List of investigational social anxiety disorder drugs explained

This is a list of investigational social anxiety disorder drugs, or drugs that are currently under development for clinical use in the treatment of social anxiety disorder (SAD; or social phobia) but are not yet approved.

Chemical/generic names are listed first, with developmental code names, synonyms, and brand names in parentheses.

This list was last comprehensively updated in August 2024. It is likely to become outdated with time.

Under development

Phase 3

• BNC-210 (IW-2143) – α₇-nicotinic acetylcholine receptor negative allosteric modulator^{[1] [2] [3]}
• Fasedienol (Aloradine; AM-005; PH-94B; 4-androstadienol) – vomeropherine^{[4] [5]}

Phase 2/3

• Riluzole sublingual (BHV-0223; Nurtec) – complex mechanism of action or glutamatergic modulator ^[6]

Phase 2

• Cannabidiol (CBD; ATL5; RLS103) – cannabinoid receptor modulator and other actions ^{[7] [8] [9]}
• FKW00GA (FKW-00GA; TGW-00AA; TGW00AA) – serotonin 5-HT_1A receptor partial agonist and serotonin 5-HT_2A receptor antagonist^{[10] [11]}
• JNJ-42165279 (JNJ-5279) – fatty acid amide hydrolase (FAAH) inhibitor^{[12] [13] [14] [15] [16]}
• Oxytocin (intranasal potentiated oxytocin; TI-001; TI-114; TNX-1900; TNX-2900) – oxytocin receptor agonist^[17]
• Vilazodone (Viibryd) – serotonin 5-HT_1A receptor partial agonist and serotonin reuptake inhibitor^[18]

Phase 1

• (R)-Midomafetamine ((R)-MDMA; R-MDMA; EMP-01) – serotonin, norepinephrine, and dopamine releasing agent, weak serotonin 5-HT_2A, 5-HT_2B, 5-HT_2C receptor agonist, entactogen, and weak psychedelic hallucinogen ^{[19] [20]}

Preclinical

• Dimethyltryptamine (DMT; N,N-Dimethyltryptamine; N,N-DMT) – non-selective serotonin receptor agonist and psychedelic hallucinogen^[21]
• PSYLO-3001 (Psylo-3001) – non-selective serotonin receptor agonist and psychedelic hallucinogen ^[22]

Phase unknown

• Fluvoxamine extended-release – selective serotonin reuptake inhibitor^[23]
• Venlafaxine controlled-release – serotonin–norepinephrine reuptake inhibitor^[24]

Not under development

No development reported

• Bupropion (Wellbutrin) – norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator^[25]
• EX-597 (KDS-4103; ORG-231295; URB-597) – fatty acid amide hydrolase (FAAH) inhibitor^{[26] [27]} `
• Guanfacine extended-release (Connexyn; Intuniv; Intuniv XR; S-877503; SHP 503; SPD-503) – α₂-adrenergic receptor agonist^[28]

Development discontinued

• AV-608 (CGP-60829; NK-608; NKP-608C; NKP608) – neurokinin NK₁ receptor antagonist^[29]
• Tradipitant (LY-686017; VLY-686) – neurokinin NK₁ receptor antagonist ^[30]
• Verucerfont (GSK-561679; NBI-77860) – corticotropin-releasing hormone receptor 1 (CRF₁) antagonist ^[31]

Formal development never or not yet started

• Small-molecule oxytocin receptor agonists (e.g., LIT-001)^[32]

Clinically used drugs

Approved drugs

Selective serotonin reuptake inhibitors

• Escitalopram (Lexapro; Cipralex) – selective serotonin reuptake inhibitor^[33]
• Fluvoxamine (Depromel; Luvox) – selective serotonin reuptake inhibitor ^[34]
• Paroxetine (Dropax; Serestill; Paxil; Seroxat) – selective serotonin reuptake inhibitor ^{[35] [36]}
• Sertraline (Zoloft; Lustral) – selective serotonin reuptake inhibitor ^[37]

Serotonin–norepinephrine reuptake inhibitors

• Venlafaxine (Dobupal; Effexor; Effexor XR; Elafax) – serotonin–norepinephrine reuptake inhibitor^[38]

Monoamine oxidase inhibitors

• Moclobemide (Manerix) – reversible inhibitor of monoamine oxidase A^{[39] [40]}

Off-label drugs

• Alcohol (over-the-counter self-medication) – GABA_A receptor positive allosteric modulator^[41]
• Atypical antipsychotics (e.g., olanzapine, quetiapine) – monoamine receptor modulators
• Benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, oxazepam) – GABA_A receptor positive allosteric modulators^[42]
• Beta blockers (e.g., atenolol, propranolol) – β-adrenergic receptor antagonists^{[43] [44]}
• Bupropion (Wellbutrin) – norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator
• Cannabidiol (CBD) – cannabinoid receptor modulator and other actions, found in cannabis^{[45] [46]}
• Gabapentinoids (e.g., gabapentin, pregabalin) – α₂δ subunit-containing voltage-dependent calcium channel blockers^[47]
• Monoamine oxidase inhibitors (e.g., phenelzine, selegiline, tranylcypromine)
• NMDA receptor antagonists (e.g., ketamine)
• Other anticonvulsants (besides gabapentinoids) (e.g., topiramate, valproic acid, tiagabine)
• Psychostimulants (e.g., amphetamine, methylphenidate)^{[48] [49]}
• Selective serotonin reuptake inhibitors (non-licensed) (e.g., citalopram, fluoxetine)
• Serotonin–norepinephrine reuptake inhibitors (non-licensed) (e.g., desvenlafaxine, duloxetine)^[50]
• Serotonin 5-HT_1A receptor agonists (e.g., buspirone)
• Tricyclic antidepressants (e.g., clomipramine, imipramine)

See also

• List of investigational drugs
• List of investigational anxiolytics
• List of investigational autism and pervasive developmental disorder drugs

Further reading

• Brady LS, Lisanby SH, Gordon JA . New directions in psychiatric drug development: promising therapeutics in the pipeline . Expert Opin Drug Discov . 18 . 8 . 835–850 . 2023 . 37352473 . 10.1080/17460441.2023.2224555 .
• Web site: PhRMA . 2023 Medicines in Development – Mental Illness . PhRMA . 5 August 2024.

External links

• AdisInsight - Springer

Notes and References

1. Web site: BNC 210 - AdisInsight. adisinsight.springer.com.
2. Hampsey E, Perkins A, Young AH . BNC210: an investigational α7-nicotinic acetylcholine receptor modulator for the treatment of anxiety disorders . Expert Opin Investig Drugs . 32 . 4 . 277–282 . April 2023 . 36927202 . 10.1080/13543784.2023.2192922 . free .
3. Web site: Bionomics Starts Phase 3 Trial of BNC210 for Social Anxiety . Synapse . 5 August 2024 . 5 August 2024.
4. Web site: Fasedienol - Pherin Pharmaceuticals/VistaGen Therapeutics - AdisInsight. adisinsight.springer.com.
5. Singewald N, Sartori SB, Reif A, Holmes A . Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder . Neuropharmacology . 226 . 109418 . March 2023 . 36623804 . 10372846 . 10.1016/j.neuropharm.2023.109418 .
6. Web site: Riluzole sublingual - Biohaven Pharmaceuticals - AdisInsight. adisinsight.springer.com.
7. Web site: Cannabidiol - ANANDA Scientific - AdisInsight. adisinsight.springer.com.
8. Web site: Phase III clinical trial of Cannabidiol - AdisInsight. adisinsight.springer.com.
9. Pelissolo A, Abou Kassm S, Delhay L . Therapeutic strategies for social anxiety disorder: where are we now? . Expert Rev Neurother . 19 . 12 . 1179–1189 . December 2019 . 31502896 . 10.1080/14737175.2019.1666713 .
10. Web site: FKW 00GA - AdisInsight. adisinsight.springer.com.
11. Sartori SB, Singewald N . Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders . Pharmacol Ther . 204 . 107402 . December 2019 . 31470029 . 10.1016/j.pharmthera.2019.107402 . free .
12. Web site: JNJ 42165279 - AdisInsight. adisinsight.springer.com.
13. Maccarrone M, Di Marzo V, Gertsch J, Grether U, Howlett AC, Hua T, Makriyannis A, Piomelli D, Ueda N, van der Stelt M . Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years . Pharmacol Rev . 75 . 5 . 885–958 . September 2023 . 37164640 . 10.1124/pharmrev.122.000600 . 10441647 . For instance, Paulus and coworkers found that JNJ-42165279 (100 mg) dampens amygdala activity during an emotion face-processing task, an effect that is associated positively with plasma AEA concentrations (Paulus et al., 2021). A lower dose of the drug (25 mg) was tested in a multicenter, placebo-controlled phase 2 trial in patients with social anxiety disorder. The study reported statistically detectable signs of efficacy, but the dosage was considered insufficient to fully inhibit FAAH (Schmidt et al., 2021)..
14. Ahmed M, Boileau I, Le Foll B, Carvalho AF, Kloiber S . The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics . Braz J Psychiatry . 44 . 1 . 81–93 . 2022 . 34468550 . 8827369 . 10.1590/1516-4446-2021-1926 . The role of the ECS specifically in social anxiety is supported by various preclinical findings which demonstrate effects of ECS modulation, via either CB1 receptor activation or FAAH inhibition, on social interaction and social anxiety.113-118 In comparison, clinical studies investigating this system in SAD are considerably limited. A recent clinical trial investigating the therapeutic effects of a FAAH inhibitor in SAD was negative. However, the authors observed a small to modest anxiolytic effect in patients with severe SAD and suggested that, based on the correlation between low trough concentrations of the inhibitor (i.e., the lowest concentration of the drug in the bloodstream) and low plasma AEA, future trials with a higher dose of the inhibitor may be warranted.119 In addition, a recently published double-blind, placebocontrolled experimental study in healthy adults found that administration of the FAAH inhibitor PF-04457845 produced a 10-fold increase in peripheral AEA levels and decreased broad-spectrum fear-related phenotypes.120 Furthermore, a 2021 double-blind, placebo-controlled clinical trial in healthy males employing the FAAH inhibitor JNJ-42165279 found that the drug attenuated activation in the amygdala, anterior cingulate, and bilateral insula during a face emotion processing task – effects which are consistent with those of previously observed anxiolytic agents.121 Moreover, higher levels of plasma AEA were associated with greater attenuation in these brain regions.121.
15. Schmidt ME, Liebowitz MR, Stein MB, Grunfeld J, Van Hove I, Simmons WK, Van Der Ark P, Palmer JA, Saad ZS, Pemberton DJ, Van Nueten L, Drevets WC . The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: a double-blind, randomized, placebo-controlled proof-of-concept study . Neuropsychopharmacology . 46 . 5 . 1004–1010 . April 2021 . 33070154 . 8115178 . 10.1038/s41386-020-00888-1 .
16. Paulus MP, Stein MB, Simmons AN, Risbrough VB, Halter R, Chaplan SR . The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial . Neuropsychopharmacology . 46 . 5 . 1011–1019 . April 2021 . 33335310 . 8105363 . 10.1038/s41386-020-00936-w .
17. Web site: Oxytocin - Tonix Pharmaceuticals - AdisInsight. adisinsight.springer.com.
18. Web site: Vilazodone - AbbVie - AdisInsight. adisinsight.springer.com.
19. Web site: EMP 01 - AdisInsight. adisinsight.springer.com.
20. Web site: Delving into the Latest Updates on EMP-01 with Synapse . Synapse . 1 November 2024 . 2 November 2024.
21. Web site: N N dimethyltryptamine - Psilera - AdisInsight. adisinsight.springer.com.
22. Web site: PSYLO 3001 - AdisInsight. adisinsight.springer.com.
23. Web site: Fluvoxamine extended release - Beijing CoSci Med Tech - AdisInsight. adisinsight.springer.com.
24. Web site: Venlafaxine controlled release - Beijing CoSci Med Tech - AdisInsight. adisinsight.springer.com.
25. Web site: Bupropion - Biovail Corporation - AdisInsight. adisinsight.springer.com.
26. Web site: EX 597 - AdisInsight. adisinsight.springer.com.
27. Kwee CM, Leen NA, Van der Kamp RC, Van Lissa CJ, Cath DC, Groenink L, Baas JM . Anxiolytic effects of endocannabinoid enhancing compounds: A systematic review and meta-analysis . Eur Neuropsychopharmacol . 72 . 79–94 . July 2023 . 37094409 . 10.1016/j.euroneuro.2023.04.001 .
28. Web site: Guanfacine extended release - Takeda - AdisInsight. adisinsight.springer.com.
29. Web site: AV 608 - AdisInsight. adisinsight.springer.com.
30. Web site: Tradipitant - Vanda Pharmaceuticals - AdisInsight. adisinsight.springer.com.
31. Web site: Verucerfont - GlaxoSmithKline - AdisInsight. adisinsight.springer.com.
32. Book: Nashar PE, Whitfield AA, Mikusek J, Reekie TA . Oxytocin . The Current Status of Drug Discovery for the Oxytocin Receptor . Methods Mol Biol . 2384 . 153–174 . 2022 . 34550574 . 10.1007/978-1-0716-1759-5_10 . 978-1-0716-1758-8 .
33. Web site: Escitalopram - Lundbeck A/S - AdisInsight. adisinsight.springer.com.
34. Web site: Fluvoxamine - AdisInsight. adisinsight.springer.com.
35. Web site: Paroxetine - Novo Nordisk - AdisInsight. adisinsight.springer.com.
36. Web site: Paroxetine hydrochloride - Italfarmaco - AdisInsight. adisinsight.springer.com.
37. Web site: Sertraline - Pfizer - AdisInsight. adisinsight.springer.com.
38. Web site: Venlafaxine - Pfizer - AdisInsight. adisinsight.springer.com.
39. Yáñez M, Padín JF, Arranz-Tagarro JA, Camiña M, Laguna R . History and therapeutic use of MAO-A inhibitors: a historical perspective of MAO-A inhibitors as antidepressant drug . Curr Top Med Chem . 12 . 20 . 2275–2282 . 2012 . 23231399 . 10.2174/156802612805220011 . Moclobemide, approved in Europe for the treatment of social phobia/social anxiety disorder, and other reversible inhibitors of MAO-A arise as a promising family of drugs for the treatment of these disorders..
40. Ipser JC, Kariuki CM, Stein DJ . Pharmacotherapy for social anxiety disorder: a systematic review . Expert Rev Neurother . 8 . 2 . 235–257 . February 2008 . 18271710 . 10.1586/14737175.8.2.235 . The SNRI venlafaxine has also been shown to be safe, well- tolerated and more effective than placebo in the short-term treatment of generalized SAD. Paroxetine, sertraline and venla- faxine are currently the only US FDA approved medications for treating SAD, with escitalopram and moclobemide also licensed for use in Europe. MAOIs, in the form of phenelzine, and certain benzodiazepines are also effective in SAD, but in view of concerns about ease of administration (e.g., MAOIs require dietary and medication restrictions) and side effects (e.g., benzodiazepines are associated with cognitive adverse events and require slow withdrawal), its seems reasonable to view these as second-line agents..
41. Carrigan MH, Randall CL . Self-medication in social phobia: a review of the alcohol literature . Addict Behav . 28 . 2 . 269–284 . March 2003 . 12573678 . 10.1016/s0306-4603(01)00235-0 .
42. Muller JE, Koen L, Seedat S, Stein DJ . Social anxiety disorder : current treatment recommendations . CNS Drugs . 19 . 5 . 377–391 . 2005 . 15907150 . 10.2165/00023210-200519050-00002 .
43. Brunello N, den Boer JA, Judd LL, Kasper S, Kelsey JE, Lader M, Lecrubier Y, Lepine JP, Lydiard RB, Mendlewicz J, Montgomery SA, Racagni G, Stein MB, Wittchen HU . Social phobia: diagnosis and epidemiology, neurobiology and pharmacology, comorbidity and treatment . J Affect Disord . 60 . 1 . 61–74 . October 2000 . 10940449 . 10.1016/s0165-0327(99)00140-8 .
44. Halaby A, Haddad R, Naja W . Non-Antidepressant Treatment of Social Anxiety Disorder: A Review . Curr Clin Pharmacol . 10 . 2 . 126–130 . 2015 . 23438729 . 10.2174/15748847113089990059 .
45. Rosário BD, Lemes JA, de Lima MP, Ribeiro DA, Viana MB . Subjective, behavioral and neurobiological effects of cannabis and cannabinoids in social anxiety . Rev Neurosci . 35 . 2 . 197–211 . February 2024 . 37812748 . 10.1515/revneuro-2023-0078 .
46. Fliegel DK, Lichenstein SD . Systematic literature review of human studies assessing the efficacy of cannabidiol for social anxiety . Psychiatry Res Commun . 2 . 4 . December 2022 . 36875967 . 9983614 . 10.1016/j.psycom.2022.100074 .
47. Caldiroli A, Capuzzi E, Tagliabue I, Ledda L, Clerici M, Buoli M . New frontiers in the pharmacological treatment of social anxiety disorder in adults: an up-to-date comprehensive overview . Expert Opin Pharmacother . 24 . 2 . 207–219 . February 2023 . 36519357 . 10.1080/14656566.2022.2159373 .
48. Villas-Boas CB, Chierrito D, Fernandez-Llimos F, Tonin FS, Sanches AC . Pharmacological treatment of attention-deficit hyperactivity disorder comorbid with an anxiety disorder: a systematic review . Int Clin Psychopharmacol . 34 . 2 . 57–64 . March 2019 . 30422834 . 10.1097/YIC.0000000000000243 . In a retrospective analysis of a case series, the monotherapy with extended-release methylphenidate was seen to be effective in reducing ADHD and social AD symptoms evaluated by the Adult ADHD Self-Report Scale (ASRS) and Liebowitz Social Anxiety Scale (LSAS) (Koyuncu et al., 2017)..
49. Koyuncu A, İnce E, Ertekin E, Tükel R . Comorbidity in social anxiety disorder: diagnostic and therapeutic challenges . Drugs Context . 8 . 212573 . 2019 . 30988687 . 6448478 . 10.7573/dic.212573 . Attention-deficit/hyperactivity disorder (ADHD), another childhood disorder that extends over adulthood, is an overlooked condition that has high rates of comorbidity with SAD.31 Only recently increasing evidence suggests that the relationship between the two disorders is closer than that was thought before. Several studies found high rates (up to 60–70%) of childhood ADHD comorbidity, especially predominantly inattentive type, in adults with SAD.67,157,158 In addition, follow-up studies showed that the lifetime prevalence of SAD among ADHD patients is higher compared to healthy controls.159 In treatment studies investigating patients with SAD plus ADHD comorbidity found that ADHD medications such as methylphenidate or atomoxetine could effectively improve symptoms of both disorders at the same time.160–163 According to a developmental hypothesis, SAD may be etiologically linked to ADHD in a subgroup of patients, and thus SAD may develop secondary to ADHD.31.
50. Mitsui N, Fujii Y, Asakura S, Imai H, Yamada H, Yoshinaga N, Kanai Y, Inoue T, Shimizu E . Antidepressants for social anxiety disorder: A systematic review and meta-analysis . Neuropsychopharmacol Rep . 42 . 4 . 398–409 . December 2022 . 35848723 . 9773641 . 10.1002/npr2.12275 .