According toAlexander Shulgin in his bookTiHKAL (Tryptamines I Have Known and Loved), ETH-LAD has a dose of 40 to 150μgorally and aduration of 8 to 12hours.[1] However, it also produced clear effects at a dose of 20μg,[1] and in other publications, Shulgin gave a lower dose range for the drug of 40 to 80μg.[2][8] Itsonset ranges from 15minutes to 1hour and peak effects occur after about 1 to 2hours.[1]
Shulgin has stated that ETH-LAD is "a little morepotent" 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 200μg or 50 to 200μg in his publications.[1][2][8] Based on the preceding findings, ETH-LAD is one of the most potentserotonergic 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 includeclosed-eye imagery, very fewvisual changes ordistortions, gentle movements of objects, LSD-like visual aspects, two-dimensional surfaces looking three-dimensional, objects looking "magical", and possibletime 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 feelinglazy,diuretic effects, noappetite loss,decongestant effects,stomach discomfort, andchills.[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]
ETH-LAD was first described in thescientific literature by Tetsukichi Niwaguchi and colleagues by 1976.[14] Subsequently, itspreclinicalpharmacology was studied and described by Andrew J. Hoffman andDavid E. Nichols in 1985.[13] ETH-LAD's properties and effects in humans were assessed byAlexander Shulgin.[8][9] These observations were reported via personal communication by Nichols in 1986,[9][15] later described by Shulgin himself in a 1994literature review,[8] and described in-depth by Shulgin himself in his 1997 bookTiHKAL (Tryptamines I Have Known and Loved).[1] ETH-LAD was encountered as a noveldesigner drug inEurope by 2016.[16][17]
On June 10, 2014, theUnited KingdomAdvisory Council on the Misuse of Drugs (ACMD) recommended that ETH-LAD be specifically named in theUK 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]
^abcdHalberstadt 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.ISBN978-0-12-398335-0. Archived fromthe 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.
^abcdefPfaff RC, Huang X, Marona-Lewicka D, Oberlender R, Nichols DE (1994)."Lysergamides revisited".NIDA Research Monograph.146:52–73.PMID8742794.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.
^abcdefNichols 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.ISBN978-3-662-55878-2.PMID28401524.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.
^abcdefghiJacob P, Shulgin AT (1994)."Structure-activity relationships of the classic hallucinogens and their analogs"(PDF).NIDA Res Monogr.146:74–91.PMID8742795. Archived fromthe 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.
^abcdefgNichols 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.PMID3952123.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.
^abWatts 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.PMID7568626.S2CID21484356.
^abcHoffman 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.PMID4032428.
^abcOberlender 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.
^abGumpper 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.PMID39354889.
^abJulio de Carvalho P (2024)."The use of prodrugs as drugs of abuse".WIREs Forensic Science.6 (3) e1514.doi:10.1002/wfs2.1514.ISSN2573-9468.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.
^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.PMID30617391.
