Notes: The smaller the value, the more avidly the drug binds to the site. All proteins are human unless otherwise specified. Refs:[13][14][15][16][7] [8][17][18][19][20][21]
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,[8] it lacks the psychedelic effects of LSD and hence is non-hallucinogenic.[27][1] Research suggests that the lack of psychedelic effects with lisuride may arise from biased agonism of the 5-HT2A receptor. Stimulation of the 5-HT2Aprotomer within the 5-HT2A–mGlu2receptor complex evokes psychedelic effects, while these effects do not occur during sole stimulation of monomeric 5-HT2A receptors. Accordingly, different G proteins are involved.[28][29] 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.[30]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.[31][32] Lisuride shows weak or no Gq pathway recruitment and this may be responsible for its non-hallucinogenic nature.[18][33] Alternatively, lisuride is an extremely potent serotonin 5-HT1A receptor agonist, and this might inhibit serotonin 5-HT2A receptor-mediated hallucinogenic effects.[34]
Although lisuride has widely been said to be non-hallucinogenic, this may not actually be true.[5][35][36] Lisuride has been associated with incidence of visual and auditory hallucinations, sensory disturbances, delusions, and other hallucinogenic effects at high doses.[5][35][36] 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.[5] Both serotonin 5-HT2A receptor agonism and dopamine D2 receptor agonism might contribute to the hallucinogenic effects of lisuride.[5] 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.[5] 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.[37][38][39][5][35][40][41] 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.[42][43] 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.[38]
Lisuride dose-dependently suppresses prolactin levels due to its dopaminergic activity.[1][44] 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.[1]
Minute amounts of lisuride suppress the firing of dorsal raphe serotonergic neurons, presumably due to agonist activity at 5-HT1A receptors.[45] 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 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.[1][53] It was marketed by the early 1970s.[54]
Society and culture
Generic names
Lisuride is the INNTooltip International Nonproprietary Name and lysuride is the BANTooltip British Approved Name.[49][55][50][51]
Brand names
Lisuride has been sold under brand names including Arolac, Cuvalit, Dopagon, Dopergin, Dopergine, Eunal, Lisenil, Lizenil, Lysenyl, Proclacam, Prolacam, and Revanil.[49][50][51][1]
Preliminary clinical research suggests that transdermal administration of lisuride may be useful in the treatment of Parkinson's disease.[1] 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.[1] 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.[56][57]
1 2 3 4 5 6 7 8 Kehler J, Lindskov MS (May 2025). "Are the LSD-analogs lisuride and ergotamine examples of non-hallucinogenic serotonin 5-HT2A receptor agonists?". Journal of Psychopharmacology. 39 (9): 889–895. doi:10.1177/02698811251330741. PMID40322975.
1 2 3 Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "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. doi:10.1124/jpet.102.039867. PMID12388666. S2CID6200455.
1 2 Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, Millan MJ (November 2002). "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. doi:10.1124/jpet.102.039875. PMID12388667. S2CID35238120.
1 2 3 4 Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, Millan MJ (November 2002). "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. doi:10.1124/jpet.102.039883. PMID12388668. S2CID19260572.
↑ Ramírez Rosas MB, Labruijere S, Villalón CM, Maassen Vandenbrink A (August 2013). "Activation of 5-hydroxytryptamine1B/1D/1F receptors as a mechanism of action of antimigraine drugs". Expert Opinion on Pharmacotherapy. 14 (12): 1599–1610. doi:10.1517/14656566.2013.806487. PMID23815106. S2CID22721405.
↑ Villalón CM, VanDenBrink AM (2017). "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. doi:10.2174/1389557516666160728121050. PMID27465216.
↑ Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "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. doi:10.1124/jpet.102.039867. PMID12388666.
↑ Egan C, Grinde E, Dupre A, Roth BL, Hake M, Teitler M, Herrick-Davis K (February 2000). "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. doi:10.1002/(SICI)1098-2396(200002)35:2<144::AID-SYN7>3.0.CO;2-K. PMID10611640.
↑ López-Giménez JF, González-Maeso J (2017). "Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways". Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol.36. Berlin, Heidelberg: Springer Berlin Heidelberg. pp.45–73. doi:10.1007/7854_2017_478. ISBN978-3-662-55878-2. PMC5756147. PMID28677096. 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)].
↑ Nichols DE (February 2004). "Hallucinogens". Pharmacol Ther. 101 (2): 131–181. doi:10.1016/j.pharmthera.2003.11.002. PMID14761703. 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.
1 2 3 Murnane KS (2018). "The renaissance in psychedelic research: What do preclinical models have to offer". Psychedelic Neuroscience. Progress in Brain Research. Vol.242. pp.25–67. doi:10.1016/bs.pbr.2018.08.003. ISBN978-0-12-814255-4. PMID30471682. 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.{{cite book}}: |journal= ignored (help)
1 2 Fantegrossi WE, Murnane KS, Reissig CJ (January 2008). "The behavioral pharmacology of hallucinogens"(PDF). Biochem Pharmacol. 75 (1): 17–33. doi:10.1016/j.bcp.2007.07.018. PMC2247373. PMID17977517. 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.
1 2 Canal CE (2018). "Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 252: 227–260. doi:10.1007/164_2018_107. ISBN978-3-030-10560-0. PMC6136989. PMID29532180. 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).
↑ Appel JB, West WB, Buggy J (January 2004). "LSD, 5-HT (serotonin), and the evolution of a behavioral assay". Neurosci Biobehav Rev. 27 (8): 693–701. doi:10.1016/j.neubiorev.2003.11.012. PMID15019419.
↑ Marona-Lewicka D, Kurrasch-Orbaugh DM, Selken JR, Cumbay MG, Lisnicchia JG, Nichols DE (October 2002). "Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats". Psychopharmacology (Berl). 164 (1): 93–107. doi:10.1007/s00213-002-1141-z. PMID12373423.
↑ Halberstadt AL, Geyer MA (June 2013). "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. doi:10.1007/s00213-013-3006-z. PMC3866102. PMID23407781. 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.
↑ Darmani NA, Mock OB, Towns LC, Gerdes CF (June 1994). "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. doi:10.1016/0091-3057(94)90542-8. PMID8090805.
↑ Rogawski MA, Aghajanian GK (1979). "Response of central monoaminergic neurons to lisuride: comparison with LSD". Life Sci. 24 (14): 1289–1297. doi:10.1016/0024-3205(79)90148-6. PMID470543.
↑ Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, Antenucci L, Kot EF, Goncharuk SA, Kaurinkoski K, Kuutti M, Fred SM, Elsilä LV, Sakson S, Cannarozzo C, Diniz CR, Seiffert N, Rubiolo A, Haapaniemi H, Meshi E, Nagaeva E, Öhman T, Róg T, Kankuri E, Vilar M, Varjosalo M, Korpi ER, Permi P, Mineev KS, Saarma M, Vattulainen I, Casarotto PC, Castrén E (June 2023). "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nat Neurosci. 26 (6): 1032–1041. doi:10.1038/s41593-023-01316-5. PMC10244169. PMID37280397.
↑ Jain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, Suomivuori CM, Huang XP, Shub L, DiBerto JF, Kim K, DeLeon C, Krumm BE, Fay JF, Keiser M, Hauser AS, Dror RO, Shoichet B, Gloriam DE, Nichols DE, Roth BL (July 2025). "The polypharmacology of psychedelics reveals multiple targets for potential therapeutics"(PDF). Neuron. doi:10.1016/j.neuron.2025.06.012. PMID40683247. 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
↑ Hilderbrand M, Hümpel M, Krause W, Täuber U (January 1987). "Pharmacokinetics of bromerguride, a new dopamine-antagonistic ergot derivative in rat and dog". European Journal of Drug Metabolism and Pharmacokinetics. 12 (1): 31–40. doi:10.1007/BF03189859. PMID3609071. S2CID22838914.
↑ Zikán V, Semonský M (1960). "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. doi:10.1135/cccc19601922. ISSN0010-0765.
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