AL-LAD

The serotonergic psychedelic class is considered physiologically safe at recreational doses, with no established lethal dose in humanssupported

Comprehensive review: hallucinogens are physiologically safe and do not produce dependence. pmid:14761703

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Risk factors include pre-existing anxiety disorders, tinnitus, and prior perceptual abnormalitiessupported

May predict vulnerability: pre-existing anxiety, tinnitus, floaters. 7854_2016_457

Claim in safety — inconclusiveinconclusiveworking →

De la Fuente Revenga et al. demonstrated that repeated administration of 5-HT₂A agonists produces progressive tolerance via 5-HT₂A receptor downregulation in frontal cortex, with cross-tolerance between psychedelic compounds (DOI and LSD confirmed)supported

Repeated DOI administration induces HTR tolerance via 5-HT2A receptor down-regulation. Cross-tolerance between DOI and LSD. acschemneuro.2c00170

Hallucinogens as a class do not engage the mesolimbic dopamine reward pathway as a primary mechanism, and do not produce compulsive drug-seeking behaviour, dose escalation, or withdrawal syndromessupported

Comprehensive review: hallucinogens are physiologically safe and do not produce dependence. pmid:14761703

Claim in safety — inconclusiveinconclusiveworking →

Cannabis modulates the psychedelic experience in a dose-dependent manner, as demonstrated by Kuc et al. in a prospective online survey (n = 321)supported

Cannabis modulates psychedelic experience in dose-dependent manner; design limitations prevent causal inferences. s00213-021-05999-1

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Relative: * Cardiovascular conditions — class-level transient sympathomimetic effects (increased heart rate, blood pressure) * Concurrent tramadol use — serotonin syndrome risk * Concurrent MAOI use — serotonin syndrome risk * Pre-existing anxiety or mood disorders — increased risk of acute psychological distress; may also be a risk factor for HPPD * Pregnancy — no teratogenicity data exist for AL-LAD; standard precautionary contraindicationpartially supported

HPPD review: rare, two types (brief flashbacks vs chronic). May predict vulnerability: pre-existing anxiety, tinnitus, floaters. 7854_2016_457

Pretreatment with the selective 5-HT₂A antagonist M100907 abolished the HTR induced by lysergamides in this series, confirming receptor-level mediation.supported

5-HT2A mechanism via M100907 blockade. dta.1884

Brandt et al. characterized AL-LAD's dose-response function in the HTR assay, observing an inverted U-shaped curve with maximal response at 200 µg/kg and an ED₅₀ of 174.9 nmol/kgsupported

Head-twitch response in C57BL/6J mice. AL-LAD ED50=174.9 nmol/kg. dta.1985

Wallach et al. demonstrated that 5-HT₂A–Gq/11 coupling — not β-arrestin2 recruitment — predicts hallucinogen-like behavioural effects, with a threshold level of Gq activation required to produce the HTRsupported

5-HT2A-Gq (not beta-arrestin2) signaling predicts psychedelic potential. Threshold Gq activation required for psychedelic-like effects. s41467-023-44016-1

Watts et al. demonstrated that LSD and structural analogs bind D₂-like receptors in rat striatum with affinity comparable to their 5-HT₂ binding, and approximately 2–3-fold lower affinity at D₁ receptors. AL-LAD's dopaminergic activity is inferred from this class-level data.supported

Affinity for D2-like receptors similar to 5-HT2 sites. D1 affinity 2-3 fold lower. pmid:7568626

5-HT₁A receptors: Partial agonism at 5-HT₁A is characteristic of the ergoline class. The related lysergamide LSM-775 exhibited functional 5-HT₁A agonism sufficient to mask its 5-HT₂A-mediated effects in the HTR assay, illustrating how 5-HT₁A activity can modulate the net pharmacological profile of lysergamides.supported

LSM-775 acts as nonselective agonist at 5-HT1A and 5-HT2A. HTR suppressed by 5-HT1A masking 5-HT2A activity. dta.2222

Wacker et al. solved the crystal structure of LSD bound to the human 5-HT₂B receptor, revealing that extracellular loop 2 (EL2) forms a "lid" over the binding pocket that restricts ligand dissociationsupported

Crystal structure of LSD in complex with 5-HT2B receptor. EL2 lid mechanism explains LSD slow binding kinetics and prolonged effect duration. j.cell.2016.12.033

Wagmann et al. investigated AL-LAD's metabolic fate using pooled human liver S9 fractionssupported

pHLS9 metabolism of nine LSD derivatives. AL-LAD metabolized by CYP1A2 and CYP3A4. s00216-018-1558-9

Brandt et al. confirmed AL-LAD as the most abundant metabolite when 1P-AL-LAD was incubated with pooled human liver microsomes (pHLM), and identified fourteen total metabolites of the 1P-AL-LAD/AL-LAD system: hydroxylation of the core ring and N6-allyl group, dihydrodiol formation, N-dealkylation, N1-deacylation, dehydrogenation, and combinations thereof.supported

1P-AL-LAD converts to AL-LAD as most abundant metabolite in pHLM (prodrug). 14 metabolites: hydroxylation, N-dealkylation, N1-deacylation, dihydrodiol formation. dta.3281

It functions as a serotonin 5-HT₂A receptor agonist with an in vivo potency approximately 75% that of LSD (ED₅₀ = 174.9 nmol/kg vs. 132.8 nmol/kg for LSD in the mouse head-twitch response assay)supported

AL-LAD ED50=174.9 nmol/kg; LSD ED50=132.8 nmol/kg. 5-HT2A mechanism confirmed. dta.1985

Claim in summary — inconclusiveinconclusiveworking →

Claim in summary — inconclusiveinconclusiveworking →

The compound entered the new psychoactive substances (NPS) market in 2013 as a blotter-distributed research chemicalsupported

AL-LAD and LSZ appeared on NPS market in 2013. dta.1985

AL-LAD's psychedelic activity is mediated through 5-HT₂A receptor agonism, confirmed by blockade of the head-twitch response with the selective antagonist M100907 in the lysergamide seriessupported

5-HT2A mechanism via M100907 blockade. dta.1884

The experiential profile — encompassing visual, cognitive, and transpersonal domains — is inferred from shared 5-HT₂A pharmacology and a single comparative user survey reporting effects similar to but weaker than LSDsupported

Survey study describing self-reported patterns of use and effects of LSD analogues (AL-LAD, 1P-LSD, ETH-LAD) and characteristics of users. hup.2599

The serotonergic psychedelic class is considered physiologically safe at recreational doses, with no established lethal dose in humanssupported

Comprehensive review: hallucinogens are physiologically safe and do not produce dependence. pmid:14761703

Tolerance develops rapidly via 5-HT₂A receptor downregulation and cross-generalizes to other serotonergic psychedelicssupported

Repeated DOI administration induces HTR tolerance via 5-HT2A receptor down-regulation. Cross-tolerance between DOI and LSD. acschemneuro.2c00170

Brandt et al. and the Halberstadt/Nichols group have characterized multiple lysergamides using the mouse HTR assay under identical experimental conditions, enabling direct potency comparisons:supported

Head-twitch response in C57BL/6J mice. AL-LAD ED50=174.9 nmol/kg; LSD ED50=132.8 nmol/kg. dta.1985

Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

The allyl group in AL-LAD is unique within this series for its unsaturated terminal carbon, which may influence both receptor binding geometry and metabolic fate (providing a site for epoxidation and hydroxylation).supported

14 metabolites: hydroxylation, N-dealkylation, N1-deacylation, dihydrodiol formation. dta.3281

Brandt et al. confirmed this relationship using pooled human liver microsomes, identifying AL-LAD as the most abundant metabolite of 1P-AL-LAD incubationsupported

1P-AL-LAD converts to AL-LAD as most abundant metabolite in pHLM (prodrug). dta.3281

This prodrug relationship parallels the established 1P-LSD → LSD conversion and reflects a common NPS market strategy of distributing 1-acyl-substituted lysergamides to circumvent scheduling of the parent compounds.supported

ALD-52, 1P-LSD, 1B-LSD act as prodrugs for LSD. 1-acyl substitution reduces monoamine receptor affinity 1-2 orders of magnitude. j.neuropharm.2019.107856

Holze et al. conducted a randomized, double-blind, placebo-controlled study of LSD microdoses (5, 10, and 20 µg oral) in healthy participants (n = 24):supported

LSD microdose (5-20 µg) PK: Tmax=1.1h, t1/2=2.7h. Threshold psychotropic effect at 10 µg. cpt.2057

The discrepancy between LSD's short plasma half-life (2.7 h) and its prolonged duration of subjective effects (8–12 h) is explained by the EL2 lid mechanism described by Wacker et al., which restricts ligand dissociation from the 5-HT₂A/₂B binding pocketsupported

EL2 lid mechanism explains LSD slow binding kinetics and prolonged effect duration. Mutation of lid accelerates LSD binding kinetics. j.cell.2016.12.033

Wagmann et al. identified the primary metabolizing enzymes as CYP1A2 and CYP3A4 using pooled human liver S9 fractionssupported

pHLS9 metabolism of nine LSD derivatives. AL-LAD metabolized by CYP1A2 and CYP3A4. s00216-018-1558-9

Brandt et al. identified fourteen metabolites of the 1P-AL-LAD/AL-LAD system in pHLM incubations, including hydroxylation products, dihydrodiols (suggesting epoxide intermediate formation), and combination metabolites arising from sequential phase I reactions.supported

14 metabolites: hydroxylation, N-dealkylation, N1-deacylation, dihydrodiol formation. dta.3281

The parent compound was not detectable in rat urine at expected recreational doses using standard immunoassay or HPLC-MS screening proceduressupported

Parent compound not detectable in rat urine at recreational doses. s00216-018-1558-9

In vitro metabolism profiling using human liver S9 fractions (CYP1A2, CYP3A4)supported

pHLS9 metabolism of nine LSD derivatives. AL-LAD metabolized by CYP1A2 and CYP3A4. s00216-018-1558-9

5-HT₂A receptor mediation confirmed via M100907 antagonist blockade in the lysergamide seriessupported

5-HT2A mechanism via M100907 blockade. dta.1884

The sole published human data source is a cross-sectional survey conducted by Coney et al. via the Global Drug Survey platformsupported

Survey study describing self-reported patterns of use and effects of LSD analogues (AL-LAD, 1P-LSD, ETH-LAD) and characteristics of users. hup.2599

HTR dose-response characterization in C57BL/6J mice (ED₅₀ = 174.9 nmol/kg)supported

Head-twitch response in C57BL/6J mice. AL-LAD ED50=174.9 nmol/kg. dta.1985

Claim in history — inconclusiveinconclusiveworking →

Claim in history — inconclusiveinconclusiveworking →

AL-LAD entered the commercial NPS market in 2013, sold as a tartrate salt on blotter paper in both powdered and blotter formsupported

AL-LAD and LSZ appeared on NPS market in 2013. dta.1985

Its emergence coincided with a broader wave of novel lysergamides — including 1P-LSD, ETH-LAD, and LSZ — marketed as legal alternatives to LSD in jurisdictions where the parent compound was controlled.supported

Review of NPS categories: stimulants, cannabinoids, benzodiazepines, dissociatives, classic hallucinogen analogs. 81 new substances identified in 2013. 2045125314559539

The receptor pharmacology presented below is reconstructed entirely from: (a) the HTR assay confirming 5-HT₂A-mediated activity; (b) class-level ergoline receptor pharmacology; and (c) data from structurally related lysergamides characterized by the Brandt/Halberstadt/Nichols research group.supported

Head-twitch response in C57BL/6J mice. AL-LAD ED50=174.9 nmol/kg; LSD ED50=132.8 nmol/kg. 5-HT2A mechanism confirmed. dta.1985

Ray's comprehensive receptorome screening demonstrated that LSD and related ergolines interact with dozens of receptor targets across the serotonergic, dopaminergic, and adrenergic familiessupported

Receptor affinity pharmacology of 25 psychedelic drugs at 51 receptors/transporters/ion channels (NIMH-PDSP). journal.pone.0009019

Wallach et al. demonstrated that the magnitude of Gq/11 activation — not β-arrestin2 recruitment — predicts whether a 5-HT₂A agonist produces hallucinogen-like effects in the HTR assaysupported

5-HT2A-Gq (not beta-arrestin2) signaling predicts psychedelic potential. Threshold Gq activation required for psychedelic-like effects. s41467-023-44016-1

The related compound ECPLA (N-ethyl-N-cyclopropyl lysergamide) was characterized with full receptor binding and functional assay data in the same research programme, demonstrating that such characterization is feasible for novel lysergamidessupported

Pharmacological characterization of ECPLA. Receptor binding data for lysergamides. 5-HT2A mechanism confirmed via HTR. s00213-018-5055-9

Claim in chemistry — inconclusiveinconclusiveworking →

The compound is also the active metabolite of the prodrug 1P-AL-LAD (1-propanoyl-AL-LAD), which undergoes hepatic N1-deacylation to yield AL-LAD as its most abundant metabolite in human liver microsome incubations.supported

1P-AL-LAD converts to AL-LAD as most abundant metabolite in pHLM (prodrug). 14 metabolites: ... N1-deacylation... dta.3281

The allyl group introduces a terminal alkene capable of metabolic epoxidation and hydroxylation.supported

AL-LAD metabolized by CYP1A2 and CYP3A4 primarily via hydroxylation and N-dealkylation. s00216-018-1558-9

The following neural mechanisms are inferred from AL-LAD's confirmed 5-HT₂A agonism and the broader serotonergic psychedelic neuroscience literature.supported

5-HT2A mechanism confirmed. dta.1985

De la Fuente Revenga et al. elucidated the neural mechanism underlying psychedelic tolerance in micesupported

Repeated DOI administration induces HTR tolerance via 5-HT2A receptor down-regulation. acschemneuro.2c00170

This mechanism is β-arrestin-2-independent, consistent with the Gq-biased signalling model of psychedelic activity.supported

5-HT2A-Gq (not beta-arrestin2) signaling predicts psychedelic potential. Beta-arrestin-biased agonists block psychedelic effects. s41467-023-44016-1

AL-LAD's emergence on the NPS market in 2013 preceded its specific scheduling in the UK and Sweden by 1–3 years, illustrating the reactive nature of NPS schedulingsupported

AL-LAD and LSZ appeared on NPS market in 2013. dta.1985

The prodrug 1P-AL-LAD was developed in part as a response to AL-LAD scheduling, exploiting regulatory gaps around 1-acyl-substituted lysergamide derivatives.supported

1P-AL-LAD converts to AL-LAD as most abundant metabolite in pHLM (prodrug). dta.3281

Users in the Coney et al. survey described it as similar in character to LSD but weaker in peak intensity and pleasurable high, with a milder comedownsupported

Survey study describing self-reported patterns of use and effects of LSD analogues (AL-LAD, 1P-LSD, ETH-LAD) and characteristics of users. hup.2599