 | |
| Clinical data | |
|---|---|
| Other names | 9,10-DH-LSD; 9,10-Dihydrolysergic acid diethylamide; Dihydro-LSD; DH-LSD; Dihydrolysergic acid diethylamide; (10ξ)-N,N-Diethyl-6-methylergoline-8β-carboxamide |
| Routes of administration | Oral[1] |
| Drug class | Serotonin receptor modulator; Non-hallucinogenic serotonin 5-HT2A receptor partial agonist |
| ATC code |
|
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C20H27N3O |
| Molar mass | 325.456 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
9,10-Dihydro-LSD, or 9,10-DH-LSD, also known simply as dihydro-LSD (DH-LSD) or as 9,10-dihydrolysergic acid diethylamide, is a non-hallucinogenic serotonin receptor modulator of the lysergamide family related to lysergic acid diethylamide (LSD).[1][2][3][4] It is the analogue of LSD in which the 9,10- double bond in the D ring of the ergoline ring system has been hydrogenated.[1][2][3]
Use and effects
[edit]In spite of its potent serotonin 5-HT2A receptor agonism,[3] 9,10-dihydro-LSD was found to be inactive in terms of psychedelic effects in humans.[1][5][3][6][7][8][9] Whereas LSD is active at an oral dose of 1 μg/kg (70 μg for a 70-kg person), 9,10-dihydro-LSD was inactive orally at doses of up to 50 μg/kg (3.5 mg for a 70-kg person).[1] As such, 9,10-dihydro-LSD does not produce psychedelic effects at doses of up to 50 times the effective doses of LSD, demonstrating less than 2% of the potency of LSD in this regard.[1]
Side effects
[edit]Despite lack psychedelic effects, 9,10-dihydro-LSD has nonetheless been reported to produce strong autonomic effects in humans, including nausea, emesis, tachycardia, shivering, polyuria, headache, and paresthesias, at doses of 100 to 200 μg.[7]
Pharmacology
[edit]Pharmacodynamics
[edit]The drug has been shown to bind to the serotonin 5-HT2A, 5-HT2C, and 5-HT1A receptors.[3] It acts as a partial agonist of the serotonin 5-HT2A receptor similarly to LSD, whereas functional activities at the other serotonin receptors were not reported.[3] At the serotonin 5-HT2A receptor, 9,10-dihydro-LSD's affinity (K0.5) was 2.9 nM (compared to 1.08 nM for LSD), whereas its activational potency (EC50) in terms of calcium release was 3,840 nM and its intrinsic activity (Emax) was 58% (relative to 595 nM and 55% for LSD, respectively).[3] Hence, 9,10-dihydro-LSD had about 2.7-fold lower affinity and 6-fold lower activational potency at the receptor compared to LSD, whereas its activational efficacy in terms of calcium release was about the same.[3] At the serotonin 5-HT2C and 5-HT1A receptors, 9,10-dihydro-LSD showed 4.6-fold and 26-fold lower affinities than those of LSD, respectively.[3] In earlier studies, 9,10-dihydro-LSD showed 52% of the serotonin antagonist activity of LSD in the isolated rat uterus in vitro.[5][4][7][10][11]
It was reported to have failed to produce the autonomic or sympathomimetic effects typical of LSD and related psychedelics in animals, such as mydriasis, piloerection, and hyperthermia,[4] although it did produce hypothermia.[7]
Chemistry
[edit]Analogues
[edit]A number of analogues and derivatives of 9,10-dihydro-LSD are known, for instance dihydroergotoxine, a mixture of dihydroergocornine, dihydroergocristine, and dihydroergocryptine, and dihydroergotamine.[12] Various 9,10-dihydrolysergamides are known to be very potent α-adrenergic antagonists, to have almost no effects on the uterus (i.e., no oxytocic activity), and to have markedly reduced central effects.[12] Dihydroergotoxine has been used to treat vascular disorders and essential hypertension, but has largely been discontinued.[12] Other 9,10-Dihydrolysergamides have shown emetic activity.[12] They often have comparable antiserotonergic activity relative to the saturated analogues.[12] In general, 9,10-dihydrolysergamides are said to be devoid of hallucinogenic activity.[6]
History
[edit]9,10-Dihydro-LSD was first described in the scientific literature by at least the 1950s.[2][8][10]
See also
[edit]- Substituted lysergamide
- 2,3-Dihydro-LSD
- Lumi-LSD (10-hydroxy-9,10-dihydro-LSD)
References
[edit]- ^ a b c d e f Brimblecombe RW, Pinder RM (1975). "Indolealkylamines and Related Compounds". Hallucinogenic Agents. Bristol: Wright-Scientechnica. pp. 98–144. ISBN 978-0-85608-011-1. OCLC 2176880. OL 4850660M.
Table 4.3.—COMPARATIVE HALLUCINOGENIC POTENCIES IN MAN OF DERIVATIVES OF D-LYSERGIC ACID* [...]
- ^ a b c Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524.
The 9,10-double bond of LSD is apparently crucial for its psychedelic action, and reducing it abolishes hallucinogenic activity (Stoll and Hofmann 1955; Hofmann 1968). Reduced 9,10-dihydro-LSD is still relatively planar, like LSD, so the reason(s) for the loss of activity is unclear (Nakahara et al. 1977). Although 9,10-dihydro-LSD lacks psychedelic effects in humans, there has so far not been a comparison of its receptor activities with those of LSD that might explain its inactivity.
- ^ a b c d e f g h i McCorvy JD (16 January 2013). Mapping the binding site of the 5-HT2A receptor using mutagenesis and ligand libraries: Insights into the molecular actions of psychedelics (Ph.D. thesis). Purdue University. Archived from the original on 16 January 2013 – via Purdue e-Pubs.
Table 5.2 Binding affinities using 3 H-LSD at 5-HT2A EL2 mutants [...] 5.2.3. Non-hallucinogenic Analogs: Lisuride and 9, 10-dihydro LSD [...] The reduced LSD analog, 9,10-dihydro LSD, which has been shown to be inactive compared to LSD (Sankar, 1975), had a slightly reduced affinity at the wild-type 5-HT2A receptor and is discussed in more detail in the next chapter. Examination of the 9,10-dihydro analog at EL2 mutants showed it had increased affinity at L229A, similar to LSD itself. L229S, by contrast, led to an even greater loss in affinity for the 9,10-dihydro analog (3.3- fold loss) compared to LSD (2.5-fold loss). [...] Table 6.2 Binding affinities using 3 H-LSD at S3.36 and Y7.43 mutants [...] Table 6.3 Calcium release at S3.36 and Y7.43 mutants [...] 6.2.3. LSD and N(6)-alkyl Analogs: In the wild-type 5-HT2A receptor, LSD, 9,10-dihydro LSD, and N(6)-alkyl analogs all had nanomolar affinity similar to LSD. In the calcium luminescence assay, however, 9,10-dihydro LSD was more than 6-fold less potent compared to LSD. [...] Figure A.2 Ergoline Ligand Structures [...] Table B.1 Binding affinities for 5-HT2A, 5-HT2C, 5-HT1A receptors using 3 H-LSD [...]
- ^ a b c Hofmann A (1968). "Psychotomimetic Agents". In Burger A (ed.). Drugs Affecting the Nervous System. Vol. 2. New York: Marcel Dekker. pp. 169–235 (210–212).
3. CHEMICAL MODIFICATIONS OF LSD-25 In order to investigate the SAR, the molecular structure of LSD was modified in the following ways: [...] (3) saturation of the double bond in position 9, 10, [...] The double bond at the 9,10 position was saturated with hydrogen (195) or by addition of the elements of water (205). [...] 6. PHARMACOLOGICAL EFFECTS AND PSYCHIC ACTIVITY OF LSD-25 DERIVATIVES [...] A more or less comprehensive pharmacological analysis of the many derivatives mentioned in Sections and 3 was carried out (229). Some of them were also studied in human beings. In order to compare the pharmacological effects and psychic activity, Cerletti (230) selected 18 typical modifications of LSD, as depicted in Figure 5.2. [...] Fig. 5.2. Correlation between psychotropic and pharmacological activity of lysergic acid derivatives. [...] TABLE 5.3 [...] On the left-hand side the psychotomimetic activity is indicated in relative logarithmic value, LSD being taken as 100 (standard). The values are derived mainly from investigations by Isbell et al. (246), but some were also obtained from personal studies (261). The stereoisomers of LSD (see Section 5.3,D.2) and the derivatives in which the double bond in ring D has been saturated are practically devoid of psychic activity. [...] Of all the many modifications of LSD none has been found so far which exceeds LSD in psychic activity. The right-hand side of Figure 5.2 shows the pharmacological effects of these derivatives expressed in relative logarithmic values. The strong line represents the syndrome of excitation, which, as already mentioned in the case of LSD, is caused by stimulation of sympathetic centers and consists of mydriasis, piloerection, hyperthermia, etc. Thc hyperthermic effect in rabbits is a good index of the central autonomic stimulation. With some compounds, e.g.. the pyrogenic effect (P) parallels the general syndrome of excitation (E-syndrome. continuous line). In the case of compounds with substitution in position 1 the hyperthermic effect is weaker than the other symptoms of sympathetic stimulation, and therefore an average value is marked with a dotted line (total E-syndrome). The thinner line of this diagram is an expression of the antagonism of these agents to serotonin. The antagonism to serotonin is a characteristic feature of LSD, as has already been mentioned.
- ^ a b Nunes F (November 1968). "LSD--an historical reevaluation". Journal of Chemical Education. 45 (11): 688–691. Bibcode:1968JChEd..45..688N. doi:10.1021/ed045p688. PMID 5696280.
Table 1. A Comparison of Psychic Effectiveness with Serotonin Antagonism [...]
- ^ a b Shulgin AT (1982). "Chemistry of Psychotomimetics". In Hoffmeister F, Stille G (eds.). Psychotropic Agents, Part III: Alcohol and Psychotomimetics, Psychotropic Effects of Central Acting Drugs. Handbook of Experimental Pharmacology. Vol. 55. Berlin: Springer Berlin Heidelberg. pp. 3–29. doi:10.1007/978-3-642-67770-0_1. ISBN 978-3-642-67772-4. OCLC 8130916.
All of the known psychotomimetic drugs that contain the alkaloid nucleus ergoline have a consistent structural feature of a carboxamide function at the 8-position and dehydration at the 9,10 position (see partial structure 7). The activity of this class of compounds is extremely sensitive to minor structural variations in this ring. Inversion of the hydrogen at the 5-position (to yield the isolysergic acid family), at the 8-position (to yield the L-lysergic acid family), and saturation of the 9,10-double bond (with hydrogen or solvent) all effectively eradicate the psychotomimetic properties of the product.
- ^ a b c d Fanchamps A (1978). "Some Compounds With Hallucinogenic Activity". Ergot Alkaloids and Related Compounds. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 567–614. doi:10.1007/978-3-642-66775-6_8. ISBN 978-3-642-66777-0. Archived from the original on 30 March 2025. Retrieved 3 June 2025.
2. Hydrogenated Derivatives: Dihydrolysergic acid diethylamide (Dihydro-LSD, No. 74b) is hydrogenated in positions C9 and C10. In oral doses of 100–200 μg, it produces strong autonomic disturbances (nausea, emesis, tachycardia, shiver, polyuria, headache, and paraesthesias) but no psychic alterations (CERLETTI, 1956). Its antiserotonin effect is about 50% of that of LSD (CERLETTI and DOEPFNER,1958a). It produces a decrease of the body temperature of the rat in all doses up to 10 mg/kg, whereas LSD produces a decrease only in doses lower than 1 μg/kg but an increase in high doses (Sandoz Res. Lab., 1959). [...] The three stereoisomers of LSD are devoid of psychotomimetic properties. The same applies to 9,10-dihydro-LSD, whereas the 2,3-dihydro analogue exhibits an appreciable potency. [...] Table 2. Psychotomimetic activity and some pharmacodynamic effects of structural analogues of LSD [...] 9,10-Dihydro-LSD (DH-LSD) [...] Cerletti, A: Lysergic acid diethylamide (LSD) and related compounds. In: Neuropharmacology. Transactions of the second conference, May 25-27,1955, Princeton, N.J., Abramson, H.A (ed.), pp. 9-84. New York: Josiah Macy Jr., Foundation 1956
- ^ a b Cerletti A (1956). "Lysergic Acid Diethylamide (LSD) and Related Compounds". In Abramson HA (ed.). Neuropharmacology: Transactions of the 2nd Conference, May 25-27, 1955, Princeton, N.J. New York: Josiah Macy. pp. 9–84.
And the situation is even more complicated since all lysergic acid derivatives, both the natural alkaloids as well as LSD and other similar compounds, can be hydrogenated by saturation of the double bond C9-C10. In this way, also a dihydro-LSD is obtained. This compound is devoid of specific effects on psychic functions.
- ^ Stoll A, Hofmann A (1955). "Amide der stereoisomeren Lysergsäuren und Dihydro-lysergsäuren. 38. Mitteilung über Mutterkornalkaloide" [Amides of the stereoisomeric lysergic acids and dihydrolysergic acids. 38. Report on ergot alkaloids]. Helvetica Chimica Acta. 38 (2): 421–433. doi:10.1002/hlca.19550380207. ISSN 0018-019X. Retrieved 3 June 2025.
- ^ a b Cerletti A, Doepfner W (January 1958). "Comparative study on the serotonin antagonism of amide derivatives of lysergic acid and of ergot alkaloids". The Journal of Pharmacology and Experimental Therapeutics. 122 (1): 124–136. doi:10.1016/S0022-3565(25)11933-2. PMID 13502837.
- ^ Cerletti A, Konzett H (1956). "Spezifische Hemmung von 5-Oxytryptamin-Effekten durch Lysergsäurediäthylamid und ähnliche Körper" [Specific inhibition of serotonin effects by lysergic acid diethylamide and similar compounds]. Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie (in German). 228 (1–2). doi:10.1007/BF00259761. ISSN 0028-1298. Retrieved 5 June 2025.
- ^ a b c d e Sankar DV (1975). LSD - A Total Study (PDF). Westbury, N.Y.: PJD Publications. ISBN 978-0-9600290-3-7. LCCN 72-95447.
The peptide alkaloids ergocristine, ergokryptine, and ergocornine have effects similar to ergotamine but they are extremely toxic and have not achieved much clinical attention. There is another synthetic alteration which has featured in the clinical pharmacology of these drugs. The C9-C10 double bond may be selectively saturated producing dihydro analogs of all these natural derivatives. For example, the dihydrogenated versions of the ergotoxines are very potent alpha-adrenergic blockers. They have almost no effects on the uterus and their central effects are markedly reduced. Mixtures of the dihydro derivatives' of ergocristine, ergokryptine and ergocornine (dihydroergotoxine) were widely used at one time for treating vascular disorders and essential hypertension, but this has been largely discontinued because of the availability of other drugs. [...] Since the 9,10-double bond of LSD is presumably conjugated with the indole ring system, it has generally been assumed that reduction of this bond would decrease the HOMO energy (58, 63), thus explaining the lack of hallucinogenic potency of dihydro-LSD (16). [...] The relative potencies of the LSD congeners are as follows (16,70): D-LSD=100; 1-acetyl-LSD=100; 1-methyl-LSD=33; 1-hydroxymethyl-LSD=7; DAM=1O; LAE=5; Dihydro-LSD=1; Lumi-LSD=<1; D-Iso-LSD=<1. [...] 9,10-Dihydrolysergamides without a substituent on the indole ring, showed emetic activity (16). The effective dose in dogs of N-propyl-9,10-dihydrolysergamide was 0.003 mg/kg and was equal to that of 9, 10-dihydroergocomine (16). [...] Newer derivatives of lysergic acid have been prepared by Borsy et al. (62). The 9, 10-dihydro derivatives were comparable to the saturated derivatives in antiserotonin activity.