In contrast to lysergic acid, which is said to have "very unexceptional biological activity", descarboxylysergic acid was, surprisingly, found to produce effects in mice that were described as remarkably similar to those of LSD.[2][3][5][6][4] However, it was said that the specific tests performed were not reliably indicative of hallucinogenic effects in humans.[6][4] Moreover, no other assays of hallucinogen-type effects were carried out, and descarboxylysergic acid is not known to have been tested in humans.[2] Subsequent research by David E. Nichols found that descarboxylysergic acid did not show LSD-like effects in animal drug discrimination tests.[7] According to Nichols, the simplest ergoline with definite known psychoactive effects in humans is the lysergamide lysergic acid amide (LSA; ergine).[2][3]
Descarboxylysergic acid was first synthesized and described by Bach, Hall, and Kornfeld in 1974.[7][4] It was subsequently studied by Nichols and his former student Robert A. Oberlender, the creator of lisdexamfetamine, in the 1980s.[7][8]
Related Research Articles
Lysergic acid diethylamide, commonly known as LSD, is a potent psychedelic drug that intensifies thoughts, emotions, and sensory perception. Often referred to as acid or lucy, LSD can cause mystical, spiritual, or religious experiences. At higher doses, it primarily induces visual and auditory hallucinations. LSD is not considered addictive, because it does not produce compulsive drug-seeking behavior. Using LSD can lead to adverse psychological reactions, such as anxiety, paranoia, and delusions. Additionally, it may trigger "flashbacks," also known as hallucinogen persisting perception disorder (HPPD), where individuals experience persistent visual distortions after use.
Ipomoea corymbosa is a species of morning glory, native throughout Latin America from Mexico as far south as Peru and widely naturalised elsewhere. Its common names include Christmasvine, Christmaspops, and snakeplant.
Ergine, also known as lysergic acid amide and lysergamide, is an ergoline alkaloid that occurs in Clavicipitaceous fungi, which includes Convolvulaceae vines, which have a permanent bond with these fungi. The most common source of ergine for consumers is the seeds of Ipomoea tricolor, Ipomoea corymbosa, and Argyreia nervosa; isoergine and lysergic acid propanolamide have also been shown to contribute to their psychoactivity.
Ergoline is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized in ergot. Some of these are implicated in the condition of ergotism, which can take a convulsive form or a gangrenous form. Even so, many ergoline alkaloids have been found to be clinically useful. Annual world production of ergot alkaloids has been estimated at 5,000–8,000 kg of all ergopeptines and 10,000–15,000 kg of lysergic acid, used primarily in the manufacture of semi-synthetic derivatives.
Lysergic acid, also known as D-lysergic acid and (+)-lysergic acid, is a precursor for a wide range of ergoline alkaloids that are produced by the ergot fungus and found in the seeds of Argyreia nervosa, and Ipomoea species.
Argyreia nervosa is a perennial climbing vine native to the Indian subcontinent and introduced to numerous areas worldwide, including Hawaii, Africa, and the Caribbean. Though it can be invasive, it is often prized for its aesthetic and medicinal value. Common names include Hawaiian baby woodrose, adhoguda अधोगुडा or vidhara विधारा (Sanskrit), elephant creeper and woolly morning glory. Its seeds are known for their powerful entheogenic properties, greater or similar to those of Ipomoea species, with users reporting significant psychedelic and spiritual experiences. The two botanical varieties are Argyreia nervosa var. nervosa described here, and Argyreia nervosa var. speciosa, the roots of which are used in Ayurvedic medicine.
Amides of lysergic acid are collectively known as lysergamides or ergoamides, and include a number of compounds with potent agonist and/or antagonist activity at various serotonin and dopamine receptors. Lysergamides contain an embedded tryptamine structure, and as a result can produce similar, often psychedelic, effects to those of the true tryptamines.
Ergonovine, also known as ergometrine and lysergic acid propanolamide is a medication used to cause contractions of the uterus to treat heavy vaginal bleeding after childbirth. It can be used either by mouth, by injection into a muscle, or injection into a vein. It begins working within 15 minutes when taken by mouth and is faster in onset when used by injection. Effects last between 45 and 180 minutes.
ᴅ-Lysergic acid α-hydroxyethylamide, also known as ᴅ-lysergic acid methyl carbinolamide, is an ergoamide and an ergoline. It is perhaps the main constituent of the parasitic fungus, Claviceps paspali; and found in trace amounts in Claviceps Purpurea. C. paspali and C. purpurea are ergot-spreading fungi. Periglandula, Clavicipitacepus fungi, are permanently symbiotically connected to an estimated 450 species of Convolvulaceae and thus generate LAH in some of them. The most well-known ones are Ipomoea tricolor, Turbina corymbosa (coaxihuitl), and Argyreia nervosa.
Methylergometrine, also known as methylergonovine and sold under the brand name Methergine, is a medication of the ergoline and lysergamide groups which is used as an oxytocic in obstetrics and as an antimigraine agent in the treatment of migraine headaches. It reportedly produces psychedelic effects similar to those of lysergic acid diethylamide (LSD) at high doses.
AL-LAD, also known as 6-allyl-6-nor-LSD, is a psychedelic drug and an analog of lysergic acid diethylamide (LSD). It is described by Alexander Shulgin in the book TiHKAL. It is synthesized starting from nor-LSD as a precursor, using allyl bromide as a reactant.
ETH-LAD, 6-ethyl-6-nor-lysergic acid diethylamide is an analogue of LSD. Its human psychopharmacology was first described by Alexander Shulgin in the book TiHKAL. ETH-LAD is a psychedelic drug similar to LSD, and is slightly more potent than LSD itself, with an active dose reported at between 20 and 150 micrograms. ETH-LAD has subtly different effects to LSD, described as less demanding.
PRO-LAD is an analogue of LSD. It is described by Alexander Shulgin in the book TiHKAL. PRO-LAD is a psychedelic drug similar to LSD, and is around as potent as LSD itself with an active dose reported at between 100 and 200 micrograms.
N-Morpholinyllysergamide, also known as lysergic acid morpholide, is a derivative of ergine (lysergamide). It is less potent than lysergic acid diethylamide (LSD) but is reported to have some LSD-like effects at doses ranging from 75 to 700 micrograms and a shorter duration. LSM-775 may only produce weak or threshold psychedelic effects in humans.
Lysergic acid 2,4-dimethylazetidide (LA-SS-Az, LSZ) is an analog of LSD developed by the team led by David E. Nichols at Purdue University. It was developed as a rigid analog of LSD with the diethylamide group constrained into an azetidine ring in order to map the binding site at the 5-HT2A receptor. There are three possible stereoisomers around the azetidine ring, with the (S,S)-(+) isomer being the most active, slightly more potent than LSD itself in drug discrimination tests using trained rats.
Methylisopropyllysergamide is an analogue of LSD that was originally discovered by Albert Hofmann at Sandoz during the original structure-activity research into LSD. It has subsequently been investigated in more detail by the team led by David E. Nichols at Purdue University. Methylisopropyllysergamide is a structural isomer of LSD, with the alkyl groups on the amide nitrogen having been subjected to a methylene shuffle. MIPLA and its ethylisopropyl homologue EIPLA are the only simple N,N-dialkyl lysergamides that approach the potency of LSD itself, being around 1/3-1/2 the potency of LSD, while all other dialkyl analogues tested are only around 1/10 as potent as LSD, although some N-monoalkyl lysergamides such as the sec-butyl and t-butyl derivatives were also found to show an activity profile and potency comparable to LSD, and the mono-isopropyl derivative is only slightly weaker than MIPLA. Apart from its lower potency, the hallucinogenic effects of methylisopropyllysergamide are similar to those of LSD itself, and the main use for this drug has been in studies of the binding site at the 5-HT2A receptor through which LSD exerts most of its pharmacological effects.
Lysergic acid 2-butyl amide (2-Butyllysergamide, LSB) is an analogue of LSD originally developed by Richard Pioch at Eli Lilly in the 1950s, but mostly publicised through research conducted by the team led by David E. Nichols at Purdue University. It is a structural isomer of LSD, with the two ethyl groups on the amide nitrogen having been replaced by a single sec-butyl group, joined at the 2-position. It is one of the few lysergamide derivatives to exceed the potency of LSD in animal drug discrimination assays, with the (R) isomer having an ED50 of 33nmol/kg for producing drug-appropriate responding, vs 48nmol/kg for LSD itself. The corresponding (R)-2-pentyl analogue has higher binding affinity for the 5-HT1A and 5-HT2A receptors, but is less potent in producing drug-appropriate responding, suggesting that the butyl compound has a higher efficacy at the receptor target. The drug discrimination assay for LSD in rats involves both 5-HT1A and 5-HT2A mediated components, and while lysergic acid 2-butyl amide is more potent than LSD as a 5-HT1A agonist, it is slightly less potent as a 5-HT2A agonist, and so would probably be slightly less potent than LSD as a hallucinogen in humans. The main use for this drug has been in studies of the binding site at the 5-HT2A receptor through which LSD exerts most of its pharmacological effects, with the stereoselective activity of these unsymmetric monoalkyl lysergamides foreshadowing the subsequent development of compounds such as lysergic acid 2,4-dimethylazetidide (LSZ).
Lysergic acid 3-pentyl amide is an analogue of LSD originally researched by David E. Nichols and colleagues at Purdue University. It has similar binding affinity to LSD itself as both a 5-HT1A and 5-HT2A agonist, and produces similar behavioral and physiological responses in animals with only slightly lower potency than LSD. Other isomers of this compound have also been explored, with the 1-pentylamide being around 75% the potency of LSD, while the (R)-2-pentylamide shows similar 5-HT2A binding affinity to LSD in vitro but has only around half the potency of LSD in producing drug-appropriate responding in mice, and the (S)-2-pentylamide is inactive.
1V-LSD, sometimes nicknamed Valerie, is a psychotropic substance and a research chemical with psychedelic effects. 1V-LSD is an artificial derivative of natural lysergic acid, which occurs in ergot alkaloids, as well as being an analogue of LSD. 1V-LSD has been sold online until an amendment to the German NpSG was enforced in 2022 which controls 1P-LSD and now 1cP-LSD, 1V-LSD and several other lysergamides.
Lysergine, also known as 9,10-didehydro-6,8β-dimethylergoline, is an ergot alkaloid and serotonin receptor agonist of the ergoline family. It is a minor constituent of ergot.
References
1 2 3 4 5 6 Hauth H (1979). "Chemical Aspects of Ergot Derivatives with Central Dopaminergic Activity". Dopaminergic Ergot Derivatives and Motor Function. Elsevier. pp.23–32. doi:10.1016/b978-0-08-024408-2.50007-5. ISBN978-0-08-024408-2. Kornfeld et al. (ref. 12) have likewise attempted to identify the part of the ergoline structure responsible for its pharmacological activity. They have shown that one of the properties of racemic 9.10-didehydro-6-methyl-ergoline (Fig. 10) is the inhibition of prolactin secretion. However, the potency of this activity is less than 10% of that of ergonine. [...] Fig. 10. dl-9,10-Didehydro-6-methyl-ergoline = dl-6-Methyl-9-ergolene = dl-Descarboxylysergic acid [...] These findings once again confirm the observation that although the ergoline skeleton contains dopaminergic and, obviously, also serotoninergic and noradrenergic components, it is the substituents alone that are responsible for the profile and intensity of the biological activity. The proof is to be found in publications reporting on the effects of substitution in ergolines and ergopeptines on biological activity (ref. 6,7,13).
1 2 3 4 5 6 Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Curr Top Behav Neurosci. Current Topics in Behavioral Neurosciences. 36: 1–43. doi:10.1007/7854_2017_475. ISBN978-3-662-55878-2. PMID28401524. 3.1 Amide Modifications of Lysergic Acid Derivatives The simplest ergoline with human psychoactive properties is lysergic acid amide (23, ergine), reported by Hofmann and Tscherter to be the active component in Rivea corymbosa seeds used by the Aztecs in various magical potions and ointments (Hofmann 1971). If the C(8) amide substituent is removed completely to provide the 8-descarboxy 24, the compound is reported to produce a mouse behavioral profile "remarkably similar to that shown by LSD" (Bach et al. 1974). Unfortunately, no other assays were carried out, nor were human studies carried out that would elucidate whether the presence of an amide substituent is an absolute requirement for activity. That is an important question because even slight modifications to the diethylamide moiety of LSD result in dramatic losses of in vivo activity. [...] With respect to lysergic acid amides, it should be pointed out that the high in vivo potency of LSD seems to depend on the presence of the N,N-diethylamide moiety.
1 2 3 4 Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT 2A agonists". Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi:10.1002/wmts.42. ISSN2190-460X. Studies of the Amide Portion of Lysergic Acid Derivatives The simplest ergoline with human psychoactive properties, and presumably 5-HT2A agonist activity, is lysergic acid amide (15, ergine), which was reported by Hofmann and Tscherter36 to be the active component in Rivea corymbosa seeds, used by the Aztecs in various magical potions and ointments (Figure 12). Surprisingly, if the C(8) amide substituent is removed completely to give 8-descarboxy lysergic acid 16, the compound is reported to produce a behavioral profile in mice 'remarkably similar to that shown by LSD'.37 [...] FIGURE 12 | The structures of lysergic acid amide 15 (ergine) and 8-descarboxy lysergic acid 16.
1 2 3 4 5 Nichols DE (June 1976). "Structural correlation between apomorphine and LSD: involvement of dopamine as well as serotonin in the actions of hallucinogens". J Theor Biol. 59 (1): 167–177. Bibcode:1976JThBi..59..167N. doi:10.1016/s0022-5193(76)80030-6. PMID7711. Another important point which should be defined is the relative importance of the substituent at the C-8 position of LSD. It has been demonstrated that small changes in substitution on the amide nitrogen produce, in every instance, a molecule with decreased hallucinogenic activity when compared with the diethylamide (Hofmann, 1968). Speculation concerning the role of the amide function of LSD as a result of this finding continues. However, Bach, Hall & Kornfeld (1974) have shown that 8-descarboxylysergic acid, completely lacking an 8 substituent, still retains a profile of activity in mice similar to LSD. Activity of this compound on rabbit aortic strips was demonstrated to be comparable to ergonovine, and on rat stomach strips was about one-third the potency of methysergide as a serotonin antagonist. Thus the importance of C-8 substitution may lie in metabolic, distribution, or conformational factors, rather than to some receptor requirement for binding at this site.
1 2 3 Hurt SD (1976). "The synthesis of analogs of the ergot alkaloids". eScholarship. Retrieved 19 January 2025. The remainder of the work in this series was undertaken because 75 that descarboxylysergic acid (l32) wº of the report by Kornfeld, et al. has interesting pharmacological properties. In mouse behavioral Screening * showed a profile of activities remarkably similar to that shown by LSD, although, previous studies have shown that such observations are not reliably predictive of hallucinogenic activity in man. Descarboxylysergic acid showed high oxytocic activity and moderate prolactin inhibition.
1 2 3 Oberlender RA (1989). Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens (Thesis). Purdue University. Retrieved 19 January 2025– via Purdue e-Pubs. This analogue, descarboxylysergic acid, was synthesized by Bach et al. (1974) and seemed to retain LSD-like activity in a simple mouse assay, suggesting that the 8-substituent is not necessary. However, the lack of LSD-like [discriminative stimulus (DS)] properties of descarboxylysergic acid (Oberlender and Nichols, unpublished data) [...]
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