PRO-LAD

PRO-LAD's psychedelic activity is presumed to arise from partial agonism at the serotonin 5-HT₂A receptor (HTR2A), the principal molecular target mediating classical psychedelic effectssupported

Comprehensive review of LSD pharmacology covering synthesis, mechanisms, receptor pharmacology, tolerance, safety. j.1755-5949.2008.00059.x

PRO-LAD's psychedelic activity is presumed to arise from partial agonism at the serotonin 5-HT₂A receptor (HTR2A), the principal molecular target mediating classical psychedelic effectssupported

Provides structural basis for LSD binding at serotonin receptors including 5-HT2A. j.cell.2016.12.033

This mechanistic assignment rests on three lines of evidence: (1) structural identity with lsd at the pharmacophore — the ergoline scaffold and C-8β diethylamide moiety are preserved; (2) complete generalization to the LSD discriminative stimulus in rats, demonstrating equivalent receptor engagement in vivo; and (3) the shared pharmacological profile of all psychoactively potent members of the N⁶-alkyl norlysergamide series.supported

The N(6)-propyl was equipotent to LSD, while the isopropyl derivative was half as active. The N(6)-ethyl and -allyl were approximately 2-3 times more potent than LSD. pmid:4032428

Claim in pharmacology — inconclusiveinconclusiveworking →

LSD acts as a partial agonist at 5-HT₁A (contributing anxiolytic components) and 5-HT₂C receptors, interacts agonistically and antagonistically with dopamine D₁ and D₂ receptors (which may mediate later-phase effects), and engages α₁ and α₂ adrenergic receptors — a profile that distinguishes lysergamides from tryptamine psychedelicssupported

LSD interacted with adrenergic and dopaminergic receptors in contrast to tryptamines. All compounds acted at 5-HT2A. j.euroneuro.2016.05.001

A 2025 comprehensive profiling study of 41 psychedelics against 318 human GPCRs confirmed that lysergamides possess potent activity at 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 crystal structure of LSD bound to the human 5-HT₂B receptor revealed that an extracellular loop 2 (EL2) "lid" clamps over the ligand within the binding pocket, explaining LSD's prolonged receptor residence time relative to its plasma half-lifesupported

Crystal structure of LSD in complex with human 5-HT2B. Reveals EL2 lid mechanism explaining LSD's exceptionally slow dissociation kinetics. j.cell.2016.12.033

All pharmacokinetic inferences derive from LSD class data.supported

First modern pharmacokinetic characterization of oral LSD in humans. pyv072

Plasma elimination follows a biexponential model with an initial half-life of ~3.6 hours and a terminal half-life of ~8.9 hourssupported

Tmax ~1.5h, half-life 3.6h (initial)/8.9h (terminal). pyv072

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

By structural analogy, PRO-LAD's toxicity profile is expected to resemble that of LSD, which is physiologically well tolerated at typical psychoactive doses with no established lethal dose in humanssupported

LSD physiologically well tolerated; psychological reactions controllable in supervised settings. j.1755-5949.2008.00059.x

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Tramadol's active metabolite O-desmethyltramadol is a potent serotonin reuptake inhibitor, and the combination with a direct 5-HT₂A agonist creates serotonin syndrome risksupported

Tramadol has mixed mechanism: mu-opioid agonism and serotonin/norepinephrine reuptake inhibition. Serotonergic adverse effects documented. s40265-021-01515-z

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Claim in summary — inconclusiveinconclusiveworking →

First synthesized as part of a systematic N⁶-alkyl norlysergamide series, PRO-LAD was pharmacologically characterized by Hoffman and Nichols in 1985 and documented with first-person human accounts by Shulgin in TiHKAL (1997)supported

A convenient method for the synthesis of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was developed. A series of these compounds was synthesized and tested for substitution in the two-lever drug discrimination assay pmid:4032428

As a lysergamide sharing LSD's ergoline scaffold and diethylamide moiety, PRO-LAD is presumed to act primarily through partial agonism at the 5-HT₂A receptor, with secondary engagement of 5-HT₁A, dopaminergic, and adrenergic targetssupported

Comprehensive review of LSD pharmacology covering synthesis, mechanisms, receptor pharmacology, tolerance, safety. j.1755-5949.2008.00059.x

By structural analogy with LSD — which is physiologically well tolerated at typical doses with no established human lethal dose — acute physiological toxicity is expected to be lowsupported

LSD physiologically well tolerated; psychological reactions controllable in supervised settings. j.1755-5949.2008.00059.x

Claim in summary — inconclusiveinconclusiveworking →

Nichols at Purdue University published the synthesis and pharmacological evaluation of a series of N⁶-alkyl norlysergic acid N,N-diethylamide derivativessupported

A convenient method for the synthesis of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was developed. A series of these compounds was synthesized and tested for substitution in the two-lever drug discrimination assay pmid:4032428

Hoffman and Nichols established that PRO-LAD was equipotent to LSD in a rat two-lever drug discrimination assay, placing it at the boundary between optimal and suboptimal N⁶ substituent size.supported

The N(6)-propyl was equipotent to LSD, while the isopropyl derivative was half as active. The N(6)-ethyl and -allyl were approximately 2-3 times more potent than LSD. pmid:4032428

No dedicated analytical characterization paper for PRO-LAD exists within the "Return of the Lysergamides" series, which has covered the related compounds 1P-LSD, AL-LAD, LSZ, ETH-LAD, and 1P-ETH-LADsupported

Characterization of AL-LAD and LSZ. dta.1985

No dedicated analytical characterization paper for PRO-LAD exists within the "Return of the Lysergamides" series, which has covered the related compounds 1P-LSD, AL-LAD, LSZ, ETH-LAD, and 1P-ETH-LADsupported

Characterization of ETH-LAD (N6-ethyl analog) and its prodrug. dta.2196

Receptor pharmacology is entirely inferred from LSD class data and from the in vivo finding that PRO-LAD is equipotent to LSD in rat drug discrimination.supported

The N(6)-propyl was equipotent to LSD pmid:4032428

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

LSD Ki ranges compiled from multiple published receptor profiling studiessupported

Receptor binding affinities at human monoamine receptors for novel tryptamines vs. classic hallucinogens. j.euroneuro.2016.05.001

Claim in receptor-pharmacology — inconclusiveinconclusiveworking →

The systematic modification of N⁶ substituents — from nor (unsubstituted) through methyl (LSD), ethyl (eth-lad), allyl (al-lad), propyl (PRO-LAD), and larger alkyl groups — constitutes a well-defined structure-activity relationship series first characterized by Hoffman and Nichols.supported

A convenient method for the synthesis of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was developed. A series of these compounds was synthesized and tested pmid:4032428

Claim in chemistry — inconclusiveinconclusiveworking →

Claim in chemistry — inconclusiveinconclusiveworking →

Population survey data on novel lysergamide use patterns have been published, but these studies aggregate data across multiple lysergamide analogs and do not provide PRO-LAD-specific clinical outcomes.supported

Survey study of novel psychedelic use patterns. Little known about use profiles or subjective effects across NP classes. s00213-022-06142-4

Population survey data on novel lysergamide use patterns have been published, but these studies aggregate data across multiple lysergamide analogs and do not provide PRO-LAD-specific clinical outcomes.supported

Survey study comparing self-reported effects of LSD analogues (AL-LAD, 1P-LSD, ETH-LAD) vs LSD. hup.2599

Population survey data on novel lysergamide use patterns have been published, but these studies aggregate data across multiple lysergamide analogs and do not provide PRO-LAD-specific clinical outcomes.supported

Large nationally representative population survey evaluating therapeutic potential of classic and novel psychedelics including lysergamides. fpsyt.2019.00896

Claim in neuroscience — inconclusiveinconclusiveworking →

LSD also engages dopaminergic and adrenergic signaling, which contributes to mesolimbic reward modulation and sympathetic arousal, respectivelysupported

LSD interacted with adrenergic and dopaminergic receptors in contrast to tryptamines. j.euroneuro.2016.05.001

The compound's prolonged receptor residence time at 5-HT₂A/₂B — maintained by the EL2 lid mechanism — produces a sustained pharmacological perturbation that outlasts plasma drug levels, a feature likely shared to a lesser degree by PRO-LAD given its shorter duration.supported

Reveals EL2 lid mechanism explaining LSD's exceptionally slow dissociation kinetics. Provides structural basis for LSD binding at serotonin receptors including 5-HT2A. j.cell.2016.12.033

The following LSD pharmacokinetic data serve as the best available reference for this lysergamide.supported

First modern pharmacokinetic characterization of oral LSD in humans. pyv072

The following LSD pharmacokinetic data serve as the best available reference for this lysergamide.supported

LSD pharmacokinetics and exposure-response relationship in healthy subjects following oral administration. s40262-017-0513-9

Altered receptor residence time: The n-propyl group may interfere with the EL2 lid-trapping mechanism identified at the 5-HT₂A/₂B binding pocket, leading to faster dissociation.supported

Reveals EL2 lid mechanism explaining LSD's exceptionally slow dissociation kinetics. j.cell.2016.12.033

PRO-LAD's pharmacological position is best understood within the N⁶-alkyl norlysergamide series systematically characterized by Hoffman and Nicholssupported

A convenient method for the synthesis of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives was developed. A series of these compounds was synthesized and tested pmid:4032428

Claim in comparative-pharmacology — inconclusiveinconclusiveworking →