PARGY-LAD

Claim in safety — inconclusiveinconclusiveworking →

In silico toxicity predictions have been generated for structurally distinct N1-acyl lysergamides (ALD-52, 1P-LSD, 1B-LSD, 1V-LSD, 1cP-LSD), yielding rat oral LD₅₀ estimates of 49–85 mg/kgsupported

In silico toxicity prediction for five N1-acyl LSD analogs. LD50 (rat): 49-85 mg/kg. s00204-025-04255-1

Claim in safety — inconclusiveinconclusiveworking →

Halpern and Pope reviewed 50 years of evidence and concluded that HPPD is genuine but uncommon, most commonly reported after LSD usesupported

Review of 20 studies on HPPD (1955-2001). HPPD is genuine but uncommon; most commonly reported after LSD use. s0376-8716(03)00036-8

Claim in safety — inconclusiveinconclusiveworking →

Predisposing factors include pre-existing anxiety, prior HPPD episodes, tinnitus, visual floaters, and concentration difficulties.supported

Predisposing factors: anxiety history, pre-drug tinnitus, eye floaters, concentration problems. 7854_2016_457

Tolerance to psychedelic effects develops rapidly following a single administration, driven by 5-HT₂A receptor downregulation in the frontal cortexpartially supported

Repeated DOI produces tolerance to HTR via 5-HT2A downregulation. acschemneuro.2c00170

Claim in safety — inconclusiveinconclusiveworking →

The tolerance mechanism is independent of β-arrestin-2 signaling and produces complete cross-tolerance between LSD and DOI.supported

Cross-tolerance between DOI and LSD. Mechanism independent of beta-arrestin-2. acschemneuro.2c00170

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Tramadol acts as a weak serotonin reuptake inhibitor in addition to its opioid agonist activitysupported

Tramadol is a weak serotonin reuptake inhibitor. pmid:16051647

Combining tramadol's serotonin reuptake inhibition with PARGY-LAD's 5-HT₂A agonism and presumed 5-HT₁A activity creates a pharmacologically plausible risk for serotonin toxicity syndromesupported

Warning associated with serotonergic antidepressants and tramadol due to potential serotonin syndrome drug-drug interaction. 0897190013504957

Claim in safety — inconclusiveinconclusiveworking →

Based on the CYP1A2/CYP3A4 metabolic pathway inferred from AL-LAD and ETH-LAD, potent inhibitors of these enzymes (fluvoxamine, ciprofloxacin for CYP1A2; ketoconazole, ritonavir for CYP3A4) may increase PARGY-LAD plasma levelssupported

CYP1A2 and CYP3A4 as primary enzymes. s00216-018-1558-9

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Concurrent tramadol use: serotonin toxicity risk via dual serotonergic mechanismsupported

Warning associated with serotonergic antidepressants and tramadol due to potential serotonin syndrome drug-drug interaction. 0897190013504957

Prior HPPD episodes or predisposing factors (anxiety disorders, pre-existing visual disturbances, tinnitus)supported

Predisposing factors: anxiety history, pre-drug tinnitus, eye floaters, concentration problems. 7854_2016_457

Severe hepatic impairment: if metabolism proceeds via CYP1A2/CYP3A4 as with structural analogs, hepatic impairment may significantly alter clearancesupported

CYP1A2 and CYP3A4 as primary enzymes. s00216-018-1558-9

Claim in pharmacology — inconclusiveinconclusiveworking →

Activation of 5-HT₂A receptors — particularly on layer V pyramidal neurons of the prefrontal cortex — triggers Gq-mediated phospholipase C signaling, activating downstream MAPK/ERK and protein kinase C cascadessupported

Active-state structure of 5-HT2A bound to 25-CN-NBOH hallucinogen. Determinants for 5-HT2A-Gq interaction. j.cell.2020.08.024

This mechanism is established as the primary pharmacological driver of classical psychedelic effects, confirmed for LSD through both receptor-blocking studies with ketanserin and structural biology.supported

Crystal structure of LSD in complex with 5-HT2B receptor. EL2 lid mechanism explains slow LSD dissociation. j.cell.2016.12.033

This mechanism is established as the primary pharmacological driver of classical psychedelic effects, confirmed for LSD through both receptor-blocking studies with ketanserin and structural biology.supported

X-ray crystal structures of 5-HT2A with LSD and methiothepin. Determinants for 5-HT2A-Gq interaction. j.cell.2020.08.024

The crystal structure of LSD bound to the 5-HT₂B receptor reveals an extracellular loop 2 (EL2) "lid" that closes over the bound ligand, explaining LSD's exceptionally slow dissociation kinetics (receptor residence time on the order of hours)supported

Crystal structure of LSD in complex with 5-HT2B receptor. EL2 lid mechanism explains slow LSD dissociation. LSD dissociates exceptionally slow from both 5-HT2B and 5-HT2A. j.cell.2016.12.033

Secondary targets, inferred from lysergamide class pharmacology, include 5-HT₁A partial agonism, dopamine D₂ partial agonism (Ki ≈ 100–400 nM for LSD), and α₂ adrenergic receptor activitysupported

Psychedelics have potent actions at nearly every serotonin, dopamine, and adrenergic receptor. j.neuron.2025.06.012

Secondary targets, inferred from lysergamide class pharmacology, include 5-HT₁A partial agonism, dopamine D₂ partial agonism (Ki ≈ 100–400 nM for LSD), and α₂ adrenergic receptor activitysupported

LSM-775 acts as a nonselective agonist at 5-HT1A and 5-HT2A receptors. dta.2222

The polypharmacology profile of 41 classical psychedelics across 318 GPCRs demonstrates that lysergamides as a class engage nearly every serotonin, dopamine, and adrenergic receptor subtypesupported

41 classical psychedelics profiled against 318 human GPCRs. Psychedelics have potent actions at nearly every serotonin, dopamine, and adrenergic receptor. j.neuron.2025.06.012

The compound does not act through monoamine reuptake inhibition or dopamine transporter binding, distinguishing it pharmacologically from stimulants.supported

Serotonergic psychedelics act via 5-HT2A. s00204-020-02693-7

Claim in pharmacology — inconclusiveinconclusiveworking →

The duration of subjective effects (8–12 hours for LSD) considerably exceeds what plasma half-life would predict, a phenomenon attributed to prolonged receptor occupancy via the EL2 lid mechanismsupported

EL2 lid mechanism explains slow LSD dissociation. LSD dissociates exceptionally slow from both 5-HT2B and 5-HT2A. j.cell.2016.12.033

Claim in pharmacology — inconclusiveinconclusiveworking →

Wagmann et al. characterized the in vitro metabolism of the structural analogs AL-LAD and ETH-LAD, identifying CYP1A2 and CYP3A4 as the primary metabolizing enzymessupported

Metabolism of ... ETH-LAD, 1P-ETH-LAD, AL-LAD ... via N-dealkylation and hydroxylation. CYP1A2 and CYP3A4 as primary enzymes. s00216-018-1558-9

Claim in pharmacology — inconclusiveinconclusiveworking →

Recent lysergamide structure-activity work has demonstrated that structural modifications at and near N6 can dissociate hallucinogenic potency from neuroplasticity-promoting effects, though whether PARGY-LAD's propargyl modification achieves such dissociation is unknown.supported

LSD analogues with structural modifications can decouple plasticity from hallucinogenesis. pnas.2416106122

In the mouse head-twitch response assay — the standard behavioral proxy for 5-HT₂A-mediated psychedelic activity — AL-LAD shows ED₅₀ = 174.9 nmol/kg versus LSD ED₅₀ = 132.8 nmol/kgsupported

AL-LAD ED50 = 174.9 nmol/kg; LSZ ED50 = 114.2 nmol/kg (vs LSD ED50 = 132.8 nmol/kg). dta.1985

Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

Claim in comparative-pharmacology — inconclusiveinconclusiveworking →

AL-LAD and ETH-LAD share a CYP1A2/CYP3A4 metabolic profilesupported

Metabolism of ... ETH-LAD, 1P-ETH-LAD, AL-LAD ... CYP1A2 and CYP3A4 as primary enzymes. s00216-018-1558-9

The 1P-AL-LAD prodrug undergoes in vivo conversion to AL-LAD, with documented metabolic pathways including depropionylation and ergoline hydroxylationsupported

1P-AL-LAD converts to AL-LAD in vitro (prodrug). Fourteen metabolites including N-dealkylation, hydroxylation, dihydrodiol formation. dta.3281

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

The active-state cryo-EM structure of the LSD–5-HT₂A–Gq complex demonstrates the ergoline scaffold engaging transmembrane helices 3, 5, and 6 in a pose that stabilizes the Gq-coupled active statepartially supported

X-ray crystal structures of 5-HT2A with LSD and methiothepin. Determinants for 5-HT2A-Gq interaction. j.cell.2020.08.024

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

The comprehensive polypharmacology screen of 41 psychedelics across 318 GPCRs confirmed potent lysergamide activity at 5-HT₁A, 5-HT₂B, 5-HT₂C, 5-HT₆, 5-HT₇, dopamine D₁/D₂/D₃, and α₁/α₂ adrenergic receptorssupported

41 classical psychedelics profiled against 318 human GPCRs. Psychedelics have potent actions at nearly every serotonin, dopamine, and adrenergic receptor. j.neuron.2025.06.012

AL-LAD and LSM-775 demonstrate nonselective 5-HT₁A agonism, which can mask the head-twitch response in rodents and modify subjective experience character in humans.supported

LSM-775 acts as a nonselective agonist at 5-HT1A and 5-HT2A receptors. 5-HT1A activation masks head twitch response. dta.2222

The closest structural analog with published animal data, AL-LAD (N6-allyl), shows ED₅₀ = 174.9 nmol/kg in the mouse head-twitch response assay versus LSD ED₅₀ = 132.8 nmol/kgsupported

AL-LAD ED50 = 174.9 nmol/kg; LSZ ED50 = 114.2 nmol/kg (vs LSD ED50 = 132.8 nmol/kg). dta.1985

Claim in chemistry — inconclusiveinconclusiveworking →

Claim in chemistry — inconclusiveinconclusiveworking →

Claim in chemistry — inconclusiveinconclusiveworking →

Claim in chemistry — inconclusiveinconclusiveworking →

Claim in summary — inconclusiveinconclusiveworking →

Claim in summary — inconclusiveinconclusiveworking →

As a lysergamide sharing the core ergoline pharmacophore, PARGY-LAD is presumed to act primarily through 5-HT₂A receptor agonism, with likely secondary activity at 5-HT₁A, dopamine D₂, and adrenergic receptors characteristic of the lysergamide classsupported

Psychedelics have potent actions at nearly every serotonin, dopamine, and adrenergic receptor. j.neuron.2025.06.012

The compound is not habit-forming; tolerance develops rapidly through 5-HT₂A receptor downregulation, with cross-tolerance to other classical psychedelics and an estimated 14-day full reset periodpartially supported

Repeated DOI produces tolerance to HTR via 5-HT2A downregulation. Cross-tolerance between DOI and LSD. acschemneuro.2c00170

Claim in neuroscience — inconclusiveinconclusiveworking →

Recent work on lysergamide structure-activity relationships has shown that structural modifications at N6 and elsewhere can dissociate hallucinogenic potency from neuroplasticity-promoting effects, raising the question of whether PARGY-LAD's reduced psychedelic potency correlates with altered neuroplastogenic potential.supported

LSD analogues with structural modifications can decouple plasticity from hallucinogenesis. Promotes cortical spinogenesis. pnas.2416106122

In vitro metabolism of the structural analogs AL-LAD and ETH-LAD proceeds primarily through CYP1A2 and CYP3A4, with metabolic reactions including N-dealkylation, ergoline hydroxylation, dihydrodiol formation, and N6-substituent transformations.supported

Metabolism of ... ETH-LAD, 1P-ETH-LAD, AL-LAD ... via N-dealkylation and hydroxylation. CYP1A2 and CYP3A4 as primary enzymes. s00216-018-1558-9

Based on the CYP1A2/CYP3A4 metabolic pathway inferred from structural analogs, potent CYP1A2 inhibitors (fluvoxamine, ciprofloxacin) and CYP3A4 inhibitors (ketoconazole, ritonavir, grapefruit juice) may increase PARGY-LAD plasma levelssupported

CYP1A2 and CYP3A4 as primary enzymes. s00216-018-1558-9

Claim in clinical-evidence — inconclusiveinconclusiveworking →

Claim in history — inconclusiveinconclusiveworking →