PARGY-LAD

# Research Output: PARGY-LAD

## Chemical Identity

**PubChem CID:** 139030999 [Ref 1]
**Molecular formula:** C₂₂H₂₅N₃O [Ref 1]
**Molecular weight:** 347.5 g/mol [Ref 1]
**InChIKey:** BPJKJUFQSNRQCR-OXQOHEQNSA-N [Ref 1]
**IUPAC name (brief seed data):** (6aR,9R)-N,N-diethyl-7-prop-2-ynyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide — confirmed via PubChem [Ref 1]
**Alternate names:** 6-propynyl-6-nor-LSD; 6-propargyl-6-nor-LSD; N-propargyl-nor-LSD; (8β)-N,N-diethyl-6-(prop-2-yn-1-yl)-9,10-didehydroergoline-8-carboxamide

**SMILES:** Not returned by PubChem API in this research session. The brief contains no SMILES; none could be confirmed. *[Flag: SMILES is a data gap — generation agent should not fabricate.]*

**Stereochemistry:** Compound name and CID indicate (6aR,9R) stereochemistry, consistent with the d-lysergamide series. The active configuration is the natural (R,R) ergoline scaffold, as with LSD. No racemic or alternate isomer preparations are documented in the published literature for this specific compound.

**Brief seed data discrepancies:** The brief leaves SMILES, InChIKey, and molecular formula blank. PubChem confirms formula C₂₂H₂₅N₃O, MW 347.5, InChIKey BPJKJUFQSNRQCR-OXQOHEQNSA-N — all absent from seed but now verified. CAS number not identified in this research; not present in PubChem entry.

---

## Pharmacology

### Receptor Binding

**No published Ki, EC50, or binding affinity data exist specifically for PARGY-LAD.** All receptor pharmacology for PARGY-LAD must be inferred from:
1. The 1985 Nichols/Hoffman synthesis paper which assessed LSD-like discriminative stimulus properties in rats [Ref 8] — this is animal behavioral data, not direct receptor binding.
2. Class-level data from closely related lysergamide analogs: AL-LAD (N6-allyl), ETH-LAD (N6-ethyl), and LSD itself.
3. The polypharmacology profile of 41 psychedelics against 318 GPCRs (Jain et al. 2025, Neuron) [Ref 7].

**Primary target — 5-HT₂A receptor:**
PARGY-LAD belongs to the lysergamide/ergoline class and shares the pharmacophore required for 5-HT₂A agonism. LSD binds 5-HT₂A with Ki ≈ 0.5–4 nM in published assays; activation of 5-HT₂A is the principal mechanism underlying classical psychedelic effects [Ref 13]. The crystal structure of LSD bound to 5-HT₂B (Wacker et al. 2017 [Ref 9]) reveals an "EL2 lid" mechanism by which the extracellular loop 2 closes over the bound ligand, explaining LSD's exceptionally slow dissociation kinetics — a feature that may partially apply to PARGY-LAD given its shared ergoline core.

The active-state 5-HT₂A–Gq complex structure with LSD (Kim et al. 2020 [Ref 10]) provides structural insight into how the lysergamide scaffold drives Gq-mediated signaling.

**Secondary targets (class-level inference):**
- **Dopamine D2 receptor:** LSD is a known partial agonist at D2 (Ki ≈ 100–400 nM). The Jain et al. (2025) polypharmacology profiling of 41 classical psychedelics [Ref 7] documents potent activity at nearly every serotonin, dopamine, and adrenergic receptor within the lysergamide class.
- **5-HT₁A receptor:** Lysergamides including AL-LAD and LSM-775 act as nonselective agonists at 5-HT₁A [Ref 4]. 5-HT₁A activation can mask the head-twitch response and modify the subjective character of the experience [Ref 4].
- **Adrenergic receptors:** Class-level profile includes α₂ adrenergic activity [Ref 7].

**Potency relative to LSD:**
The single human potency data point comes from Shulgin's TiHKAL (1997) [Ref 26]: PARGY-LAD shows qualitative activity starting at ~160 µg and full psychedelic effects at ~500 µg. Given LSD typically produces full effects at 75–150 µg, this places PARGY-LAD at approximately 25–40% the potency of LSD. This is consistent with prior Nichols laboratory findings in animal drug discrimination models [Ref 8], though see **Gaps & Flags** for an unresolved potency discrepancy.

The closest structural analog with published behavioral data is AL-LAD (N6-allyl). Brandt et al. (2017) [Ref 2] reported AL-LAD ED₅₀ = 174.9 nmol/kg in the mouse head-twitch response (HTR) assay — slightly less potent than LSD (ED₅₀ = 132.8 nmol/kg). The propargyl group in PARGY-LAD (a triple-bond variant of AL-LAD's allyl double bond) is expected to further reduce potency, consistent with the TiHKAL potency report.

### Mechanism of Action

PARGY-LAD is expected to act as a 5-HT₂A receptor agonist, triggering Gq-mediated phospholipase C activation and downstream signaling cascades including MAPK/ERK, as established for LSD and its structural analogs [Ref 9], [Ref 10], [Ref 13]. The REBUS model (Carhart-Harris & Friston 2019 [Ref 31]) describes how 5-HT₂A agonism relaxes high-level predictive priors, leading to perceptual alterations and increased global brain integration.

Activation of cortical 5-HT₂A receptors, particularly in layer V pyramidal neurons, is the primary driver of the psychedelic effect. The compound is not expected to act via dopamine transporter or monoamine reuptake, distinguishing it pharmacologically from stimulants [Ref 22].

### Pharmacokinetics

**No human pharmacokinetic data have been published for PARGY-LAD.**

For class-level analog inference, LSD oral pharmacokinetics are the best reference:
- Dolder et al. (2017) [Ref 19]: Oral LSD reaches plasma Tmax at approximately 1.5–4 hours; terminal elimination half-life ~3.6 hours; duration of effects considerably exceeds plasma half-life due to receptor residence time.
- Holze et al. (2019) [Ref 11]: Novel oral LSD formulation; established exposure-response relationship for subjective effects.

The shorter reported duration for PARGY-LAD (6–8 hours) vs. LSD (8–12 hours) may reflect lower receptor occupancy at effective doses or faster receptor dissociation — but no pharmacokinetic data confirm this. This is class/community inference.

**Metabolism (class-level analog inference from AL-LAD and ETH-LAD):**
Wagmann et al. (2019) [Ref 5] established that AL-LAD and ETH-LAD are primarily metabolized via:
- **CYP1A2** and **CYP3A4** (primary enzymes)
- Metabolic reactions: N-dealkylation, hydroxylation of the core ergoline ring, dihydrodiol formation, dehydrogenation, and N6-group transformations

For PARGY-LAD, the propargyl (prop-2-yn-1-yl) group at N6 would be subject to similar oxidative metabolism. The alkyne group may undergo oxidation or epoxidation by CYPs. No specific metabolite data exist for PARGY-LAD.

---

## History

PARGY-LAD was first synthesized and characterized by **Andrew J. Hoffman and David E. Nichols** at Purdue University and reported in a 1985 paper published in the *Journal of Medicinal Chemistry*: "Synthesis and LSD-like discriminative stimulus properties in a series of N(6)-alkyl norlysergic acid N,N-diethylamide derivatives" [Ref 8]. This paper evaluated a series of N6-alkyl substituted norlysergic acid diethylamide analogs for LSD-like activity using rat drug discrimination assays — a standard preclinical model for psychedelic-like effects.

The broader context: Nichols and colleagues at Purdue published a series of reports on lysergamides from 1984 to 1997, synthesizing approximately 30 novel lysergamide analogs with the goal of mapping structure-activity relationships at serotonin receptors [Ref 16]. PARGY-LAD (the N6-propargyl analog) was one compound in this series.

**TiHKAL (1997):** Alexander Shulgin referenced PARGY-LAD in *TiHKAL: The Continuation* [Ref 26], noting human psychoactive effects beginning at approximately 160 µg with full activity at approximately 500 µg. This is the only published first-person human experience report for the compound.

**NPS market emergence:** PARGY-LAD appeared on the research chemical/NPS market approximately in September 2014, sold alongside AL-LAD, ETH-LAD, and PRO-LAD as a grey-market psychedelic [Ref 18]. However, a significant caveat: a sample submitted to Wedinos (a UK drug testing service) and labeled "PARGY-LAD" was found to contain AL-LAD and LSZ instead [Ref 18]. The vendor reportedly ceased restocking without explanation. This raises substantial questions about whether any commercially distributed "PARGY-LAD" at that time was authentic.

**Institutional/clinical history:** PARGY-LAD has never entered clinical trials. No regulatory agency has formally assessed it for medical use. No pharmaceutical interest in PARGY-LAD has been documented.

---

## Subjective Effects

**No controlled human studies on PARGY-LAD have been published.** All subjective effect data derives from:

1. **TiHKAL (Shulgin, 1997)** [Ref 26] — the only first-person human report attributable to a known scientist: activity at ~160 µg, full effects at ~500 µg, described as qualitatively LSD-like but requiring substantially higher doses.

2. **Structural analog inference from AL-LAD** — Coney et al. (2017) [Ref 20] surveyed users of AL-LAD, 1P-LSD, and ETH-LAD. AL-LAD users reported LSD-like visual effects, moderate-to-strong intensity, similar duration, and a slightly more "manageable" subjective character compared to LSD — consistent with AL-LAD's ~30% lower potency.

3. **Community self-report** via PsychonautWiki [Ref 17] — lists typical lysergamide effect domains including: visual geometry, drifting, color enhancement, auditory enhancement, synesthesia, ego dissolution, introspection, time alteration, euphoria, and muscle tension. No PARGY-LAD-specific community survey data have been systematically collected.

**Duration (oral route):**
- Onset: 30–45 minutes [Ref 17]
- Total duration: 6–8 hours [Ref 17]
- These figures are community consensus, consistent with AL-LAD (reported 6–8 hours) and shorter than LSD (8–12 hours).

**Effect character vs. LSD:**
Based on structural analog reasoning: PARGY-LAD's N6-propargyl modification (like AL-LAD's N6-allyl) would not be expected to dramatically alter the qualitative character of the experience, since the diethylamide and core ergoline scaffold — responsible for receptor interactions — are preserved. The primary observable difference is reduced potency.

*All effect profile data must be clearly labeled as class/community-consensus provenance in the generated article.*

---

## Safety & Toxicity

### LD50 / Lethal Dose
**No LD50 data have been published for PARGY-LAD.** The brief correctly notes the toxic dose is unknown.

For comparative reference:
- LSD: No human deaths attributed directly to its pharmacological effects [web-retrieved, StatPearls LSD toxicology entry].
- In silico predictions for N1-acyl LSD analogs (a structurally different series — N1-acyl rather than N6-propargyl): Jurowski et al. (2026) [Ref 25] predicted rat oral LD₅₀ values of 49–85 mg/kg for ALD-52, 1P-LSD, 1B-LSD, 1V-LSD, and 1cP-LSD. **These values are NOT directly applicable to PARGY-LAD**, which bears a different structural modification at N6, not N1. They are noted as an indirect structural class reference only.

### Adverse Events and Overdose
**No case reports of PARGY-LAD-specific adverse events or overdose have been published.** All safety information is class-level.

Class-level adverse effects for lysergamides (primarily from LSD literature):
- **Acute psychiatric:** Panic, paranoia, anxiety, thought disorganization, psychosis precipitation in vulnerable individuals, suicidal ideation [web-retrieved, StatPearls LSD toxicology]
- **Cardiovascular:** Hypertension, tachycardia, hyperthermia; arrhythmias rare; most severe cardiovascular events associated with polydrug use [web-retrieved, StatPearls]
- **Hallucinogen Persisting Perception Disorder (HPPD):** A rare but documented condition following hallucinogen use. Halpern & Pope (2003) [Ref 24] reviewed 50 years of evidence, concluding HPPD is genuine but uncommon; most commonly reported after LSD use. Doyle et al. (2022) [Ref 23] characterized risk factors, prevention, and treatment in a scoping review. Halpern et al. (2018) [Ref 27] identified predisposing factors: anxiety history, pre-existing tinnitus, visual floaters, and concentration difficulties.

### Dependence Liability
Lysergamides including LSD do not produce physical dependence and are not reinforcing in standard animal self-administration models. Psychological dependence is considered very low. Compulsive use is rare [Ref 13, Ref 22].

---

## Harm Reduction

### Contraindications
Based on class-level pharmacology (no PARGY-LAD-specific data):
- Personal or family history of schizophrenia, bipolar disorder, or other psychotic spectrum conditions
- Concurrent use of tramadol (dangerous interaction — see Interactions section)
- Concurrent use of lithium (class-level seizure risk with psychedelics)
- Concurrent use of MAOIs (high serotonin toxicity risk)
- Cardiovascular disease or uncontrolled hypertension
- Pregnancy or lactation (no safety data for any lysergamide in human pregnancy)
- Predisposition to HPPD (prior HPPD episodes, anxiety disorders, pre-existing visual disturbances) [Ref 27]

### Set and Setting
The importance of set (mindset) and setting (environment) for psychedelic experiences is well-established in the literature [Ref 29, web-retrieved from Carhart-Harris et al.]. Lower doses are strongly recommended for inexperienced users given the substantially higher dose requirement compared to LSD.

### Testing and Identification
Given documented adulteration of commercial "PARGY-LAD" samples in 2014 (Wedinos testing found AL-LAD + LSZ instead [Ref 18]), reagent testing and ideally mass spectrometry identification are strongly recommended before consumption. Standard Ehrlich reagent (turns purple with ergoline alkaloids) will detect the indole ring but cannot distinguish between PARGY-LAD and other lysergamides. Mass spectrometry is required for structural confirmation.

### Emergency Response
Acute adverse reactions ("bad trips") are managed supportively: calm environment, minimal stimulation, reassurance, reduce sensory input [web-retrieved, StatPearls LSD toxicology]. Low-dose benzodiazepines (diazepam) for severe anxiety. Avoid antipsychotics where possible; if required for severe persistent psychosis, haloperidol or risperidone have been used. No specific reversal agent exists.

---

## Tolerance & Dependence

### Tolerance Development
Tolerance to psychedelic effects develops very rapidly — typically beginning almost immediately after the first dose [Ref 21]. The mechanism involves 5-HT₂A receptor downregulation in the frontal cortex [Ref 21].

De la Fuente Revenga et al. (2022) [Ref 21] demonstrated in mice that:
- A single administration of DOI produces measurable tolerance by 24 hours
- Repeated administration (4 days) produces progressive tolerance to the head-twitch response
- Tolerance mechanism is independent of β-arrestin-2 signaling
- Cross-tolerance occurs between LSD and DOI (both 5-HT₂A agonists)

**Cross-tolerance:** PARGY-LAD is expected to show complete cross-tolerance with other classical psychedelics acting via 5-HT₂A (LSD, psilocybin, mescaline, DMT). This is class-level inference consistent with the 5-HT₂A receptor downregulation mechanism [Ref 21].

### Tolerance Timeline (community consensus, no PARGY-LAD-specific data)
- Buildup: Almost immediately after ingestion [seed data, consistent with class pharmacology]
- Half-life: Approximately 6 days [seed data]
- Full reset: Approximately 14 days [seed data]

### Dependence
No physical dependence. PARGY-LAD is not expected to produce withdrawal syndrome. Psychological compulsive use is rare in the classical psychedelic class [Ref 13].

---

## Interactions

### Tramadol — DANGEROUS [Ref 14], [Ref 15]
Tramadol is a weak serotonin reuptake inhibitor (SRI) in addition to its opioid agonist activity (Gillman 2005 [Ref 15]). Combining any serotonergic drug that acts via a different mechanism with an SRI risks serotonin toxicity syndrome. PARGY-LAD's 5-HT₂A agonism and possible 5-HT₁A activity, combined with tramadol's SRI activity, creates a plausible serotonin toxicity scenario. Park et al. (2014) [Ref 14] documented that the tramadol–serotonergic interaction is well-recognized and clinically meaningful, even if not always leading to severe outcomes.

The "dangerous" interaction classification in the brief is consistent with published pharmacological evidence. However, no PARGY-LAD + tramadol case report exists in the literature. This is class-level pharmacological reasoning.

### Cannabis — Unknown
No published data on PARGY-LAD + cannabis combinations exist. Anecdotally, cannabis can intensify and prolong psychedelic experiences, sometimes precipitating anxiety or paranoia. Without substance-specific data, classification as "unknown" is appropriate.

### MAOIs (not listed in brief but safety-critical)
Combining serotonergic psychedelics with MAOIs poses severe serotonin toxicity risk. Gillman (2005) [Ref 15] identifies MAOIs as the drug class most capable of raising intra-synaptic serotonin to life-threatening levels in combination with SRIs or serotonergic drugs. MAOIs + lysergamides represents a very high-risk combination; it is not explicitly listed in the brief but should be flagged.

### Lithium
Combination of lithium with classical psychedelics has been associated with seizure risk in case reports. This is not specific to PARGY-LAD but applies class-wide.

### CYP interactions
Given AL-LAD and ETH-LAD are primarily metabolized by CYP1A2 and CYP3A4 [Ref 5], CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) and CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) may increase PARGY-LAD plasma levels. CYP inducers (e.g., rifampicin, carbamazepine) may decrease levels. This is class/structural analog inference.

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## Legal Status

### United States
PARGY-LAD is not explicitly listed in Schedule I or Schedule II of the Controlled Substances Act. As a structural analog of LSD (a Schedule I substance), it would be treated as a Schedule I substance under the **Federal Analogue Act (21 U.S.C. § 813)** if intended for human consumption [Ref 16, web-retrieved]. Prosecution under the FAA requires demonstrating "substantially similar" structure and pharmacology to a scheduled substance — both criteria are met for PARGY-LAD given its lysergamide scaffold and LSD-like discriminative stimulus properties [Ref 8].

### United Kingdom
Covered by the **Psychoactive Substances Act 2016**, which bans all psychoactive substances except specifically exempt categories (alcohol, tobacco, caffeine, licensed medicines). PARGY-LAD is not exempt; production, supply, and possession with intent to supply are criminal offenses.

### Germany
Controlled under the **Neue-psychoaktive-Stoffe-Gesetz (NpSG)** since July 18, 2019. Production, import, and supply for placement on the market are punishable offenses.

### Australia
PARGY-LAD may qualify as a **Schedule 9 (Prohibited Substance)** under the Therapeutic Goods Act as an LSD structural analog. Explicit scheduling has not been confirmed in this research.

### Canada
Not explicitly scheduled under the Controlled Drugs and Substances Act. May be subject to analog provisions in Canadian drug law if marketed for human use.

### International
Not listed under UN Convention on Psychotropic Substances schedules. Not specifically named in any international treaty instrument.

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## Clinical Trials

No clinical trials have been registered for PARGY-LAD on ClinicalTrials.gov (search conducted 2026-05-11, no results returned).

No investigational new drug applications (INDs) or equivalent regulatory submissions have been identified for PARGY-LAD.

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## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. This section has no feedback items to analyze.

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## Gaps & Flags

### Data Gaps (no source found)
1. **SMILES string** — PubChem did not return a SMILES via the API in this session. Should be retrievable from PubChem CID 139030999 directly. Generation agent should not fabricate.
2. **CAS number** — Not identified in any source.
3. **Specific receptor binding data (Ki/EC50)** — None published for PARGY-LAD. All pharmacology is class/structural analog inference. ⚠️ *Flag for editorial review: generation agent must clearly attribute any receptor binding figures to the analog class, not to PARGY-LAD.*
4. **Human pharmacokinetics** — No Tmax, half-life, or bioavailability data for PARGY-LAD exist. LSD class data used as inference base.
5. **Metabolite identification** — No published metabolite characterization for PARGY-LAD. AL-LAD/ETH-LAD metabolic data used as inference.
6. **LD50 / lethal dose** — No data. In silico predictions for N1-acyl LSD analogs (Jurowski et al. 2026 [Ref 25]) are structurally distinct and should NOT be cited as PARGY-LAD-specific.
7. **Physical properties** — No melting point, solubility, or stability data found in published literature.

### Contradictions / Discrepancies
1. **Potency discrepancy — FLAG FOR EDITORIAL REVIEW:** The Bluelight.org forum thread (2014) [Ref 18] reports that "Dr. Nichols apparently conducted testing showing PARGY-LAD was 'inactive.'" However, TiHKAL (1997) [Ref 26] and subsequent secondary sources describe activity at 160 µg and full effects at 500 µg. The Nichols 1985 J Med Chem paper [Ref 8] is titled to suggest LSD-like discriminative stimulus properties in the series — though PARGY-LAD's individual result within that paper is not available from the abstract. Possible explanations: Nichols may have found the compound inactive at lower doses in rat drug discrimination (a more stringent test) while Shulgin observed activity in human use at 500 µg. These results may not be contradictory if dose-dependence is considered. Cannot fully resolve without accessing the full Nichols 1985 paper text.

2. **Commercial sample authenticity (2014):** Wedinos drug testing [Ref 18] found a commercially sold "PARGY-LAD" sample contained AL-LAD + LSZ, not PARGY-LAD. This means that community experience reports from 2014 attributable to "PARGY-LAD" may actually reflect AL-LAD and/or LSZ effects, not PARGY-LAD itself. All community self-report data should be treated with this caveat.

### Areas Relying on Structural Analog Inference
The following content sections rely on structural analog/class inference rather than PARGY-LAD-specific data, and must be labeled accordingly in the article:
- All receptor binding affinities and targets
- Mechanism of action (except that 5-HT₂A agonism is implicit from class)
- Pharmacokinetics (Tmax, half-life, metabolism, CYP enzymes)
- Metabolic pathway
- Cardiovascular adverse effects
- Dependence liability
- Cross-tolerance mechanism and timeline
- CYP-mediated drug interactions
- Dosing potency (except TiHKAL data point)

### Safety-Critical Values Not Confirmed by Published Source
- **Tramadol "dangerous" interaction:** Pharmacologically plausible and consistent with published tramadol serotonergic mechanism data [Ref 14, Ref 15], but no PARGY-LAD + tramadol case report or controlled study exists. ⚠️ Editorial review recommended.
- **Tolerance half-life (6 days) and full reset (14 days):** Community consensus values, not derived from controlled pharmacological study of PARGY-LAD. Consistent with class behavior but unverified for this compound specifically.
- **Dose ranges:** Consistent with TiHKAL's reference to full activity at 500 µg. PsychonautWiki community consensus. No clinical trial or controlled study confirms.
- **Duration (6–8 hours):** Community consensus; plausible given AL-LAD duration data but unverified for PARGY-LAD specifically.

### MAOI Interaction (Not Listed in Brief)
MAOIs are not listed in the brief's known interactions but represent a class-wide severe hazard for serotonergic psychedelics. Should be considered for addition.