Chemistry:Lisuride

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Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline family which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels.[1][2] It is taken by mouth.[1][2]

Side effects of lisuride include nausea and vomiting, dizziness, headache, fatigue or drowsiness, insomnia or sleep, gastrointestinal disturbances such as abdominal pain or diarrhea, nasal congestion or runny nose, and hypotension, and hallucinations or confusion (particularly at higher doses).[1][3] Rarely, serious side effects such as cardiac or pulmonary fibrosis have been reported with long-term use, but they are extremely uncommon.[4]

Lisuride acts as a mixed agonist and antagonist of dopamine, serotonin, and adrenergic receptors.[1][2][5][6][7] Activation of specific dopamine receptors is thought to be responsible for its effectiveness in the treatment of Parkinson's disease and ability to suppress prolactin levels,[1][2] while interactions with serotonin receptors are thought to be principally involved in its effectiveness for migraine.[8][9] It is very similar in chemical structure to lysergic acid diethylamide (LSD).[1][3]

Medical uses

Lisuride is used to lower prolactin and, in low doses, to prevent migraine attacks.[2] The use of lisuride as initial antiparkinsonian medication for Parkinson's disease has been advocated, delaying the need for levodopa until lisuride becomes insufficient for controlling the parkinsonian symptoms.[2][additional citation(s) needed] Evidence is insufficient to support lisuride in the treatment of advanced Parkinson's disease as an alternative to levodopa or bromocriptine.[10][11]

Side effects

Side effects of lisuride include nausea and lowered blood pressure, among others.[4]

Pharmacology

Pharmacodynamics

Lisuride activities
Target Affinity (Ki, nM)
5-HT1A 0.15–6.9 (Ki)
1.3 (EC50)
98% (Emax)
5-HT1B 16–18.6 (Ki)
26.3 (EC50)
85% (Emax)
5-HT1D 0.977–>10,000
3.24 (EC50)
81% (Emax)
5-HT1E 44.3
5-HT1F ND
5-HT2A 0.74–5.4 (Ki)
0.78–7,900 (EC50)
6–73% (Emax)
5-HT2B 1.07–2.9 (Ki)
1.10 (IC50)
0% (Emax)
5-HT2C 5.3–>10,000 (Ki)
7.76–23,614 (EC50)
17–79% (Emax)
5-HT3 >10,000
5-HT4 ND
5-HT5A 3.1
5-HT6 7.3
5-HT7 6.8
α1A 5.5–24.6 (Ki)
9.77 (IC50)
0% (Emax)
α1B 16.6–250.9
α1D 2.95
α2A 0.055–1.8 (Ki)
0.295 (IC50)
0% (Emax)
α2B 0.13–0.5 (Ki)
0.933 (IC50)
0% (Emax)
α2C 0.4 (Ki)
1.07 (IC50)
0% (Emax)
β1 8.2–67.6
β2 7.94–35.3
β3 ND
D1 64.6–>10,000 (Ki)
8.3–9.4 (EC50)
31–38% (Emax)
D2 0.18–6.7 (Ki)
0.288–0.724 (EC50)
21–55% (Emax)
D3 0.39–135.7 (Ki)
0.575 (EC50)
49% (Emax)
D4 3.8–6.77 (Ki)
5.89 (EC50)
32% (Emax)
D5 3.5–77
H1 ND
H2 114.3
H3 >10,000
H4 ND
M1–M5 >10,000
I1 >10,000
σ1 ND
σ2 ND
TAAR1 ND
SERT >10,000 (Ki)
NET >10,000
DAT >10,000 (Ki)
Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs:[12][13][14][15][6]
[7][16][17][18][19][20]

Lisuride is a ligand of dopamine, serotonin, and adrenergic receptors as well as the histamine H1 receptor.[5] It has sub-nanomolar affinity for the dopamine D2, and D3 receptors, serotonin 5-HT1A and 5-HT1D receptors, and α2A-, α2B-, and α2C-adrenergic receptors, and low-nanomolar affinity for the dopamine D1, D4, and D5 receptors, serotonin 5-HT2A, 5-HT2B, and 5-HT2C receptors, α1A-, α1B-, and α1D-adrenergic receptors, and histamine H1 receptor.[5][21][22] Lisuride is a partial agonist of the D2, D3, D4, 5-HT2A, 5-HT2C, 5-HT5A, and H1 receptors, a full or near-full agonist of the 5-HT1A, 5-HT1B, and 5-HT1D receptors, and a silent antagonist of the 5-HT2B receptor and α1A-, α2A-, α2B-, and α2C-adrenergic receptors.[7][22][23][24][25] Due to its highly non-selective pharmacological activity, lisuride is described as a "dirty drug".[2] The effectiveness of lisuride in Parkinson's disease and hyperprolactinemia is thought to be mostly due to activation of dopamine D2 receptors.[2]

While lisuride has a similar receptor binding profile to the more well-known and chemically similar ergoline lysergic acid diethylamide (LSD; N,N-diethyllysergamide) and acts as a partial agonist of the serotonin 5-HT2A receptor likewise,[7] it lacks the psychedelic effects of LSD and hence is non-hallucinogenic.[26][2] Research suggests that the lack of psychedelic effects with lisuride may arise from biased agonism of the 5-HT2A receptor. Stimulation of the 5-HT2A protomer within the 5-HT2A–mGlu2 receptor complex evokes psychedelic effects, while these effects do not occur during sole stimulation of monomeric 5-HT2A receptors. Accordingly, different G proteins are involved.[27][28] Lisuride behaves as an agonist at the 5-HT2A receptor monomer. Since it competitively antagonizes the effects of LSD, it may be regarded as a protomer antagonist of the 5-HT2A–mGluR heteromer.[29] GPCR oligomers are discrete entities and usually possess properties distinct from their parent monomeric receptors. However, this theory is controversial, and other research has found that 5-HT2A–mGlu2 dimers may not be essential for psychedelic effects.[30][31] Lisuride shows weak or no Gq pathway recruitment and this may be responsible for its non-hallucinogenic nature.[17][32] Alternatively, lisuride is an extremely potent serotonin 5-HT1A receptor agonist, and this might inhibit serotonin 5-HT2A receptor-mediated hallucinogenic effects.[33]

Although lisuride has widely been said to be non-hallucinogenic, this may not actually be true.[3][34][35] Lisuride has been associated with incidence of visual and auditory hallucinations, sensory disturbances, delusions, and other hallucinogenic effects at high doses.[3][34][35] It may simply be that typical therapeutic doses of lisuride are too low to adequately engage the serotonin 5-HT2A receptor and produce hallucinogenic effects but that hallucinogenic effects can be produced at higher doses.[3] Both serotonin 5-HT2A receptor agonism and dopamine D2 receptor agonism might contribute to the hallucinogenic effects of lisuride.[3] Lisuride's potent activities at other receptors besides the serotonin 5-HT2A receptor and its associated prominent side effects at higher doses, like nausea, hypotension, blurred vision, and anxiety, may limit its potential for being dosed high enough to produce hallucinogenic effects.[3] In animals, lisuride partially to fully substitutes for LSD and other psychedelics in drug discrimination tests in rodents and monkeys, but does not produce the head-twitch response in rodents.[36][37][38][3][34][39][40] However, lisuride does produce the head-twitch response in the least shrew, a non-rodent species that is said to be highly sensitive to serotonin 5-HT2A receptor agonists.[41][42] When a modified drug discrimination paradigm is employed in which animals are trained to discriminate two training drugs (lisuride and LSD) and vehicle however, lisuride no longer substitutes for LSD.[37]

Lisuride dose-dependently suppresses prolactin levels due to its dopaminergic activity.[2][43] As an antagonist of the serotonin 5-HT2B receptor, lisuride has no risk of cardiac valvulopathy, in contrast to related ergolines like pergolide and cabergoline.[2]

Minute amounts of lisuride suppress the firing of dorsal raphe serotonergic neurons, presumably due to agonist activity at 5-HT1A receptors.[44] Noradrenergic neurons of the locus coeruleus were accelerated by the drug at somewhat higher doses, consistent with α1-adrenergic receptor antagonist activity. Pars compacta dopamine neurons demonstrated a variable response.

Lisuride, along with the psychedelic drugs LSD and psilocin, has been reported to act as a potent positive allosteric modulator of the tropomyosin receptor kinase B (TrkB), one of the receptors of brain-derived neurotrophic factor (BDNF).[45][46] However, subsequent studies with LSD and psilocin failed to reproduce these findings and instead found no interaction of these agents with TrkB.[47]

Pharmacokinetics

Absorption of lisuride from the gastrointestinal tract with oral administration is complete.[4] The absolute bioavailability of lisuride is 10 to 20% due to high first-pass metabolism.[4] The plasma protein binding of lisuride is 60 to 70%.[4] Peak levels of lisuride occur 60 to 80 minutes after ingestion with high variability between individuals.[4] The elimination half-life of lisuride is approximately 2 hours.[4] This is shorter than most other dopamine agonists.[4] Lisuride has more than 15 known metabolites.[4]

Chemistry

Chemical structures of lisuride and lysergic acid diethylamide (LSD).

Lisuride, also known as 1,1-diethyl-3-(6-methyl-9,10-didehydroergolin-8α-yl)urea, is an ergoline derivative. It is almost identical in chemical structure to lysergic acid diethylamide (LSD), except that LSD's 8-position carboxamide group has been replaced with a urea group and the 8-position stereochemistry is inverted. Lisuride is described as the free base and as the hydrogen maleate salt.[48][49][50]

Analogues

Bromination of lisuride gives bromerguride (2-bromolisuride), which has a "reversed pharmacodynamic profile" compared to that of lisuride.[51]

Other analogues of lisuride include terguride, proterguride, mesulergine, and etisulergine, among others.

History

Lisuride was synthesized by Zikán and Semonský at the Research Institute for Pharmacy and Biochemistry at Prague (later SPOFA) as an antimigraine agent analogous to methysergide and was described in 1960.[2][52] It was marketed by the early 1970s.[53]

Society and culture

Generic names

Lisuride is the INN and lysuride is the BAN.[48][54][49][50]

Brand names

Lisuride has been sold under brand names including Arolac, Cuvalit, Dopagon, Dopergin, Dopergine, Eunal, Lisenil, Lizenil, Lysenyl, Proclacam, Prolacam, and Revanil.[48][49][50][2]

Availability

Lisuride was previously more widely available throughout the world,[49][2] but as of 2020 it appears to be marketed only in Egypt, France, Italy, Kuwait, Lebanon, Mexico, New Zealand, and Pakistan.[50] Lisuride is not currently available in the United States.

Research

Preliminary clinical research suggests that transdermal administration of lisuride may be useful in the treatment of Parkinson's disease.[2] As lisuride has poor bioavailability when taken orally and has a short half-life, continuous transdermal administration offers significant advantages and could make the compound a much more consistent therapeutic agent.[2] Lisuride was under development as a transdermal patch and subcutaneous implant for the treatment of Parkinson's disease, restless legs syndrome, and dyskinesias in the 2000s and 2010s, but development was discontinued.[55][56]

See also

  • Non-hallucinogenic 5-HT2A receptor agonist

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Lisuride: An 8-Alpha-Ergoline with Ergot Antagonistic Properties". NeuroPsychopharmacotherapy. Cham: Springer International Publishing. 2021. p. 1–43. doi:10.1007/978-3-319-56015-1_287-1. ISBN 978-3-319-56015-1. https://link.springer.com/10.1007/978-3-319-56015-1_287-1. Retrieved 6 May 2025. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 "Classical dopamine agonists". Journal of Neural Transmission 126 (4): 449–454. April 2019. doi:10.1007/s00702-019-01989-y. PMID 30805732. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 "Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?". Journal of Psychopharmacology 39 (9): 889–895. May 2025. doi:10.1177/02698811251330741. PMID 40322975. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 "DA agonists -- ergot derivatives: lisuride: management of Parkinson's disease". Movement Disorders 17 (Suppl 4): S74–S78. 2002. doi:10.1002/mds.5565. PMID 12211144. 
  5. ↑ 5.0 5.1 5.2 "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 791–804. November 2002. doi:10.1124/jpet.102.039867. PMID 12388666. 
  6. ↑ 6.0 6.1 "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 805–814. November 2002. doi:10.1124/jpet.102.039875. PMID 12388667. 
  7. ↑ 7.0 7.1 7.2 7.3 "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes". The Journal of Pharmacology and Experimental Therapeutics 303 (2): 815–822. November 2002. doi:10.1124/jpet.102.039883. PMID 12388668. 
  8. ↑ "Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs". Expert Opinion on Pharmacotherapy 14 (12): 1599–1610. August 2013. doi:10.1517/14656566.2013.806487. PMID 23815106. 
  9. ↑ "The Role of 5-Hydroxytryptamine in the Pathophysiology of Migraine and its Relevance to the Design of Novel Treatments". Mini Reviews in Medicinal Chemistry 17 (11): 928–938. 2017. doi:10.2174/1389557516666160728121050. PMID 27465216. 
  10. ↑ "Lisuride for levodopa-induced complications in Parkinson's disease". The Cochrane Database of Systematic Reviews 1999 (2). 2000. doi:10.1002/14651858.CD001515. PMID 10796801. 
  11. ↑ "Lisuride versus bromocriptine for levodopa-induced complications in Parkinson's disease". The Cochrane Database of Systematic Reviews 1999 (2). 2000. doi:10.1002/14651858.CD001514. PMID 10796800. 
  12. ↑ "Kᵢ Database". 26 March 2025. https://pdsp.unc.edu/kidb2/kidb/web/kis-results/index?KisResultsSearch%5Binput_receptors%5D=&KisResultsSearch%5Binput_sources%5D=&KisResultsSearch%5Binput_species%5D=&KisResultsSearch%5Binput_hot_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D=&KisResultsSearch%5Binput_test_ligands%5D%5B%5D=1079&KisResultsSearch%5Binput_citations%5D=&KisResultsSearch%5BsearchType%5D=&KisResultsSearch%5Bki_val_from%5D=&KisResultsSearch%5Bki_val_to%5D=&KisResultsSearch%5Bcustom_ki_val%5D=. 
  13. ↑ BindingDB BDBM85531 CAS_18016-80-3::lisuride, R. 128. September 1999. pp. 13–20. doi:10.1038/sj.bjp.0702751. PMID 10498829. PMC 1571597. https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=85531. Retrieved 26 March 2025. 
  14. ↑ "Psychedelics and the human receptorome". PLOS ONE 5 (2). February 2010. doi:10.1371/journal.pone.0009019. PMID 20126400. Bibcode: 2010PLoSO...5.9019R. 
  15. ↑ "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes". J Pharmacol Exp Ther 303 (2): 791–804. November 2002. doi:10.1124/jpet.102.039867. PMID 12388666. 
  16. ↑ "Mapping the binding site of the 5-HT2A receptor using mutagenesis and ligand libraries: Insights into the molecular actions of psychedelics". 16 January 2013. https://docs.lib.purdue.edu/dissertations/AAI3545320/.  Alt URL
  17. ↑ 17.0 17.1 "Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited". ACS Pharmacol Transl Sci 7 (3): 641–653. March 2024. doi:10.1021/acsptsci.3c00192. PMID 38481684. 
  18. ↑ "Agonist high and low affinity state ratios predict drug intrinsic activity and a revised ternary complex mechanism at serotonin 5-HT(2A) and 5-HT(2C) receptors". Synapse 35 (2): 144–150. February 2000. doi:10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K. PMID 10611640. 
  19. ↑ Increased 5-HT2A receptor signalling efficacy differentiates serotonergic psychedelics from non-psychedelics, 16 June 2024, doi:10.1101/2024.06.13.594677, https://www.biorxiv.org/content/biorxiv/early/2024/06/16/2024.06.13.594677.full.pdf, retrieved 26 March 2025 
  20. ↑ "Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy". Naunyn Schmiedebergs Arch Pharmacol 355 (6): 682–688. June 1997. doi:10.1007/pl00005000. PMID 9205951. 
  21. ↑ "Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats". Psychopharmacology 164 (1): 93–107. October 2002. doi:10.1007/s00213-002-1141-z. PMID 12373423. 
  22. ↑ 22.0 22.1 "Agonist activity of LSD and lisuride at cloned 5HT2A and 5HT2C receptors". Psychopharmacology 136 (4): 409–414. April 1998. doi:10.1007/s002130050585. PMID 9600588. 
  23. ↑ "Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis". Clinical Neuropharmacology 29 (2): 80–86. 2006. doi:10.1097/00002826-200603000-00005. PMID 16614540. 
  24. ↑ "8R-lisuride is a potent stereospecific histamine H1-receptor partial agonist". Molecular Pharmacology 65 (3): 538–549. March 2004. doi:10.1124/mol.65.3.538. PMID 14978232. 
  25. ↑ "Inactive and active state structures template selective tools for the human 5-HT5A receptor". Nature Structural & Molecular Biology 29 (7): 677–687. July 2022. doi:10.1038/s41594-022-00796-6. PMID 35835867. 
  26. ↑ "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chem Rev 124 (1): 124–163. January 2024. doi:10.1021/acs.chemrev.3c00375. PMID 38033123. 
  27. ↑ "Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists". Neuroscience Letters 493 (3): 76–79. April 2011. doi:10.1016/j.neulet.2011.01.046. PMID 21276828. 
  28. ↑ "Identification of a serotonin/glutamate receptor complex implicated in psychosis". Nature 452 (7183): 93–97. March 2008. doi:10.1038/nature06612. PMID 18297054. Bibcode: 2008Natur.452...93G. 
  29. ↑ "Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior". Neuron 53 (3): 439–452. February 2007. doi:10.1016/j.neuron.2007.01.008. PMID 17270739. 
  30. ↑ "Psychedelics: preclinical insights provide directions for future research". Neuropsychopharmacology 49 (1): 119–127. January 2024. doi:10.1038/s41386-023-01567-7. PMID 36932180. "This group has also reported that a heterodimeric complex between mGluR2 metabotropic glutamate and 5-HT2A receptors may be responsible for these actions [108–110]. Others have provided data suggesting the complex as such is not essential for the actions of psychedelics at 5-HT2A receptors [111].". 
  31. ↑ "Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. 36. Berlin, Heidelberg: Springer Berlin Heidelberg. 2017. pp. 45–73. doi:10.1007/7854_2017_478. ISBN 978-3-662-55878-2. "Because DOI-induced head-twitch behavior is not rescued in mGlu2 knockout mice over-expressing mGlu2ΔTM4N [a mGlu2/mGlu3 chimeric construct that does not form heteromers with the 5-HT2A receptor (Gonzalez-Maeso et al. 2008; Fribourg et al. 2011)] in frontal cortex (Moreno et al. 2012), these findings suggest that the 5-HT2A-mGlu2 receptor complex is critical for the hallucinogen-like behaviors induced by 5-HT2A receptor agonists (Figs. 6 and 7). [...] However, further investigation of this heteromeric receptor complex is definitely necessary because the functional significance of GPCR homo- and heteromerization remains a controversial topic (Bouvier and Hebert 2014; Lambert and Javitch 2014) [in addition, see: Delille et al. (2012), Frederick et al. (2015)]." 
  32. ↑ "Differential in Vitro Activation Profiles for Psychedelic versus Non-psychedelic Ergolines at the 5-HT2A Receptor". Emerging Trends in Drugs, Addictions, and Health 4. 2024. doi:10.1016/j.etdah.2023.100109. 
  33. ↑ "Hallucinogens". Pharmacol Ther 101 (2): 131–181. February 2004. doi:10.1016/j.pharmthera.2003.11.002. PMID 14761703. "As an interesting aside, noted in the previous section, there has been much controversy over the years as to why lisuride, a structural analogue of LSD, is not hallucinogenic (see, e.g., Egan et al., 1998). It is known, however, that lisuride is an extremely potent (Ki = 0.2 nM, EC50 = 0.6 nM) 5-HT1A receptor agonist (Marona-Lewicka et al., 2002). Based on the observation that 5-HT1A receptors are localized on cortical neurons (Martin-Ruiz et al., 2001) and have effects opposite to 5-HT2A receptor activation (Araneda & Andrade, 1991), one could speculate that the lack of hallucinogenic activity for lisuride may be due to an overriding stimulation of inhibitory cortical 5-HT1A receptors relative to a much weaker effect on excitatory cortical 5-HT2A receptors.". 
  34. ↑ 34.0 34.1 34.2 "The renaissance in psychedelic research: What do preclinical models have to offer". Psychedelic Neuroscience. Progress in Brain Research. 242. 2018. 25–67. doi:10.1016/bs.pbr.2018.08.003. ISBN 978-0-12-814255-4. "It should be noted when it comes to lisuride that its status as a non-psychedelic 5-HT2A receptor agonist is controversial as there appears to be some generalization in the subjective effects of lisuride and LSD in laboratory animals (Appel et al., 1999; Callahan and Appel, 1990; Fiorella et al., 1995) and high toxic doses of lisuride may induce reactions in humans that include visual and auditory hallucinations, reduced awareness, delusions, and paranoid ideation (Critchley et al., 1986; Lees and Bannister, 1981; Parkes et al., 1981). Nevertheless, such effects are not representative of typical experiences with lisuride administration, or psychedelic administration, and it would be hard to argue for substantial overlap in the effects of lisuride and psychedelics at typical doses. As such, we remain hopeful that lisuride and related compounds can be used to elucidate the critical signaling pathways of psychedelics and establish novel non-psychedelic 5-HT2A receptor agonists." 
  35. ↑ 35.0 35.1 "The behavioral pharmacology of hallucinogens". Biochem Pharmacol 75 (1): 17–33. January 2008. doi:10.1016/j.bcp.2007.07.018. PMID 17977517. PMC 2247373. https://www.iceers.org/Documents_ICEERS_site/Scientific_Papers/ayahuasca/Fantegrossi%20et%20al_2008_Behavioral_Pharm_Hallucinogens.pdf. "With regard to lisuride, the designation of this compound as non-hallucinogenic is by no means well established. Animals trained to discriminate LSD generalize their responding to lisuride [148,149], which has lead [sic] to the classification of this agent as a false positive under these procedures. Indeed, the substitution of lisuride for LSD has long been noted as a deficiency of the drug discrimination procedure, at least in terms of hallucinogen-induced stimulus control. But what is the evidence that lisuride is without hallucinogen action in man? Lisuride has been investigated as an anti-migraine medication, and as a therapeutic for Parkinson's disease. Several reports of the effects of lisuride in man thus appeared in the clinical literature in the early 1980s, and numerous such reports indicate that lisuride elicited toxic side effects including visual hallucination, reduced awareness, delusions, auditory hallucination, euphoria, morbid jealousy and paranoid ideation [150–155]. This side effect profile is not entirely inconsistent with the psychological effects of some hallucinogens. Nevertheless, the hallucinatory effects of lisuride, when present, are sometimes slow in onset, and at least one report explicitly states that no LSD-like effects have been observed in healthy volunteers [156]. Thus, the hallucinogenic status of this most interesting ergoline will likely remain controversial.". 
  36. ↑ Nichols, David E. (2016). "Psychedelics" (in en). Pharmacological Reviews 68 (2): 264–355. doi:10.1124/pr.115.011478. ISSN 0031-6997. PMID 26841800. 
  37. ↑ 37.0 37.1 "Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action". Handb Exp Pharmacol. Handbook of Experimental Pharmacology 252: 227–260. 2018. doi:10.1007/164_2018_107. ISBN 978-3-030-10560-0. PMID 29532180. "Similar to the head-twitch model, compounds targeting receptors other than 5-HT2A modulate the discriminative stimulus effects of serotonergic psychedelics, and false positives, false negatives, and misunderstood results have emerged (Benneyworth et al. 2005; Reissig et al. 2005; Winter 2009). For example, lisuride substitutes for a number of serotonergic psychedelics in the two-lever drug discrimination paradigm; however, this can be overcome by training animals to discriminate two training drugs and vehicle. Thus, when animals are trained to discriminate lisuride, LSD, and vehicle, lisuride does not substitute for LSD (Appel et al. 2004).". 
  38. ↑ "Hallucinogens in Drug Discrimination". Behavioral Neurobiology of Psychedelic Drugs. Curr Top Behav Neurosci. 36. 2018. pp. 201–219. doi:10.1007/7854_2017_476. ISBN 978-3-662-55878-2. 
  39. ↑ "LSD, 5-HT (serotonin), and the evolution of a behavioral assay". Neurosci Biobehav Rev 27 (8): 693–701. January 2004. doi:10.1016/j.neubiorev.2003.11.012. PMID 15019419. 
  40. ↑ "Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats". Psychopharmacology (Berl) 164 (1): 93–107. October 2002. doi:10.1007/s00213-002-1141-z. PMID 12373423. 
  41. ↑ "Characterization of the head-twitch response induced by hallucinogens in mice: detection of the behavior based on the dynamics of head movement". Psychopharmacology (Berl) 227 (4): 727–739. June 2013. doi:10.1007/s00213-013-3006-z. PMID 23407781. "Although most 5-HT2A agonists induce the HTR in mice and rats, one notable exception is the non-hallucinogenic LSD analog lisuride (Gerber et al., 1985; González-Maeso et al., 2003, 2007). It was recently proposed that the behavioral differences between LSD and lisuride may be due to 5-HT2A functional selectivity, whereby lisuride activates the 5-HT2A receptor but does not recruit the specific signaling mechanisms necessary to induce the HTR and provoke hallucinogenesis (González-Maeso et al., 2007). Alternatively, as we have discussed previously (Halberstadt and Geyer, 2010), lisuride is a weak 5-HT2A partial agonist (Cussac et al., 2008), and it is possible that lisuride does not activate the receptor with sufficient efficacy to induce the HTR. The fact that lisuride has been found to induce the HTR in the least shrew (Cryptotis parva), a non-rodent species that is reportedly highly sensitive to 5-HT2A agonists (Darmani, 1994), is consistent with the latter hypothesis.". 
  42. ↑ "The head-twitch response in the least shrew (Cryptotis parva) is a 5-HT2- and not a 5-HT1C-mediated phenomenon". Pharmacol Biochem Behav 48 (2): 383–396. June 1994. doi:10.1016/0091-3057(94)90542-8. PMID 8090805. 
  43. ↑ "Dopamine Agonists: From the 1970s to Today". Neuroendocrinology 109 (1): 34–41. 2019. doi:10.1159/000499470. PMID 30852578. 
  44. ↑ "Response of central monoaminergic neurons to lisuride: comparison with LSD". Life Sci. 24 (14): 1289–1297. 1979. doi:10.1016/0024-3205(79)90148-6. PMID 470543. 
  45. ↑ "The Effects of Psychedelics on Neuronal Physiology". Annu Rev Physiol 86: 27–47. February 2024. doi:10.1146/annurev-physiol-042022-020923. PMID 37931171. 
  46. ↑ "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nat Neurosci 26 (6): 1032–1041. June 2023. doi:10.1038/s41593-023-01316-5. PMID 37280397. 
  47. ↑ "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics". Neuron 113 (19): 3129–3142.e9. July 2025. doi:10.1016/j.neuron.2025.06.012. PMID 40683247. https://www.cell.com/cms/10.1016/j.neuron.2025.06.012/attachment/7d8365fe-51f3-4a28-bf40-9999bec837f6/mmc11.pdf. "Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63". 
  48. ↑ 48.0 48.1 48.2 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 747–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA747. 
  49. ↑ 49.0 49.1 49.2 49.3 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 612–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA612. 
  50. ↑ 50.0 50.1 50.2 50.3 "Dopergin". https://www.drugs.com/international/lisuride.html. 
  51. ↑ "Pharmacokinetics of bromerguride, a new dopamine-antagonistic ergot derivative in rat and dog". European Journal of Drug Metabolism and Pharmacokinetics 12 (1): 31–40. January 1987. doi:10.1007/BF03189859. PMID 3609071. 
  52. ↑ "Mutterkornalkaloide XVI. Einige N-(D-6-methylisoergolenyl-8)-, N-(D-6-methylergolenyl-8)- und N-(D-6-methylergolin(I)-yl-8)-N'-substituierte harnstoffe". Collection of Czechoslovak Chemical Communications 25 (7): 1922–1928. 1960. doi:10.1135/cccc19601922. ISSN 0010-0765. 
  53. ↑ "General Anesthetics". Pharmacology and Pharmacotherapeutics. Popular Prakashan. 1973. pp. 929–. ISBN 978-81-7991-527-1. https://books.google.com/books?id=7d493VOD4P8C&pg=PA929. 
  54. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. 31 October 1999. pp. 170–. ISBN 978-0-7514-0499-9. https://books.google.com/books?id=mqaOMOtk61IC&pg=PA170. 
  55. ↑ "Lisuride - Axxonis Pharma". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800024391. 
  56. ↑ "Lisuride implant - Titan Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800027415. 



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