ETH-LAD

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ETH-LAD
ETH-LAD v2.svg
Clinical data
Other namesETH-LAD; ETHLAD; 6-Ethyl-6-nor-lysergic acid diethylamide; 6-Ethyl-6-nor-LSD; N(6)-Ethyl-nor-LSD; 9,10-Didehydro-N,N,6-triethylergoline-8β-carboxamide
Routes of
administration 		Oral [1] [2]
Drug class Serotonin receptor agonist; Serotonergic psychedelic; Hallucinogen
Legal status
Legal status
  • DE: NpSG (Industrial and scientific use only)
  • UK: Class A
  • Illegal in France [3]
Pharmacokinetic data
Onset of action 15 minutes–1 hour [1]
Duration of action 8–12 hours [1]
Identifiers
  • (6aR,9R)-N,N-diethyl-7-ethyl-4,6,6a,7,8,9-
    hexahydroindolo-[4,3-fg]quinoline-9-carboxamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H27N3O
Molar mass 337.467 g·mol−1
3D model (JSmol)
  • CCN(C([C@@H]1C=C2C3=CC=CC4=C3C(C[C@H]2N(CC)C1)=CN4)=O)CC
  • InChI=1S/C21H27N3O/c1-4-23(5-2)21(25)15-10-17-16-8-7-9-18-20(16)14(12-22-18)11-19(17)24(6-3)13-15/h7-10,12,15,19,22H,4-6,11,13H2,1-3H3/t15-,19-/m1/s1 Yes check.svgY
  • Key:MYNOUXJLOHVSMQ-DNVCBOLYSA-N Yes check.svgY
   (verify)

ETH-LAD, or ETHLAD, also known as 6-ethyl-6-nor-LSD, is a psychedelic drug of the lysergamide family related to lysergic acid diethylamide (LSD; also known as METH-LAD). [4] [5] It is slightly more potent than LSD and is among the most potent psychedelics known. [6] [4] [7] [2] [8] [9] The drug is taken orally. [1]

Contents

It acts as a serotonin receptor agonist, including of the serotonin 5-HT2A receptor. [10] [11] In addition, it binds to dopamine receptors. [10] [12] The drug produces psychedelic-like effects in animals. [7] [6] [13] It is closely structurally related to LSD and to other psychedelic lysergamides like PRO-LAD and AL-LAD. [1] [7] [8] [6]

ETH-LAD was first described in the scientific literature by 1976. [14] Its effects in humans were assessed and reported by Alexander Shulgin in the 1980s and 1990s. [9] [15] [8] [1] The drug was encountered as a novel recreational designer drug in Europe by 2016. [16] [17] In addition, a prodrug of ETH-LAD, 1P-ETH-LAD, has been developed and encountered as a designer drug. [18] [19]

Use and effects

According to Alexander Shulgin in his book TiHKAL (Tryptamines I Have Known and Loved), ETH-LAD has a dose of 40 to 150 μg orally and a duration of 8 to 12 hours. [1] However, it also produced clear effects at a dose of 20 μg, [1] and in other publications, Shulgin gave a lower dose range for the drug of 40 to 80 μg. [2] [8] Its onset ranges from 15 minutes to 1 hour and peak effects occur after about 1 to 2 hours. [1]

Shulgin has stated that ETH-LAD is "a little more potent" than LSD or roughly twice as potent as LSD in humans. [2] [8] Other researchers have described it as "slightly more potent" or "somewhat more potent" than LSD in humans. [4] [9] For comparison, Shulgin lists the dose range of LSD as 60 to 200 μg or 50 to 200 μg in his publications. [1] [2] [8] Based on the preceding findings, ETH-LAD is one of the most potent serotonergic psychedelics known in humans, if not the most potent known psychedelic. [6] [4] [7] [8] [9] As a result of this, it has been said that LSD can no longer be considered the most potent psychedelic. [15]

The effects of ETH-LAD have been reported to include closed-eye imagery, very few visual changes or distortions, gentle movements of objects, LSD-like visual aspects, two-dimensional surfaces looking three-dimensional, objects looking "magical", and possible time slowing. [1] It was described as making the body feel balanced, thinking being easy, concepts easy to follow through, mind capable of realistic and down-to-earth thought, and warmth and humor being present. [1] Other reported effects included feeling lazy, diuretic effects, no appetite loss, decongestant effects, stomach discomfort, and chills. [1]

Compared to LSD, ETH-LAD was described as lacking the push and sparkle of LSD, allowing for extraordinary experiences with none of LSD's demands, being less aggressive than LSD and lacking its "taking control" nature, having a greatly modified degree of visual distortion relative to LSD, having visual effects similar to LSD but much more gentle, and being more allowing than demanding. [1]

Interactions

Pharmacology

Pharmacodynamics

ETH-LAD acts as a serotonin receptor agonist, including of the serotonin 5-HT2A receptor. [10] [11] It shows greater potency and efficacy as a serotonin 5-HT2A receptor agonist than LSD in vitro . [10] In addition to the serotonin 5-HT2A receptor, the drug binds with high affinity to the serotonin 5-HT1A and 5-HT2C receptors. [10] Like LSD, ETH-LAD also binds with lower affinity to the dopamine D1, D2, D3, D4, and D5 receptors. [10] [12]

ETH-LAD shows psychedelic-like effects in animals, specifically rodent drug discrimination tests. [7] [6] [13] It is about 1.6- to 2.3-fold more potent than LSD in these tests. [7] [6] [5] [9] Similarly to LSD, ETH-LAD shows moderate anti-inflammatory effects in preclinical research, but with slightly higher potency. [11]

Pharmacokinetics

The in-vitro metabolism of ETH-LAD has been studied. [20]

Chemistry

ETH-LAD, also known as 9,10-didehydro-N,N,6-triethylergoline-8β-carboxamide or as 6-ethyl-6-nor-LSD, is a substituted lysergamide derivative related to lysergic acid diethylamide (LSD; also known as METH-LAD). [1] It is the 6-ethyl derivative of nor-LSD (6-nor-LSD; H-LAD) and is the derivative of LSD with an ethyl group instead of methyl group at the 6 position of the ergoline ring system. [1]

Properties

According to Alexander Shulgin, ETH-LAD may be chemically unstable in solution. [1]

Synthesis

The chemical synthesis of ETH-LAD has been described. [1]

Analogues

Analogues of ETH-LAD include nor-LSD, LSD, PRO-LAD, IP-LAD, AL-LAD, FLUORETH-LAD, and CE-LAD, among others. [1] 1P-ETH-LAD, a prodrug of ETH-LAD, has been developed and encountered as a novel designer drug. [18] [19]

History

ETH-LAD was first described in the scientific literature by Tetsukichi Niwaguchi and colleagues by 1976. [14] Subsequently, its preclinical pharmacology was studied and described by Andrew J. Hoffman and David E. Nichols in 1985. [13] ETH-LAD's properties and effects in humans were assessed by Alexander Shulgin. [8] [9] These observations were reported via personal communication by Nichols in 1986, [9] [15] later described by Shulgin himself in a 1994 literature review, [8] and described in-depth by Shulgin himself in his 1997 book TiHKAL (Tryptamines I Have Known and Loved). [1] ETH-LAD was encountered as a novel designer drug in Europe by 2016. [16] [17]

Society and culture

Switzerland

ETH-LAD is illegal in Switzerland as of December 2015. [21]

United Kingdom

On June 10, 2014, the United Kingdom Advisory Council on the Misuse of Drugs (ACMD) recommended that ETH-LAD be specifically named in the UK Misuse of Drugs Act as a class A drug despite not identifying it as ever having been sold or any harm associated with its use. [22] The UK Home office accepted this advice and announced a ban of the substance to be enacted on 6 January 2015. [23]

See also

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Shulgin A, Shulgin A (September 1997). TiHKAL: The Continuation. Berkeley, California: Transform Press. ISBN   0-9630096-9-9. OCLC   38503252.
  2. 1 2 3 4 5 Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN   978-0-12-433951-4 . Retrieved 1 February 2025.
  3. ↑ "Arrêté du 20 mai 2021 modifiant l'arrêté du 22 février 1990 fixant la liste des substances classées comme stupéfiants". www.legifrance.gouv.fr (in French). 20 May 2021.
  4. 1 2 3 4 Halberstadt AL, Geyer MA (2013). "[Chapter 61:] Neuropharmacology of Lysergic Acid Diethylamide (LSD) and Other Hallucinogens". In Miller PM, Blume AW, Kavanagh DJ, Kampman KM, Bates ME, Larimer ME, Petry NM, De Witte P, Ball SA (eds.). Biological Research on Addiction: Comprehensive Addictive Behaviors and Disorders. Vol. 2. Elsevier. pp. 625–635. doi:10.1016/b978-0-12-398335-0.00061-3. ISBN   978-0-12-398335-0. Archived from the original on 28 March 2025. The semisynthetic lysergamide LSD (N,N-diethyllysergamide; Fig. 61.9) is one of the most potent hallucinogens, with typical doses ranging from 60–200 μg. LSD contains two chiral centers and its action is highly stereospecific, with 5R,8R being the only active configuration. The diethyl amide group in LSD is optimal for activity, and potency drops by an order of magnitude if other alkyl groups or heterocyclic rings are substituted. It has been reported, however, that derivatives of LSD in which the N(6) methyl group is replaced by other alkyl groups are active, with the 6-ethyl compound (N(6)-ethyl-nor-LSD, ETH-LAD) being slightly more potent than LSD.
  5. 1 2 Nichols DE, Oberlender R, McKenna DJ (1991). "Stereochemical Aspects of Hallucinogenesis". In Watson RR (ed.). Biochemistry and Physiology of Substance Abuse. Vol. 3. Boca Raton, Fla.: CRC Press. pp. 1–39. ISBN   978-0-8493-4463-3. OCLC   26748320. TABLE 1 Effects of N-(6)-Alkyl Subtituents on LSD-Like Behavior and Serotonin Receptor Affinity in Rats [...]
  6. 1 2 3 4 5 6 Pfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994). "Lysergamides revisited". NIDA Research Monograph. 146: 52–73. PMID   8742794. The DD data indicate that the n-propyl is slightly more active than LSD, although not significantly so, but the ethyl and allyl compounds were significantly more potent than LSD. [...] This was an area of the structure-activity relationships (SAR) that had been unfilled, and there is now some knowledge of the effect of the N(6) alkyl group on activity of lysergamide hallucinogens. If the animal data are used as a criterion, it is known that LSD is, in fact, not the most potent LSD-like agent; the ethyl and allyl compounds are more potent. Clinical data presented by Jacob and Shulgin (this volume) seem to corroborate this observation.
  7. 1 2 3 4 5 6 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. One other structural modification that has led to potent psychedelics is replacement of the N(6)-methyl of LSD with a variety of other alkyl groups (Hoffman and Nichols 1985). In a rat drug discrimination assay, in animals trained to discriminate LSD from saline, the N(6)-allyl derivative had about twice the potency of LSD itself. The N(6)-ethyl was about 1.6-fold more potent than LSD, with the N(6)-npropyl being essentially comparable in potency to LSD. The N(6)-isopropyl had about 40% of the potency of LSD, with the N(6)-n-butyl having approximately 10% of the potency of LSD. Neither norLSD (N(6)=H), or N(6)-2-phenethyl-norLSD gave full substitution in the rats. Anecdotal human experiments then confirmed that the N(6)-allyl (AL-LAD) and N(6)-ethyl (ETH-LAD) congeners were psychoactive in man at doses that were not all that different from LSD itself, but the two compounds had psychopharmacology that was different from that of LSD (Shulgin and Shulgin 1997). The same source reported that the N(6)-n-propyl was much less active, with an oral dose in the range of 100–200 μg. The N(6)-propynyl (pargy-LAD) had some activity at 160 μg, and the N(6)-n-butyl was reported to do "something" at 500 μg. The N(6)-2-phenethyl congener was inactive up to 500 μg. These human reports, although anecdotal, do generally parallel the results obtained in the drug discrimination tests.
  8. 1 2 3 4 5 6 7 8 9 Jacob P, Shulgin AT (1994). "Structure-activity relationships of the classic hallucinogens and their analogs" (PDF). NIDA Res Monogr. 146: 74–91. PMID   8742795. Archived from the original (PDF) on August 5, 2023. The last and by far most potent family of the tryptamine hallucinogens is found in the ergolines related to LSD. These are listed in table 9. Classically, the diethylamide has been considered the most potent of all and the prototype for comparison. [...] However, variations of the N-6 substitution have maintained the potency of LSD and in some cases enhanced it. [...] TABLE 9. LSD analogs.
  9. 1 2 3 4 5 6 7 Nichols DE (February 1986). "Studies of the Relationship Between Molecular Structure and Hallucinogenic Activity" . Pharmacol Biochem Behav. 24 (2): 335–340. doi:10.1016/0091-3057(86)90362-x. PMID   3952123. The ergolines can be viewed as rigid tetracyclic tryptamines. Within this class of compound is found the semisynthetic d-lysergic acid diethylamide (Fig 8) (d-LSD), the most potent of the hallucinogenic drugs. [...] Of the many structural modifications which have been made to the LSD structure, none had yielded a compound more potent than LSD itself. This report will briefly describe some derivatives of LSD which do appear to have somewhat higher potency than LSD. [...] The observations of potency comparable to, or greater than LSD [with N(6)-alkyl-substituted lysergamides] was of great interest. It seemed likely, based on the generalization in the drug discrimination assay and the high potencies of several of the derivatives, that these might well be more potent hallucinogens in man than LSD. Very recently, preliminary studies were carried out (A T Shulgin, personal communication) which indicated that indeed, the N(6)-ethyl and the N(6)-allyl-nor-LSD derivatives are somewhat more potent than LSD, by perhaps a factor of 2–3. Early results also indicated that N(6)-propyl-nor-LSD retains activity comparable to LSD, but with perhaps less visual distortion. These preliminary results were obtained after only a few experiments with each compound and further evaluation to define the potency and character of these lysergamides is underway.
  10. 1 2 3 4 5 6 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 26 March 2025 – via Purdue e-Pubs. Alt URL
  11. 1 2 3 Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD (April 2021). "Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore". ACS Pharmacol Transl Sci. 4 (2): 488–502. doi:10.1021/acsptsci.0c00063. PMC   8033619 . PMID   33860179.
  12. 1 2 Watts VJ, Lawler CP, Fox DR, Neve KA, Nichols DE, Mailman RB (April 1995). "LSD and structural analogs: pharmacological evaluation at D1 dopamine receptors". Psychopharmacology. 118 (4): 401–409. doi:10.1007/BF02245940. PMID   7568626. S2CID   21484356.
  13. 1 2 3 Hoffman AJ, Nichols DE (September 1985). "Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives". Journal of Medicinal Chemistry. 28 (9): 1252–1255. doi:10.1021/jm00147a022. PMID   4032428.
  14. 1 2 Niwaguchi T, Nakahara Y, Ishii H (1976). "Lysergic Acid Diethylamideおよび関連化合物に関する研究(第4報)Norlysergic Acidの各種Amide誘導体ならびに関連化合物の合成" [Studies on Lysergic Acid Diethylamide and Related Compounds. IV. Syntheses of Various Amide Derivatives of Norlysergic Acid and Related Compounds]. Yakugaku Zasshi. 96 (5): 673–678. doi: 10.1248/yakushi1947.96.5_673 . ISSN   0031-6903. PMID   987200 . Retrieved 27 March 2025.
  15. 1 2 3 Oberlender RA (May 1989). "Stereoselective aspects of hallucinogenic drug action and drug discrimination studies of entactogens". Purdue e-Pubs. Purdue University. Of the many structural modifications to LSD that have been evaluated for their effect on activity over the last forty five years, very few have led to compounds with comparable potency. Only derivatives in which various alkyl groups replaced the methyl at the N-6 position of LSD seem to retain or even surpass the potency of the parent drug. Of these compounds, the n-propyl derivative was found to be equipotent to LSD, while the ethyl and allyl derivatives were more potent in the rat than the parent drug by factors of 1.6 and 2, respectively (Hoffman and Nichols, 1985). These DD-based estimates of potency were subsequently confirmed in preliminary studies with humans (A.T. Shulgin, cited in Nichols, [1986a]). Thus, LSD can no longer be considered the most potent hallucinogen. [...] Nichols DE (1986a) Studies of the relationship between molecular structure and hallucinogenic activity. Pharmacol Biochem Behav 24: 335-340.
  16. 1 2 "EMCDDA–Europol 2016 Annual Report on the implementation of Council Decision 2005/387/JHA". Europol. 23 October 2018. Retrieved 27 March 2025.
  17. 1 2 Gumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)". Br J Pharmacol bph.17361. doi:10.1111/bph.17361. PMID   39354889.
  18. 1 2 Julio de Carvalho P (2024). "The use of prodrugs as drugs of abuse". WIREs Forensic Science. 6 (3) e1514. doi: 10.1002/wfs2.1514 . ISSN   2573-9468. Other analogues of LSD, such as 6N substituted AL-LAD e ETH-LAD, do not degrade into LSD, but have their own prodrugs—1P-AL-LAD/1cP-AL-LAD (Brandt, Kavanagh, Westphal, Pulver, Morton, et al., 2022; Brandt, Kavanagh, Westphal, Pulver, Schwelm, et al., 2022; Kavanagh et al., 2023) and 1P-ETH-LAD (Brandt et al., 2017), respectively—that undergo diacylation resulting in the parent drug.
  19. 1 2 Brandt SD, Kavanagh PV, Westphal F, Elliott SP, Wallach J, Stratford A, et al. (October 2017). "Return of the lysergamides. Part III: Analytical characterization of N6 -ethyl-6-norlysergic acid diethylamide (ETH-LAD) and 1-propionyl ETH-LAD (1P-ETH-LAD)". Drug Test Anal. 9 (10): 1641–1649. doi:10.1002/dta.2196. PMC   6230477 . PMID   28342178.
  20. ↑ Wagmann L, Richter LH, Kehl T, Wack F, Bergstrand MP, Brandt SD, et al. (July 2019). "In vitro metabolic fate of nine LSD-based new psychoactive substances and their analytical detectability in different urinary screening procedures". Anal Bioanal Chem. 411 (19): 4751–4763. doi:10.1007/s00216-018-1558-9. PMID   30617391.
  21. ↑ "Verordnung des EDI über die Verzeichnisse der Betäubungsmittel, psychotropen Stoffe, Vorläuferstoffe und Hilfschemikalien". Der Bundesrat.
  22. ↑ Advisory Council on the Misuse of Drugs (ACMD) (10 June 2014). "Update of the Generic Definition for Tryptamines" (PDF). UK Home Office. p. 12. Retrieved 10 June 2014.
  23. ↑ "The Misuse of Drugs Act 1971 (Amendment) (No. 2) Order 2014".
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