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Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT 2A ) activation, whereas LSD-induced head twitching is dependent on 5-HT 2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT 2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects. Moliner et al. show that psychedelics directly bind to the BDNF receptor TrkB with high affinity and promote BDNF-mediated plasticity and antidepressant-like effects, whereas their hallucinogenic-like effects are independent of TrkB binding.

All modern clinical studies using the classic hallucinogen lysergic acid diethylamide (LSD) in healthy subjects or patients in the last 25 years are reviewed herein. There were five recent studies in healthy participants and one in patients. In a controlled setting, LSD acutely induced bliss, audiovisual synesthesia, altered meaning of perceptions, derealization, depersonalization, and mystical experiences. These subjective effects of LSD were mediated by the 5-HT receptor. LSD increased feelings of closeness to others, openness, trust, and suggestibility. LSD impaired the recognition of sad and fearful faces, reduced left amygdala reactivity to fearful faces, and enhanced emotional empathy. LSD increased the emotional response to music and the meaning of music. LSD acutely produced deficits in sensorimotor gating, similar to observations in schizophrenia. LSD had weak autonomic stimulant effects and elevated plasma cortisol, prolactin, and oxytocin levels. Resting-state functional magnetic resonance studies showed that LSD acutely reduced the integrity of functional brain networks and increased connectivity between networks that normally are more dissociated. LSD increased functional thalamocortical connectivity and functional connectivity of the primary visual cortex with other brain areas. The latter effect was correlated with subjective hallucinations. LSD acutely induced global increases in brain entropy that were associated with greater trait openness 14 days later. In patients with anxiety associated with life-threatening disease, anxiety was reduced for 2 months after two doses of LSD. In medical settings, no complications of LSD administration were observed. These data should contribute to further investigations of the therapeutic potential of LSD in psychiatry.

Drugs active at G protein–coupled receptors (GPCRs) can differentially modulate either canonical or noncanonical signaling pathways via a phenomenon known as functional selectivity or biased signaling. We report biochemical studies showing that the hallucinogen lysergic acid diethylamide, its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for β-arrestin signaling at the 5-HT 2B 5-hydroxytryptamine (5-HT) receptor, whereas they are relatively unbiased at the 5-HT 1B receptor. To investigate the structural basis for biased signaling, we determined the crystal structure of the human 5-HT 2B receptor bound to ERG and compared it with the 5-HT 1B /ERG structure. Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities.

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders 1 – 3 . These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT 2A (ref. 4 ). However, 5-HT 1A also plays a part in the behavioural effects of tryptamine hallucinogens 5 , particularly 5-methoxy- N,N -dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads 6 . Although 5-HT 1A is a validated therapeutic target 7 , 8 , little is known about how psychedelics engage 5-HT 1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT 1A , systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure–activity relationship analyses of 5-methoxytryptamines at both 5-HT 1A and 5-HT 2A enable the characterization of molecular determinants of 5-HT 1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT 1A agonists. We show that a 5-HT 1A -selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT 1A -targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders. Detailed analyses of the serotonin receptor 5-HT 1A and the psychedelic 5-methoxy- N,N -dimethyltryptamine reveal the differences in receptor structural pharmacology that mediate signalling specificity, efficacy and potency, findings that may facilitate the development of new neuropsychiatric therapeutics.

Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT 1B G protein–coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT 2B receptor, the 5-HT 1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.

Lysergic acid diethylamide (LSD) analogs, often referred to as new psychoactive substances, are synthesized to mimic controlled substances while evading drug regulations. This study emphasizes the challenges of identifying these compounds, particularly their isomeric forms. Gas chromatography–mass spectrometry (GC–MS) and UV spectroscopy were employed to analyze 13 LSD analogs. The effects of different solvents on the detection of these analogs were analyzed, demonstrating that solvents like diethyl ether, tert-butyl methyl ether, dichloromethane and acetone provided the best sensitivity and stability. Methanol, on the other hand, causes alcoholysis of many LSD analogs, which may lead to false results. Additionally, effective chromatographic separation of isomers was established, including LSD, MiPLA, LAMPA, 1P-LSD and 1P-MiPLA, as well as 1cP-LSD and 1cP-MiPLA, which is crucial for accurate identification. The elution order of the determined compounds with the use of developed chromatographic method was as follows: LSD, MiPLA, LAMPA, AL-LAD, LSZ, 2-Br-LSD, ALD-52, 1P-LSD, 1P-MiPLA, 1B-LSD, 1V-LSD, 1cP-LSD and 1cP-MiPLA. Differences in ion ratios observed in mass spectrometry (MS) were also analyzed to distinguish between closely related compounds. Several key ions for LSD analogs were able to be identified, including 221, 208, 207, 196, 194, 192, 181, 167, 154, 152 and 128 m/z. In analogs with an N-diethyl group (or variants like N-methyl-propyl in LAMPA or N-methyl-isopropyl in MiPLA), mass spectra showed fragments 100, 72 and 58 m/z. For LSZ, the cyclic group at R1 produces ions 98 and 70 m/z. Analogs with an N6 allyl group (e.g., AL-LAD) show a characteristic ion 247 m/z. This method allows for the correct differentiation of structural isomers based on their unique ion fragmentation patterns and relative intensities. UV spectroscopy was used as a supplementary tool for screening, though it has limitations in analyzing complex mixtures. This work contributes to the forensic identification of designer LSD analogs, ensuring reliable detection for legal and toxicological investigations.

Nanometric biocompatible Metal-Organic Frameworks (nanoMOFs) are promising candidates for drug delivery. Up to now, most studies have targeted the intravenous route, related to pain and severe complications; whereas nanoMOFs for oral administration, a commonly used non-invasive and simpler route, remains however unexplored. We propose here the biofriendly preparation of a suitable oral nanocarrier based on the benchmarked biocompatible mesoporous iron(III) trimesate nanoparticles coated with the bioadhesive polysaccharide chitosan (CS). This method does not hamper the textural/structural properties and the sorption/release abilities of the nanoMOFs upon surface engineering. The interaction between the CS and the nanoparticles has been characterized through a combination of high resolution soft X-ray absorption and computing simulation, while the positive impact of the coating on the colloidal and chemical stability under oral simulated conditions is here demonstrated. Finally, the intestinal barrier bypass capability and biocompatibility of CS-coated nanoMOF have been assessed in vitro , leading to an increased intestinal permeability with respect to the non-coated material, maintaining an optimal biocompatibility. In conclusion, the preservation of the interesting physicochemical features of the CS-coated nanoMOF and their adapted colloidal stability and progressive biodegradation, together with their improved intestinal barrier bypass, make these nanoparticles a promising oral nanocarrier.

RationaleThe lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds.ObjectiveIn this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens.MethodsCompetitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes.ResultsECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2 nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3 nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7 nmol/kg) was slightly less potent than ECPLA.ConclusionsThese findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.

Synthesis of the MIL-100 metal-organic framework particles was carried out by hydrothermal (HT) and microwave (MW)-assisted methods. Transmission electron microscopy showed formation of microparticles in the course of hydrothermal synthesis and nanoparticles for microwave-assisted synthesis. Powder X-ray diffraction confirmed formation of larger crystallites for hydrothermal synthesis. Particle aggregation in aqueous solution was observed by dynamic light scattering. However, the stability of both samples could be improved in acetic acid solution. Nitrogen sorption isotherms showed high porosity of the particles. ᶫ-leucine molecule was used as a model molecule for loading in the porous micro- and nanoparticles. Loading was estimated by FTIR spectroscopy and thermogravimetric analysis. UV-VIS spectroscopy quantified ᶫ-leucine release from the particles in aqueous solution. Cytotoxicity studies using the HeLa cell model showed that the original particles were somewhat toxic, but ᶫ-leucine loading ameliorated the toxic effects, likely due to signaling properties of the amino acid.

•Emerging new psychoactive substances are reviewed from user forums and available literature.•Four classes, namely psychostimulants, lefetamine-based compounds, hallucinogens and benzodiazepines are covered.•The effects of each of these materials and doses are described. The purpose of this review is to identify emerging or new psychoactive substances (NPS) by undertaking an online survey of the UK NPS market and to gather any data from online drug forums and published literature. Drugs from four main classes of NPS were identified: psychostimulants, dissociative anaesthetics, hallucinogens (phenylalkylamine-based and lysergamide-based materials) and finally benzodiazepines. For inclusion in the review, the ‘user reviewers’ on drugs forums were selected based on whether or not the particular NPS of interest was used alone or in combination. NPS that were used alone were considered. Each of the classes contained drugs that are modelled on existing illegal materials and will be covered by the UK New Psychoactive Substances Bill in 2016.