Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential

doi:10.1038/s41467-023-44016-1

. 2023 Dec 15;14(1):8221.

doi: 10.1038/s41467-023-44016-1.

Identification of 5-HT_2A receptor signaling pathways associated with psychedelic potential

Jason Wallach¹, Andrew B Cao², Maggie M Calkins², Andrew J Heim^{3

4}, Janelle K Lanham², Emma M Bonniwell², Joseph J Hennessey², Hailey A Bock², Emilie I Anderson², Alexander M Sherwood⁵, Hamilton Morris⁶, Robbin de Klein⁷, Adam K Klein^{8

9}, Bruna Cuccurazzu⁸, James Gamrat⁶, Tilka Fannana⁶, Randy Zauhar^{3

10}, Adam L Halberstadt^{11

12

13}, John D McCorvy^{14

15

16}

Affiliations

¹ Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA. jwallach@sju.edu.
² Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
³ Department of Chemistry, Saint Joseph's University, Philadelphia, PA, 19104, USA.
⁴ Chemical Computing Group ULC, 910-1010 Sherbrooke W, Montréal, QC, H3A 2R7, Canada.
⁵ Usona Institute, Madison, WI, 53711, USA.
⁶ Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA.
⁷ Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA.
⁸ Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA.
⁹ Gilgamesh Pharmaceuticals, New York, NY, 10003, USA.
¹⁰ Artemis Discovery, LLC, Suite 300, 709 N 2nd Street, Philadelphia, PA, 19123, USA.
¹¹ Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA. ahalberstadt@health.ucsd.edu.
¹² Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA. ahalberstadt@health.ucsd.edu.
¹³ Center for Psychedelic Research, University of California San Diego, La Jolla, CA, 92093, USA. ahalberstadt@health.ucsd.edu.
¹⁴ Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.
¹⁵ Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.
¹⁶ Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.

PMID: 38102107
PMCID: PMC10724237
DOI: 10.1038/s41467-023-44016-1

Identification of 5-HT_2A receptor signaling pathways associated with psychedelic potential

Jason Wallach et al. Nat Commun. 2023.

. 2023 Dec 15;14(1):8221.

doi: 10.1038/s41467-023-44016-1.

Authors

Affiliations

¹ Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA. jwallach@sju.edu.
² Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
³ Department of Chemistry, Saint Joseph's University, Philadelphia, PA, 19104, USA.
⁴ Chemical Computing Group ULC, 910-1010 Sherbrooke W, Montréal, QC, H3A 2R7, Canada.
⁵ Usona Institute, Madison, WI, 53711, USA.
⁶ Department of Pharmaceutical Sciences, Saint Joseph's University, Philadelphia, PA, 19104, USA.
⁷ Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA.
⁸ Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA.
⁹ Gilgamesh Pharmaceuticals, New York, NY, 10003, USA.
¹⁰ Artemis Discovery, LLC, Suite 300, 709 N 2nd Street, Philadelphia, PA, 19123, USA.
¹¹ Research Service, VA San Diego Healthcare System, San Diego, CA, 92161, USA. ahalberstadt@health.ucsd.edu.
¹² Department of Psychiatry, University of California San Diego, La Jolla, CA, 92093, USA. ahalberstadt@health.ucsd.edu.
¹³ Center for Psychedelic Research, University of California San Diego, La Jolla, CA, 92093, USA. ahalberstadt@health.ucsd.edu.
¹⁴ Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.
¹⁵ Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.
¹⁶ Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. jmccorvy@mcw.edu.

PMID: 38102107
PMCID: PMC10724237
DOI: 10.1038/s41467-023-44016-1

Abstract

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT_2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT_2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT_2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT_2A-Gq but not 5-HT_2A-β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT_2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT_2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT_2A agonists. We also demonstrate that β-arrestin-biased 5-HT_2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT_2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.

PubMed Disclaimer

Conflict of interest statement

JW, ALH, and JDM submitted a patent application for the compounds in this study entitled “Selective, partial, and arrestin-biased 5-HT_2A agonists with utility in various disorders,” PCT WO2022241006A1. AKK is currently an employee of Gilgamesh Pharmaceuticals. All other authors declare no competing interests.

Figures

**Fig. 1. Psychedelics exhibit similar Gq and β-arrestin2 activity at 5-HT_2AR.**
Schematic of 5-HT_2A receptor G protein dissociation (A) and β-arrestin recruitment (B) to determine transducer preferences. (C) Determination of 5-HT_2A receptor G protein-wide and β-arrestin1/2 transducer preferences as estimated by magnitude net BRET for each transducer as stimulated by 5-HT. Data represent the mean and SEM from three independent experiments, which were performed at 37 °C with 60-minute compound incubations. D-K Comparison of 5-HT_2A receptor Gq dissociation (red) and β-arrestin2 recruitment (blue) for 5-HT (D) and several classes of psychedelics: (E) Psilocin, (F) DMT, (G) 5-MeO-DMT, (H) 2C-I, (I) DOI, (J) 25I-NBOMe, K LSD. Data represent the mean and SEM from three independent experiments, which were performed at 37 °C with 60-minute compound incubations. L Heat map of Gq dissociation and β-arrestin2 recruitment kinetics displayed as log (E_MAX/EC₅₀) for the psychedelics tested. Data represent the mean and SEM from three independent experiments, which were performed at 37 °C at the indicated compound incubation time points. Source data are provided as a Source Data file.

**Fig. 2. Rational design of a 5-HT_2A-selective agonist template.**
A N-Benzylation of 25N **(1)** to 25N-NB **(2)** leads to reduced 5-HT_2B receptor efficacy, as measured by Gq dissociation by BRET. Data represent the mean and SEM from three independent experiments performed at 37 °C with 60-minute compound incubation. B Role of N-benzyl ring electrostatics in 5-HT_2A receptor potency leading to development of 25N-NB-2-OH-3-Me **(18)** using QSAR correlation between 5-HT_2A receptor pK_i and Hammett σ constant values (Pearson’s R = −0.8887, R² = 0.7897, 2-tailed p < 0.0001, N = 15). C The relationship between steric bulk and 5-HT_2A/2C receptor selectivity is shown for the halogen series, leading to the identification of the 5-HT_2A receptor-selective agonist 25N-NBI **(10)** (*left*). Also shown is a 5-HT_2A/2C receptor selectivity heatmap comparing the 25N halogen series to 25CN-NBOH (*right*). D Comparison of 5-HT_2A receptor (green) 5-HT_2B receptor (red) and 5-HT_2C receptor (purple) Gq dissociation activities for 25N-NBI **(10)** (*left*) and 25CN-NBOH (*right*). Data represent mean and SEM from three independent experiments, which were performed at 37 °C with 60-minute compound incubation. E 5-HT_2A receptor Gq dissociation and β-arrestin2 BRET concentration response curves for 25N-NBOH (3, *top*) and 25N-NB-2-OH-3-Me (**18,** *bottom*) showing addition of a 3-methyl group leads to reduced Gq-efficacy. Data represent mean and SEM from three independent experiments, which were performed at 37 °C with 60-minute compound incubation. F 25N-NBI **(10)** induced fit docking (IFD) with orthosteric site residue side chains displayed. The window shows a zoom-in view illustrating key ligand-residue interactions within the orthosteric site and illustrating the close proximity of the 2’- and 3’-positions to TM6 and TM7, which are known to influence ligand bias. G Summary of structure-activity relationships (SAR) for the 25N series encompassing key effects on electrostatics, 5-HT_2A receptor selectivity, and reduced Gq E_MAX. Source data are provided as a Source Data file.

**Fig. 3. Structure-based design of β-arrestin-biased 5-HT_2A agonists.**
A Effect of the larger N-substituted 25N analogs 25N-N1-Nap **(16)** and 25N-NBPh **(17)** on 5-HT_2A receptor Gq dissociation (red) and β-arrestin2 (blue) recruitment. Data represent the mean and SEM from three independent experiments performed at 37 °C with 60-minute compound incubation. B Outward pivot of TM6 for 25CN-NBOH and 25N-N1-Nap **(16)** MD simulations relative to the inactive 5-HT_2A receptor structure with final frame shown as representative. Note the intermediate TM6 tilt angle with 25N-N1-Nap **(16)** relative to that of 25CN-NBOH. C Change in W366^6.48 toggle switch χ² angle. χ² angle given is the absolute difference in peak angle relative to the inactive state. Final frame shown as representative. D Distribution and time dependence W366^6.48 χ² angle of 25CN-NBOH (yellow) and 25N-N1-Nap **(16)** (orange) simulations. E Effect of 5-HT_2A receptor W336^6.48Y mutation on 25N-NBOMe **(4)**, 25N-NBPh **(17)**, and 25N-N1-Nap **(16)** Gq dissociation (red) versus β-arrestin2 (blue) recruitment activities. Data represent the mean and SEM from three independent experiments performed at 37 °C with 60-minute compound incubation. Source data are provided as a Source Data file.

**Fig. 4. β-Arrestin-biased 5-HT_2A agonists lack psychedelic potential.**
A 25N-NBOMe **(4)** induces the head-twitch response (HTR) (W_5,19.46 = 84.56, p < 0.0001). B 25N-N1-Nap **(16)** does not induce the HTR (F_5,26 = 1.39, p = 0.2618). C 25N-NBPh **(17)** does not induce the HTR (F_4,18 = 0.89, p = 0.4903). D 25N-NB-2-OH-3-Me **(18)** does not induce the HTR (F_2,25 = 0.55, p = 0.7377). E Illustration showing the procedures used to confirm that compounds tested in panels F–H are brain penetrant and capable of engaging 5-HT_2A receptors in the CNS of mice. Mice were pretreated with vehicle or drug, ( ± )-DOI (1 mg/kg IP) was injected 10 minutes later, and then HTR activity was assessed for 20 minutes. F Pretreatment with 25N-N1-Nap **(16)** blocks the HTR induced by (±)-DOI (F_3,16 = 68.43, p < 0.0001). G Pretreatment with 25N-NBPh **(17)** blocks the HTR induced by (±)-DOI (W_3,14.64 = 144.6, p < 0.0001). H Pretreatment with 25N-NB-2-OH-3-Me **(18)** blocks the HTR induced by (±)-DOI (F_3,16 = 18.39, p < 0.0001). P values are provided if there were significant differences between groups (Tukey’s test or Dunnett’s T3 test). HTR counts from individual male C57BL/6 J mice as well as group means are shown. Drug doses are presented as mg/kg. I 5-HT_2A receptor Gq-mediated calcium flux activity comparing 5-HT (open circles) antagonist activity for 25N-N1-Nap **(16)** (red), 25N-NB-2-OH-3-Me **(18)** to M100,907 (black circles). Data represent the mean and SEM from three independent experiments. Source data are provided as a Source Data file.

**Fig. 5. Psychedelic potential is correlated with 5-HT_2A-Gq signaling.**
A Scatter plot showing the relationship between 5-HT_2A receptor Gq-efficacy (E_MAX values) and head-twitch response (HTR) magnitude (maximum counts per minute induced by the compound) for 14 members of the 25N series. Spearman’s rank correlation coefficient R_s is shown. The regression line generated by fitting the data using non-linear regression is included as a visual aid. B Scatter plot showing the relationship between 5-HT_2A receptor β-arrestin2 recruitment efficacy (E_MAX values) and HTR magnitude for 14 members of the 25N series. C Scatter plot showing the relationship between 5-HT_2A receptor Gq-efficacy (E_MAX values) and HTR magnitude for 24 phenethylamine psychedelics. To illustrate the non-linear nature of the relationship, the regression line generated by fitting the data using non-linear regression is shown. D Scatter plot showing the relationship between 5-HT_2A receptor β-arrestin2 recruitment efficacy (E_MAX values) and HTR magnitude for 24 phenethylamine psychedelics. Source data are provided as a Source Data file.

**Fig. 6. 5-HT_2A-Gq signaling predicts psychedelic potential.**
A–G Activity in the HTR assay can be predicted based on 5-HT_2A receptor Gq-efficacy. As predicted, 25O-NBOMe **(32)** (F_5,26 = 37.01, p < 0.0001), 2C2-NBOMe **(31)** (W_6,12.67 = 96.28, p < 0.0001), and 25O-NBcP **(33)** (F_5,25 = 20.57, p < 0.0001) induced head twitches, whereas 25O-NBPh-10’-OH **(35)** (F_4,27 = 2.58, p = 0.0601), 25O-NB-3-I **(34)** (F_5,25 = 0.26, p = 0.9288), and 25D-N1-Nap **(26)** (F_3,20 = 0.37, p = 0.7748) did not induce head twitches. **(H)** Pretreatment with the Gαq/11 inhibitor YM-254890 blocks the HTR induced by R-(-)-DOI (F_3,12 = 8.69, p = 0.0025). Mice were treated ICV with YM-254890 or vehicle and then all of the animals received R-(-)-DOI (1 mg/kg IP) 15 minutes later. **(I)** Pretreatment with the phospholipase C (PLC) inhibitor edelfosine blocks the HTR induced by R-(-)-DOI (F_2,16 = 11.34, p = 0.0009) and 25N-NBOMe **(4)** (F_2,16 = 6.40, p = 0.0091). Mice received three consecutive injections of vehicle or the indicated dose of edelfosine at 20-minute intervals and then a HTR-inducing drug was administered 10 minutes after the third injection. HTR counts from individual male C57BL/6 J mice as well as group means are shown. P values are provided if there were significant differences vs. vehicle control (Tukey’s test or Dunnett’s T3 test). The dose of YM-254890 is presented in µg; other drug doses are presented as mg/kg. Source data are provided as a Source Data file.

**Fig. 7. Non-psychedelics do not achieve 5-HT_2A Gq-signaling efficacy threshold.**
A Effect of (+)-lysergic acid diethylamide (LSD), psilocin, 5-methoxy-*N,N*-dimethyltryptamine (5-MeO-DMT), *N,N*-diethyltryptamine (DET), lisuride, ( + )−2-bromolysergic acid diethylamide (2-Br-LSD), 6-methoxy-*N,N*-dimethyltryptamine (6-MeO-DMT), and 6-fluoro-*N,N*-diethyltryptamine (6-F-DET) on 5-HT_2A receptor Gq dissociation (red) and β-arrestin2 (blue) recruitment. The BRET data for LSD, psilocin, and 5-MeO-DMT are from Fig. 1; the data for 2-Br-LSD were published previously. Data represent the mean and SEM from three independent experiments. B Effect of LSD, psilocin, 5-MeO-DMT (F_4,26 = 3.09, p = 0.0331), DET, lisuride, 2-Br-LSD, 6-MeO-DMT (F_5,26 = 4.19, p = 0.0063), and 6-F-DET (F_4,23 = 13.49, p < 0.0001) on the head-twitch response (HTR) in mice. The HTR data for LSD, DET, psilocin, lisuride, and 2-Br-LSD were re-analyzed from published experiments^,,,. HTR counts from individual male C57BL/6 J mice as well as group means are shown. P-values are provided if there were significant differences between groups (Tukey’s test). C Scatter plot and linear regression showing the correlation between 5-HT_2A receptor Gq-efficacy (E_MAX values) and HTR magnitude (maximum counts per minute induced by each drug). Pearson’s correlation coefficient R is shown. The p-value is 2-tailed. Drug doses are presented as mg/kg. Source data are provided as a Source Data file.

**Fig. 8. In vitro and in vivo effects of β-arrestin-biased 5-HT_2A agonists.**
A Scheme of NanoBit Internalization Assay for 5-HT_2AR measuring loss of surface expression with the membrane impermeable LgBit. B 5-HT_2AR internalization concentration response calculated as percent basal surface expression and normalized to 0% of max 5-HT response. Data represent mean and SEM from 3 independent experiments with 5-HT (black), DOI (blue), pimavanserin (grey), 25N-NBOMe **(4)** (green), 25N-N1-Nap **(16)** (red) and 25N-NBPh **(17)** (purple). C Cartoon showing the procedures used to induce tolerance in the head-twitch response (HTR) assay. Mice were injected with vehicle or drug once daily for 5 consecutive days and then challenged with (±)-DOI (1 mg/kg IP) 24 hours after the last injection. D Repeated administration of (±)-DOI and 25N-N1-Nap **(16)** (F_2,16 = 16.68, p = 0.0001), but not pimavanserin (t₁₀ = 1.067, 2-tailed p = 0.3111), induces a tolerance to the HTR induced by DOI. Mice was treated with vehicle, 25N-N1-Nap **(16)** (20 mg/kg/day SC), or (±)-DOI (10 mg/kg/day SC). Additional mice were treated with vehicle or pimavanserin (1 mg/kg/day SC). HTR counts are expressed as a percentage of the response in the respective control group; data from individual male C57BL/6 J mice as well as group means are shown. P-values are provided if there were significant differences between groups (Tukey’s test). E Pimavanserin blocks the response to (±)-DOI injected 20-minutes later (F_3,16 = 8.19, p = 0.0016). HTR counts from individual mice as well as group means are shown. P values are provided if there were significant differences between groups (Tukey’s test). F 25N-N1-Nap **(16)** attenuates phencyclidine (PCP)-induced hyperactivity (pretreatment × PCP: F_1,20 = 7.09, p = 0.015; pretreatment × PCP × time: F_2,40 = 11.03, p = 0.0002). Locomotor activity was measured as distance traveled (cm), presented as group means ± SEM. N = 6 male C57BL/6 J mice/group. *p < 0.05, significant difference vs. vehicle; ^#p < 0.05, significant difference vs. PCP alone (Tukey’s test). G M100907 attenuates PCP-induced hyperactivity (pretreatment × PCP: F_1,20 = 7.41, p = 0.0131). N = 6 male C57BL/6 J mice/group. *p < 0.05, significant difference vs. vehicle; ^#p < 0.05, significant difference vs. PCP alone (Tukey’s test). Drug doses are presented as mg/kg. Source data are provided as a Source Data file.

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Identification of 5-HT_2A Receptor Signaling Pathways Responsible for Psychedelic Potential.
Wallach J, Cao AB, Calkins MM, Heim AJ, Lanham JK, Bonniwell EM, Hennessey JJ, Bock HA, Anderson EI, Sherwood AM, Morris H, de Klein R, Klein AK, Cuccurazzu B, Gamrat J, Fannana T, Zauhar R, Halberstadt AL, McCorvy JD. Wallach J, et al. bioRxiv [Preprint]. 2023 Jul 31:2023.07.29.551106. doi: 10.1101/2023.07.29.551106. bioRxiv. 2023. Update in: Nat Commun. 2023 Dec 15;14(1):8221. doi: 10.1038/s41467-023-44016-1. PMID: 37577474 Free PMC article. Updated. Preprint.

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References

1. Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J. Neurol. Sci. 2020;411:116715. doi: 10.1016/j.jns.2020.116715. - DOI - PubMed
1. Romeo B, Karila L, Martelli C, Benyamina A. Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis. J. Psychopharmacol. 2020;34:1079–1085. doi: 10.1177/0269881120919957. - DOI - PubMed
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1. Mastinu, A. et al. The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology. Int. J. Mol. Sci.24, 10.3390/ijms24021329 (2023). - PMC - PubMed
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[1] Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J. Neurol. Sci. 2020;411:116715. doi: 10.1016/j.jns.2020.116715. - DOI - PubMed

[2] Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J. Neurol. Sci. 2020;411:116715. doi: 10.1016/j.jns.2020.116715. - DOI - PubMed

[3] Romeo B, Karila L, Martelli C, Benyamina A. Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis. J. Psychopharmacol. 2020;34:1079–1085. doi: 10.1177/0269881120919957. - DOI - PubMed

[4] Romeo B, Karila L, Martelli C, Benyamina A. Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis. J. Psychopharmacol. 2020;34:1079–1085. doi: 10.1177/0269881120919957. - DOI - PubMed

[5] Johnson MW, Hendricks PS, Barrett FS, Griffiths RR. Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharm. Ther. 2019;197:83–102. doi: 10.1016/j.pharmthera.2018.11.010. - DOI - PubMed

[6] Johnson MW, Hendricks PS, Barrett FS, Griffiths RR. Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharm. Ther. 2019;197:83–102. doi: 10.1016/j.pharmthera.2018.11.010. - DOI - PubMed

[7] Mastinu, A. et al. The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology. Int. J. Mol. Sci.24, 10.3390/ijms24021329 (2023). - PMC - PubMed

[8] Mastinu, A. et al. The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology. Int. J. Mol. Sci.24, 10.3390/ijms24021329 (2023). - PMC - PubMed

[9] Cameron LP, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021;589:474–479. doi: 10.1038/s41586-020-3008-z. - DOI - PMC - PubMed

[10] Cameron LP, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2021;589:474–479. doi: 10.1038/s41586-020-3008-z. - DOI - PMC - PubMed

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Identification of 5-HT_2A receptor signaling pathways associated with psychedelic potential

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Identification of 5-HT_2A receptor signaling pathways associated with psychedelic potential

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