynamics. Due to turbulence, olfactory signals travel as bursts of variable concentration and spacing and are characterized by long-tail distributions of odor/no-odor events, challenging the computing capacities of olfactory systems. How animals encode complex olfactory scenes to track the plume far from the source remains unclear. Here we focus on the coding of the plume temporal dynamics in moths. We compare responses of olfactory receptor neurons (ORNs) and antennal lobe projection neurons (PNs) to sequences of pheromone stimuli either with white-noise patterns or with realistic turbulent temporal structures simulating a large range of distances (8 to 64 m) from the odor source. For the first time, we analyze what information is extracted by the olfactory system at large distances from the source. Neuronal responses are analyzed using linear-nonlinear models fitted with white-noise stimuli and used for predicting responses to turbulent stimuli. We found that neuronal firing rate is less correlated with the dynamic odor time course when distance to the source increases because of improper coding during long odor and no-odor events that characterize large distances. Rapid adaptation during long puffs does not preclude however the detection of puff transitions in PNs. Individual PNs but not individual ORNs encode the onset and offset of odor puffs for any temporal structure of stimuli. A higher spontaneous firing rate coupled to an inhibition phase at the end of PN responses contributes to this coding property. This allows PNs to decode the temporal structure of the odor plume at any distance to the source, an essential piece of information moths can use in their tracking behavior.

Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort.

BACKGROUND: Medicinal cannabis registries typically report pain as the most common reason for use. It would be clinically useful to identify patterns of cannabis treatment in migraine and headache, as compared to arthritis and chronic pain, and to analyze preferred cannabis strains, biochemical profiles, and prescription medication substitutions with cannabis. METHODS: Via electronic survey in medicinal cannabis patients with headache, arthritis, and chronic pain, demographics and patterns of cannabis use including methods, frequency, quantity, preferred strains, cannabinoid and terpene profiles, and prescription substitutions were recorded. Cannabis use for migraine among headache patients was assessed via the ID Migraine™ questionnaire, a validated screen used to predict the probability of migraine. RESULTS: Of 2032 patients, 21 illnesses were treated with cannabis. Pain syndromes accounted for 42.4% (n = 861) overall; chronic pain 29.4% (n = 598;), arthritis 9.3% (n = 188), and headache 3.7% (n = 75;). Across all 21 illnesses, headache was a symptom treated with cannabis in 24.9% (n = 505). These patients were given the ID Migraine™ questionnaire, with 68% (n = 343) giving 3 "Yes" responses, 20% (n = 102) giving 2 "Yes" responses (97% and 93% probability of migraine, respectively). Therefore, 88% (n = 445) of headache patients were treating probable migraine with cannabis. Hybrid strains were most preferred across all pain subtypes, with "OG Shark" the most preferred strain in the ID Migraine™ and headache groups. Many pain patients substituted prescription medications with cannabis (41.2-59.5%), most commonly opiates/opioids (40.5-72.8%). Prescription substitution in headache patients included opiates/opioids (43.4%), anti-depressant/anti-anxiety (39%), NSAIDs (21%), triptans (8.1%), anti-convulsants (7.7%), muscle relaxers (7%), ergots (0.4%). CONCLUSIONS: Chronic pain was the most common reason for cannabis use, consistent with most registries. The majority of headache patients treating with cannabis were positive for migraine. Hybrid strains were preferred in ID Migraine™, headache, and most pain groups, with "OG Shark", a high THC (Δ9-tetrahydrocannabinol)/THCA (tetrahydrocannabinolic acid), low CBD (cannabidiol)/CBDA (cannabidiolic acid), strain with predominant terpenes ß-caryophyllene and ß-myrcene, most preferred in the headache and ID Migraine™ groups. This could reflect the potent analgesic, anti-inflammatory, and anti-emetic properties of THC, with anti-inflammatory and analgesic properties of ß-caryophyllene and ß-myrcene. Opiates/opioids were most commonly substituted with cannabis. Prospective studies are needed, but results may provide early insight into optimizing crossbred cannabis strains, synergistic biochemical profiles, dosing, and patterns of use in the treatment of headache, migraine, and chronic pain syndromes.

Rationale for cannabis-based interventions in the opioid overdose crisis.

BACKGROUND: North America is currently in the grips of a crisis rooted in the use of licit and illicit opioid-based analgesics. Drug overdose is the leading cause of accidental death in Canada and the US, and the growing toll of opioid-related morbidity and mortality requires a diversity of novel therapeutic and harm reduction-based interventions. Research suggests that increasing adult access to both medical and recreational cannabis has significant positive impacts on public health and safety as a result of substitution effect. Observational and epidemiological studies have found that medical cannabis programs are associated with a reduction in the use of opioids and associated morbidity and mortality. AIMS AND METHODS: This paper presents an evidence-based rationale for cannabis-based interventions in the opioid overdose crisis informed by research on substitution effect, proposing three important windows of opportunity for cannabis for therapeutic purposes (CTP) to play a role in reducing opioid use and interrupting the cycle towards opioid use disorder: 1) prior to opioid introduction in the treatment of chronic pain; 2) as an opioid reduction strategy for those patients already using opioids; and 3) as an adjunct therapy to methadone or suboxone treatment in order to increase treatment success rates. The commentary explores potential obstacles and limitations to these proposed interventions, and as well as strategies to monitor their impact on public health and safety. CONCLUSION: The growing body of research supporting the medical use of cannabis as an adjunct or substitute for opioids creates an evidence-based rationale for governments, health care providers, and academic researchers to consider the implementation and assessment of cannabis-based interventions in the opioid crisis.

Low doses of a neonicotinoid insecticide modify pheromone response thresholds of central but not peripheral olfactory neurons in a pest insect.

Insect pest management relies mainly on neurotoxic insecticides, including neonicotinoids, leaving residues in the environment. There is now evidence that low doses of insecticides can have positive effects on pest insects by enhancing various life traits. Because pest insects often rely on sex pheromones for reproduction, and olfactory synaptic transmission is cholinergic, neonicotinoid residues could modify chemical communication. We recently showed that treatments with different sublethal doses of clothianidin could either enhance or decrease behavioural sex pheromone responses in the male moth, Agrotis ipsilon. We investigated now effects of the behaviourally active clothianidin doses on the sensitivity of the peripheral and central olfactory system. We show with extracellular recordings that both tested clothianidin doses do not influence pheromone responses in olfactory receptor neurons. Similarly, in vivo optical imaging does not reveal any changes in glomerular response intensities to the sex pheromone after clothianidin treatments. The sensitivity of intracellularly recorded antennal lobe output neurons, however, is upregulated by a lethal dose 20 times and downregulated by a dose 10 times lower than the lethal dose 0. This correlates with the changes of behavioural responses after clothianidin treatment and suggests the antennal lobe as neural substrate involved in clothianidin-induced behavioural changes.

New electroantennography method on a marine shrimp in water.

Antennular chemoreception in aquatic decapods is well studied via the recording of single chemoreceptor neuron activity in the antennule, but global responses of the antennule (or antennae in insects) by electroantennography (EAG) has so far been mainly restricted to aerial conditions. We present here a well-established underwater EAG method to record the global antennule activity in the marine shrimp Palaemon elegans in natural (aqueous) conditions. EAG responses to food extracts, recorded as net positive deviations of the baseline, are reproducible, dose-dependent and exhibit sensory adaptation. This new EAG method opens a large field of possibilities for studying in vivo antennular chemoreception in aquatic decapods, in a global approach to supplement current, more specific techniques.

Reactive searching and infotaxis in odor source localization.

Male moths aiming to locate pheromone-releasing females rely on stimulus-adapted search maneuvers complicated by a discontinuous distribution of pheromone patches. They alternate sequences of upwind surge when perceiving the pheromone and cross- or downwind casting when the odor is lost. We compare four search strategies: three reactive versus one cognitive. The former consist of pre-programmed movement sequences triggered by pheromone detections while the latter uses Bayesian inference to build spatial probability maps. Based on the analysis of triphasic responses of antennal lobe neurons (On, inhibition, Off), we propose three reactive strategies. One combines upwind surge (representing the On response to a pheromone detection) and spiral casting, only. The other two additionally include crosswind (zigzag) casting representing the Off phase. As cognitive strategy we use the infotaxis algorithm which was developed for searching in a turbulent medium. Detection events in the electroantennogram of a moth attached to a robot indirectly control this cyborg, depending on the strategy in use. The recorded trajectories are analyzed with regard to success rates, efficiency, and other features. In addition, we qualitatively compare our robotic trajectories to behavioral search paths. Reactive searching is more efficient (yielding shorter trajectories) for higher pheromone doses whereas cognitive searching works better for lower doses. With respect to our experimental conditions (2 m from starting position to pheromone source), reactive searching with crosswind zigzag yields the shortest trajectories (for comparable success rates). Assuming that the neuronal Off response represents a short-term memory, zigzagging is an efficient movement to relocate a recently lost pheromone plume. Accordingly, such reactive strategies offer an interesting alternative to complex cognitive searching.

Heterogeneity and convergence of olfactory first-order neurons account for the high speed and sensitivity of second-order neurons.

In the olfactory system of male moths, a specialized subset of neurons detects and processes the main component of the sex pheromone emitted by females. It is composed of several thousand first-order olfactory receptor neurons (ORNs), all expressing the same pheromone receptor, that contact synaptically a few tens of second-order projection neurons (PNs) within a single restricted brain area. The functional simplicity of this system makes it a favorable model for studying the factors that contribute to its exquisite sensitivity and speed. Sensory information--primarily the identity and intensity of the stimulus--is encoded as the firing rate of the action potentials, and possibly as the latency of the neuron response. We found that over all their dynamic range, PNs respond with a shorter latency and a higher firing rate than most ORNs. Modelling showed that the increased sensitivity of PNs can be explained by the ORN-to-PN convergent architecture alone, whereas their faster response also requires cell-to-cell heterogeneity of the ORN population. So, far from being detrimental to signal detection, the ORN heterogeneity is exploited by PNs, and results in two different schemes of population coding based either on the response of a few extreme neurons (latency) or on the average response of many (firing rate). Moreover, ORN-to-PN transformations are linear for latency and nonlinear for firing rate, suggesting that latency could be involved in concentration-invariant coding of the pheromone blend and that sensitivity at low concentrations is achieved at the expense of precise encoding at high concentrations.

Co-use of psychedelics with other substances: Findings from the global psychedelic survey.

BACKGROUND/AIMS: While most psychedelic substances are considered to carry a relatively low risk of acute or long-term harm, co-use with other psychoactive substances may increase health and social harm. Using a large international survey of adults who use psychedelics, we sought to comprehensively characterize psychedelic co-use. METHODS: We used data from the 2023 Global Psychedelic Survey, a web-based survey of adults ⩾21 with lifetime use of psychedelics. We explored patterns of co-use (prevalence, secondary substances used, timing, and motives of co-use) and examined sociodemographic and psychedelic use-related characteristics associated with co-use overall and by specific psychedelics. RESULTS: In total, 5370 respondents were included in this analysis, of whom 3228 (56.3%) reported typically co-using at least one of the 11 psychedelic substances of interest, with co-use lowest for ayahuasca (14.8%) and highest for nitrous oxide (54.5%). Cannabis and alcohol were the most common secondary substances. Depressants were the only secondary substance class that increased in use following psychedelic experiences. Greater experience with psychedelics was significantly associated with co-use, as was using for recreational purposes or to reduce/substitute the use of other substances. Personal exploration and therapeutic purposes for psychedelic use were negatively associated with co-use. CONCLUSIONS: In this detailed analysis of psychedelic co-use, we observed high rates of co-use with certain psychedelics, specifically when used recreationally. Our findings highlight psychedelic-specific consumers for whom harm reduction messaging around co-use practices may be best tailored. Further research is justified to assess whether specific patterns of co-use might reduce or increase potential harms.

The Global Psychedelic Survey: Consumer characteristics, patterns of use, and access in primarily anglophone regions around the world.

OBJECTIVES: Despite advancements in policies governing psychedelic substances globally, our understanding of real-world psychedelic use and its variations across international jurisdictions remains limited. We implemented the Global Psychedelic Survey (GPS) to capture information about psychedelic consumer characteristics, access, and usage patterns around the world. METHODS: The GPS was administered online in Spring 2023 to English-speaking adults (≥21 years) who use(d) psychedelics. We categorized survey responses into major catchment regions (Canada/US, Europe/UK, Australia/NZ, All Other). We used descriptive and bivariable statistics to characterize consumers' socio-demographic characteristics, psychedelic access sources, and usage patterns. We examined regional differences in psychedelic use patterns using multinomial logistic regression. RESULTS: We analyzed 6379 responses from 85 countries including Canada/US (n = 4434), Europe/UK (n = 771), Australia/NZ (n = 864), and Other (n = 310). Psilocybin, LSD, and MDMA were the most used psychedelics and personal growth was the most common use motive across all catchments. There were significant regional differences in psychedelic use patterns, including types of psychedelics used (e.g., less ibogaine use in Europe/UK and Australia/NZ relative to Canada/US), frequency of use (e.g., lower frequency use in Australia/NZ relative to Canada/US), motivations for use (e.g., less therapeutic use in Europe/UK and Other relative to Canada/US), and types of dosing regimens (e.g., more "micro"-dosing in Canada/US). DISCUSSION: In this large sample of adult psychedelic consumers from regions around the world, infrequent psychedelic use centered around life enhancement was common. Respondents indicated preference for legal access via quality-controlled sources. Jurisdictional differences in access and usage patterns likely reflect region-specific regulations and traditional practices. Further research should explore opportunities to increase representation of non-White respondents in psychedelic research via translation of studies into several languages and incorporation of culturally reflective, community-based study development.

Protocol for aerial trapping and analyses of candidate pheromone compounds released by moths via gas chromatography-mass spectrometry.

Detection of pheromones is pivotal to chemical ecology and agronomy; however, analytic detection of the volatile pheromone components from odorized air is highly challenging. Here, we introduce a protocol for the detection of airborne pheromones from female moths, which are key models for chemosensory studies. We describe a step-by-step guide from pheromone collection to quantitative estimation of pheromone components. We also detail procedures for gas chromatography-mass spectrometry (GC-MS) analysis. This protocol has potential applications beyond chemosensory research, particularly in environmental chemistry. For complete details on the use and execution of this protocol, please refer to Ghosh et al.1.

Age-related Patterns of Medical Cannabis Use: A Survey of Authorized Patients in Canada.

Objective: An increasing number of Canadians are registering as authorized users of medical cannabis. Older patients comprise a growing subset of this population; however, relatively little information exists around age-related patterns of medical cannabis use. Methods: The Canadian Cannabis Patient Survey (CCPS) is a large cross-sectional survey of authorized medical cannabis patients in Canada. This publication summarizes the results of the CCPS 2021, with a focus on age-related outcomes and the elderly sub-population. Results: The survey was completed by 2,697 patients. The mean age of participants was 54.3 years of age and the proportion of female respondents was 49.1%. Among older patients, pain was the most common symptom, while anxiety was the most common symptom reported by younger patients. Older patients exhibited a significant preference for oral administration over inhalation of medical cannabis when compared to younger patients, respectively (p>0.05). Among patients taking prescription opioids, most of whom were older patients, 54% reported a decrease in use concurrent with medical cannabis. Conclusions: Older patients comprise a growing subset of medical cannabis patients, which is also reflected in CCPS participants over time. This patient population exhibits different patterns of use compared to their younger counterparts, preferring high CBD orally ingested formulations, which they use primarily to treat pain-related illnesses/symptoms. Overall, study participants reported that cannabis had a high degree of efficacy in alleviating their illness/symptoms, and many reported a reduction in their use of prescription opioids, alcohol, tobacco, and other substances.

Stimulus duration encoding occurs early in the moth olfactory pathway.

Pheromones convey rich ethological information and guide insects' search behavior. Insects navigating in turbulent environments are tasked with the challenge of coding the temporal structure of an odor plume, obliging recognition of the onset and offset of whiffs of odor. The coding mechanisms that shape odor offset recognition remain elusive. We designed a device to deliver sharp pheromone pulses and simultaneously measured the response dynamics from pheromone-tuned olfactory receptor neurons (ORNs) in male moths and Drosophila. We show that concentration-invariant stimulus duration encoding is implemented in moth ORNs by spike frequency adaptation at two time scales. A linear-nonlinear model fully captures the underlying neural computations and offers an insight into their biophysical mechanisms. Drosophila use pheromone cis-vaccenyl acetate (cVA) only for very short distance communication and are not faced with the need to encode the statistics of the cVA plume. Their cVA-sensitive ORNs are indeed unable to encode odor-off events. Expression of moth pheromone receptors in Drosophila cVA-sensitive ORNs indicates that stimulus-offset coding is receptor independent. In moth ORNs, stimulus-offset coding breaks down for short ( < 200 ms) whiffs. This physiological constraint matches the behavioral latency of switching from the upwind surge to crosswind cast flight upon losing contact with the pheromone.

Psychedelic substitution: altered substance use patterns following psychedelic use in a global survey.

Introduction: Recent research suggests that psychedelics may have potential for the treatment of various substance use disorders. However, most studies to date have been limited by small sample sizes and neglecting to include non-North American and European populations. Methods: We conducted a global, cross-sectional online survey of adults (n = 5,268, 47.2% women) self-reporting past or current psychedelic use and investigated whether psychedelic use was associated with changes in use of other substances. Results: Nearly three-quarters (70.9%; n = 3,737/5,268) reported ceasing or decreasing use of one or more non-psychedelic substances after naturalistic psychedelic use. Among those with previous use, 60.6% (n = 2,634/4,344) decreased alcohol use, 55.7% (n = 1,223/2,197) decreased antidepressant use, and 54.2% (n = 767/1,415) decreased use of cocaine/crack. Over a quarter of the sample indicated that their decrease in substance use persisted for 26 weeks or more following use of a psychedelic. Factors associated with decreased use included a motivation to either decrease one's substance use or self-treat a medical condition. Importantly, 19.8% of respondents also reported increased or initiated use of one or more other substances after psychedelic use, with illicit opioids (14.7%; n = 86/584) and cannabis (13.3%; n = 540/4,064) having the highest proportions. Factors associated with increased substance use included having a higher income and residing in Canada or the US. Discussion: Although limited by cross-sectional study design, this large observational study will help inform future studies aiming to investigate the relationship between substance use patterns and psychedelic use.

A carboxylesterase, Esterase-6, modulates sensory physiological and behavioral response dynamics to pheromone in Drosophila.

BACKGROUND: Insects respond to the spatial and temporal dynamics of a pheromone plume, which implies not only a strong response to 'odor on', but also to 'odor off'. This requires mechanisms geared toward a fast signal termination. Several mechanisms may contribute to signal termination, among which odorant-degrading enzymes. These enzymes putatively play a role in signal dynamics by a rapid inactivation of odorants in the vicinity of the sensory receptors, although direct in vivo experimental evidences are lacking. Here we verified the role of an extracellular carboxylesterase, esterase-6 (Est-6), in the sensory physiological and behavioral dynamics of Drosophila melanogaster response to its pheromone, cis-vaccenyl acetate (cVA). Est-6 was previously linked to post-mating effects in the reproductive system of females. As Est-6 is also known to hydrolyze cVA in vitro and is expressed in the main olfactory organ, the antenna, we tested here its role in olfaction as a putative odorant-degrading enzyme. RESULTS: We first confirm that Est-6 is highly expressed in olfactory sensilla, including cVA-sensitive sensilla, and we show that expression is likely associated with non-neuronal cells. Our electrophysiological approaches show that the dynamics of olfactory receptor neuron (ORN) responses is strongly influenced by Est-6, as in Est-6° null mutants (lacking the Est-6 gene) cVA-sensitive ORN showed increased firing rate and prolonged activity in response to cVA. Est-6° mutant males had a lower threshold of behavioral response to cVA, as revealed by the analysis of two cVA-induced behaviors. In particular, mutant males exhibited a strong decrease of male-male courtship, in association with a delay in courtship initiation. CONCLUSIONS: Our study presents evidence that Est-6 plays a role in the physiological and behavioral dynamics of sex pheromone response in Drosophila males and supports a role of Est-6 as an odorant-degrading enzyme (ODE) in male antennae. Our results also expand the role of Est-6 in Drosophila biology, from reproduction to olfaction, and highlight the role of ODEs in insect olfaction.