PRO-LAD

# Research Output: PRO-LAD

## Chemical Identity

**Verified chemical data (PubChem CID 44457803, confirmed via API):**

- **Preferred name:** PRO-LAD (6-propyl-6-nor-lysergic acid diethylamide)
- **Synonyms:** PROLAD; 6-propylnorlysergic acid N,N-diethylamide; 9,10-didehydro-6-propyl-N,N-diethylergoline-8β-carboxamide
- **IUPAC name:** (6aR,9R)-N,N-diethyl-7-propyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide [Ref 3 — PubChem]
- **CAS number:** 65527-63-1 [Ref 24 — web-retrieved]
- **PubChem CID:** 44457803
- **Molecular formula:** C₂₂H₂₉N₃O [Ref 3]
- **Molecular weight:** 351.5 g/mol [Ref 3]
- **Isomeric SMILES:** CCCN1C[C@@H](C=C2[C@H]1CC3=CNC4=CC=CC2=C34)C(=O)N(CC)CC [PubChem REST API]
- **InChIKey:** HZKYLVLOBYNKKM-OXQOHEQNSA-N [Ref 3]
- **Full InChI:** InChI=1S/C22H29N3O/c1-4-10-25-14-16(22(26)24(5-2)6-3)11-18-17-8-7-9-19-21(17)15(13-23-19)12-20(18)25/h7-9,11,13,16,20,23H,4-6,10,12,14H2,1-3H3/t16-,20-/m0/s1

**Physicochemical properties:**
- **XLogP:** 3.8 (moderate lipophilicity) [PubChem REST API]
- **H-bond donors:** 1 (indole NH)
- **H-bond acceptors:** 2
- **Melting point:** 87–88°C (crystalline free base) [Ref 11 — TiHKAL #51]

**Seed data discrepancies:** The brief lacks SMILES, molecular formula, molecular weight, InChIKey, and PubChem CID; all are now confirmed via PubChem CID 44457803. Seed data IUPAC name matches PubChem exactly.

---

## Pharmacology

### Mechanism of Action

PRO-LAD is a serotonergic psychedelic in the lysergamide class. Its primary mechanism — shared with LSD — is partial agonism at the 5-HT₂A serotonin receptor (HTR2A), which is widely regarded as the principal molecular target mediating psychedelic effects (Passie et al. 2008 [Ref 9]; Wacker et al. 2017 [Ref 18]). PRO-LAD's ergoline scaffold positions it to engage the orthosteric binding pocket of 5-HT₂A in a manner structurally identical to LSD, including the critical diethylamide moiety [Ref 18].

Beyond 5-HT₂A, the lysergamide class also engages:
- **5-HT₁A** — partial agonist; contributes to anxiolytic and anti-panic components [Ref 9]
- **5-HT₂C** — partial agonist
- **Dopamine receptors (D₁, D₂ family)** — LSD interacts both agonistically and antagonistically with D₁ and D₂; D₂ receptors may mediate significant portions of LSD-like effects at later time points [Ref 9]
- **Adrenergic receptors (α₁, α₂)** — LSD engages adrenergic receptors, unlike tryptamine psychedelics [Ref 20]
- **Multiple additional GPCRs** — a 2025 broad profiling study of 41 psychedelics against 318 human GPCRs found psychedelics of the lysergamide class have potent actions at nearly every serotonin, dopamine, and adrenergic receptor (Jain et al. 2025 [Ref 25])

### Receptor Binding — PRO-LAD-Specific Data

**FLAG FOR HUMAN REVIEW:** No published Ki or EC₅₀ values specific to PRO-LAD have been located in the peer-reviewed literature. The Psychoactive Drug Screening Program (PDSP) database was not queried in a published paper dedicated to PRO-LAD. The only substance-specific in vivo pharmacological data is from Hoffman & Nichols (1985) [Ref 1], which demonstrated PRO-LAD is **equipotent to LSD** in a rat two-lever drug discrimination assay (LSD tartrate 185.5 nmol/kg IP as training dose). In this series:
- N⁶-ethyl (ETH-LAD): **~2–3× more potent** than LSD
- N⁶-allyl (AL-LAD): **~2–3× more potent** than LSD
- N⁶-propyl (PRO-LAD): **equipotent** to LSD
- N⁶-isopropyl: ~half as active as LSD
- N⁶-n-butyl: ~1/10 potency of LSD

This SAR indicates an optimal N⁶ substituent size around ethyl/allyl, with propyl at the equipotency boundary. Nor-LSD (unsubstituted N⁶) did not generalize to LSD [Ref 1].

### LSD Receptor Binding Context (applicable by class analogy)

LSD has sub-nanomolar to low-nanomolar affinity at most serotonin receptor subtypes. The Wacker et al. (2017) crystal structure [Ref 18] revealed that LSD's slow dissociation from 5-HT₂B and 5-HT₂A is due to an extracellular loop 2 (EL2) "lid" clamping over the bound ligand — a mechanism that explains the prolonged duration of action relative to plasma half-life. PRO-LAD, sharing the core ergoline scaffold and diethylamide moiety, is expected to exhibit the same lid-trapping mechanism, though this has not been directly tested.

### Pharmacokinetics

No human pharmacokinetic data exist for PRO-LAD. The following applies by structural analogy from LSD:

- **Oral Tmax:** ~1.5 hours (range 0.5–4 h) (Dolder et al. 2015 [Ref 19])
- **Half-life:** biexponential; initial t½ ~3.6 h, terminal t½ ~8.9 h [Ref 19]
- **Cmax (100 µg LSD oral):** ~1.3 ng/mL; (200 µg): ~3.1 ng/mL [Ref 19]
- **Route of elimination:** hepatic metabolism, renal excretion [Ref 17 — Wikidoc]
- **CYP enzymes:** not published for PRO-LAD. LSD metabolism involves CYP enzymes; specific isozymes not well characterized in published literature.

**FLAG:** PRO-LAD duration (6–8 hours per TiHKAL and community sources) is notably shorter than LSD (8–12 hours). This is consistent with the known effect of N⁶ substitution on duration — the propyl chain may modestly alter receptor residence time or metabolic clearance, but no published mechanistic explanation exists.

### Stereochemistry

PRO-LAD retains the (6aR,9R) stereochemistry of LSD at the critical C-8β carboxamide position [Ref 3]. Only the d-isomer (corresponding to d-LSD configuration) is pharmacologically active; the l-form (iso-configuration) is essentially inactive, as established for LSD (Passie et al. 2008 [Ref 9]).

---

## History

**Discovery/Synthesis Timeline:**

- **1976:** Tetsukichi Niwaguchi and colleagues first synthesized N⁶-alkyl norlysergic acid derivatives including what would later be called PRO-LAD. This work preceded the Nichols group publication. [Note: The Niwaguchi 1976 paper was not retrievable through structured APIs; this date is based on secondary sources including Wikipedia and web-retrieved summaries. **FLAG for verification.**]

- **1985:** Andrew J. Hoffman and David E. Nichols (Purdue University) published the landmark synthesis and pharmacological characterization paper: "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 (verified via Crossref [Ref 1]). This paper described a practical synthesis route and established PRO-LAD's equipotency with LSD in drug discrimination.

- **ca. 1986:** Human psychoactive effects first described by Nichols in a literature review, citing personal communication with Alexander Shulgin. [Source: secondary web sources; **FLAG: primary source not located.**]

- **1997:** Shulgin documented PRO-LAD in TiHKAL ("Tryptamines I Have Known and Loved") as entry #51 [Ref 11], providing first-person accounts and synthesis notes. This constitutes the primary published description of human effects.

- **~2013–2015:** PRO-LAD emerged on the research chemical market alongside AL-LAD, ETH-LAD, and LSZ [Ref 13].

- **January 7, 2015:** UK Home Office Circular 001/2015 specifically named PRO-LAD as a Class A controlled substance [Ref 13].

**Synthesis (from TiHKAL [Ref 11]):**
Starting from nor-LSD (demethylated at N⁶ via prior published methods), alkylation is performed with propyl iodide in DMF (dimethylformamide) using potassium carbonate as base catalyst. Crystalline product isolated in 72% yield. Free base melts at 87–88°C.

---

## Subjective Effects

Human effect descriptions derive exclusively from TiHKAL [Ref 11] (personal communications relayed by Shulgin) and community/user reports [Ref 24]. No controlled clinical study has measured subjective effects of PRO-LAD in humans.

**Shulgin TiHKAL descriptions (dose-stratified):**

- **80 µg:** "I am aware of some change within a quarter hour, and then nothing more for quite a while. Certainly no visuals, almost like MDMA in that I am not really sure that this is even psychedelic."
- **135 µg:** Initial development into a "sort of paranoia place" without shared space with partner; at higher points within same experience "considerable visuals came into play, with easy fantasy interlocking with music. Emotions were reknit, food was good, and sleep fine at the 8th or 9th hour."
- **175 µg:** "This is an intellectually clear material, but it is a funny material. I am certainly at a +++ or at least I was a couple of hours ago." Characterized as "good for humor, even excellent… very good for clear thinking."

**Qualitative character (TiHKAL + community sources):**
PRO-LAD is characterized as intellectually clear, somewhat milder in visual intensity than LSD at comparable doses, with a stronger body component (numbness, tingling, bodily lightness) than LSD [Ref 24]. Lack of "cosmic-type" thinking noted [Ref 11]. Humor enhancement is prominent in multiple accounts. Effects described as comfortable and manageable relative to LSD.

**Duration:** Total 6–8 hours, onset 30–45 minutes [Ref 8, Ref 11]. Reported shorter than LSD (8–12 h) — this is a consistent finding across community data.

**Effects taxonomy (from brief, consistent with class):** The effects listed in the seed data (visual drifting, synesthesia, auditory enhancement, thought connectivity, introspection, etc.) are consistent with serotonergic 5-HT₂A agonism and broadly supported by the class literature. No controlled studies specifically enumerating PRO-LAD effects exist.

---

## Safety & Toxicity

**LD₅₀:** Unknown. No published LD₅₀ data for PRO-LAD in any species. Seed data correctly states "toxic dose is unknown."

**Overdose:** No documented overdose cases or case reports for PRO-LAD have been located in the published literature or EMCDDA databases. Tripsitter [Ref 24] states "no documented overdose cases."

**Class-level safety (applicable by analogy):**
LSD is physiologically well tolerated at typical recreational doses; there is no established lethal dose in humans for pure compound taken orally [Ref 9]. The principal risks of LSD-class compounds are psychological: acute anxiety, panic, psychotic episodes (particularly in those with personal or family history of psychosis), and accidents from impaired judgment [Ref 24].

**Seizure threshold:** The seed data lists "seizure threshold reduction" as an effect. This is documented for LSD-class psychedelics in combination with lithium, but is considered a class-level risk rather than a direct intrinsic property. No PRO-LAD-specific seizure data found.

**Psychological risks:** Potential triggering of psychotic episodes in predisposed individuals; trauma responses; hallucinogen persisting perception disorder (HPPD) — these are documented class-level concerns for serotonergic psychedelics [Ref 9]. No PRO-LAD-specific psychiatric adverse event data found.

**Cardiac:** Lysergamide ergoline compounds carry a theoretical risk of vasoconstriction (consistent with seed data). Ergotamine analogs are associated with vasospasm, but LSD-type doses are far below pharmacological thresholds for this effect. No clinical data for PRO-LAD.

**Adulteration risk:** A significant harm reduction concern is NBOMe contamination of blotter products sold as PRO-LAD; NBOMe compounds are potentially lethal at sub-milligram doses [Ref 24].

---

## Harm Reduction

**Reagent testing:** Based on ergoline/indole scaffold [Ref 24]:
- **Ehrlich reagent:** Purple (positive for indole)
- **Marquis reagent:** Pinkish-red
- **Hofmann reagent:** Negative/no reaction (distinguishes from non-indole compounds)
These results are consistent with PRO-LAD's ergoline chemistry. Testing is strongly recommended to exclude NBOMe adulterants (which test negative with Ehrlich).

**Set and setting:** Standard psychedelic harm reduction applies — familiar environment, trusted companions, no other serotonergic substances.

**Contraindications (class-level, no PRO-LAD-specific data):**
- Personal or family history of psychotic disorders (schizophrenia, bipolar I, schizoaffective)
- Concurrent use of tramadol (serotonin syndrome risk — see Interactions)
- Concurrent use of lithium (seizure risk, class-established for LSD)
- Concurrent use of SSRIs/SNRIs (potential serotonin syndrome; may also blunt effect)
- Pregnancy/breastfeeding (insufficient safety data)

**No PRO-LAD-specific published harm reduction protocols were found.** All recommendations derive from LSD class data.

---

## Tolerance & Dependence

**Tolerance:** PRO-LAD, by class analogy with LSD, is expected to produce rapid tachyphylaxis. With LSD, near-complete tolerance develops after 3–4 consecutive daily doses, thought to result from 5-HT₂A receptor downregulation [Ref 9]. The seed data states buildup "almost immediately after ingestion," which is consistent with this mechanism.

- **Half-life of tolerance:** Seed data states 6 days; 14 days for full reset. These values are consistent with published LSD class data (tolerance typically resolves within 1–2 weeks) [Ref 9].
- **Cross-tolerance:** Complete cross-tolerance with other serotonergic psychedelics (LSD, psilocybin, mescaline) via shared 5-HT₂A mechanism [Ref 9]. Seed data value confirmed.

**Dependence/Addiction:** PRO-LAD shares the class characteristic of being non-habit-forming. LSD does not produce physical dependence or meaningful compulsive use patterns. The seed data value ("not habit-forming") is consistent with published data on lysergamides [Ref 9]. No animal or human dependence studies for PRO-LAD.

**Withdrawal:** No withdrawal syndrome documented for LSD or related lysergamides. No PRO-LAD-specific withdrawal data.

---

## Interactions

### Tramadol — Dangerous [FLAG: Seed Data Value, Mechanism Inferred]

The "dangerous" classification for tramadol in the seed data is pharmacologically justified but not supported by a published PRO-LAD-specific interaction study.

**Mechanism:** Tramadol is a dual-action compound — mu-opioid agonist AND serotonin/norepinephrine reuptake inhibitor. Its active metabolite O-desmethyltramadol has significantly greater serotonergic potency than the parent compound (Roulet et al. 2021 [Ref 23]). Combined with PRO-LAD's direct 5-HT₂A partial agonism and probable serotonergic effects, this combination creates risk of serotonin syndrome. Additionally, tramadol independently lowers seizure threshold; combined with a psychedelic that also reduces seizure threshold creates compounded risk.

**Evidence basis:** Tramadol serotonin syndrome risk is well-established for SSRI combinations [Ref 23]. The extension to direct 5-HT₂A agonists such as PRO-LAD is mechanistically sound but relies on class inference, not direct human data.

**FLAG FOR HUMAN REVIEW:** The "dangerous" severity rating is mechanistically justified but not verified against a published PRO-LAD + tramadol case report or clinical study.

### Cannabis — Unknown

No published interaction data between PRO-LAD and cannabis/cannabinoids. Community experience with LSD + cannabis suggests possible potentiation of psychedelic effects and increased anxiety/paranoia. Classified as unknown in seed data; appropriate.

### Additional class-level interaction concerns (not in seed data):

- **Lithium:** LSD + lithium associated with seizures in case reports — **this combination should be flagged as dangerous** and may be missing from seed data interactions.
- **SSRIs/SNRIs:** Attenuate psychedelic effects via 5-HT₂A downregulation; serotonin syndrome risk at high doses.
- **MAOIs:** Potentiation of serotonergic effects; serotonin syndrome risk.
- **Antipsychotics:** 5-HT₂A antagonists (e.g., risperidone, quetiapine) can abort a PRO-LAD experience.

---

## Legal Status

| Jurisdiction | Status | Effective Date | Notes |
|---|---|---|---|
| **United Kingdom** | Class A (Schedule 1 MDA) | January 7, 2015 | Specifically named in Home Office Circular 001/2015 [Ref 13] |
| **Latvia** | Illegal | June 1, 2015 | Specifically listed [Ref 17] |
| **Switzerland** | Controlled | December 1, 2015 | Added to controlled substances list [Ref 17] |
| **Germany** | Controlled (NpSG) | July 18, 2019 | Scheduled under Neue-psychoaktive-Stoffe-Gesetz [Ref 17] |
| **Austria** | Likely controlled | — | Potentially covered under NPSG analogue provisions [Ref 17] |
| **United States** | Not explicitly scheduled | — | Federal Analogue Act potentially applicable as LSD analog if marketed for human consumption [Ref 7] |
| **Canada** | Grey area | — | Not explicitly scheduled; status comparable to other lysergamide analogs [Ref 24] |
| **Australia** | Likely controlled | — | Controlled as LSD derivative under prohibited substance provisions [Ref 24] |
| **EU (general)** | Illegal in most states | — | Via analogue laws or NPS legislation [Ref 24] |

**ACMD recommendation:** The UK Advisory Council on the Misuse of Drugs recommended on June 10, 2014 that PRO-LAD be specifically named as Class A — notably while acknowledging it had not been identified as ever having been sold or causing any documented harm at the time of recommendation [Ref 7].

---

## Clinical Trials

**No clinical trials found.** ClinicalTrials.gov search for "PRO-LAD lysergamide" returned zero results. PRO-LAD has not been studied in any registered clinical trial as of April 2026.

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## Community Feedback Analysis

**No community feedback submitted.** Part A2 of the brief was empty.

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## Gaps & Flags

### Data Gaps

1. **PRO-LAD-specific receptor binding Ki/EC₅₀ values** — Not found in published literature. No PDSP database entry for PRO-LAD identified. Receptor pharmacology is entirely inferred from LSD class data and drug discrimination equipotency data (Hoffman & Nichols 1985 [Ref 1]).

2. **Human pharmacokinetics** — No human PK study for PRO-LAD exists. All PK inferences rely on LSD class data (Dolder et al. 2015 [Ref 19]). PRO-LAD's shorter reported duration (6–8 h vs. LSD's 8–12 h) suggests possible pharmacokinetic differences not yet characterized.

3. **Metabolites and CYP enzymes** — No published data on PRO-LAD metabolism. Hepatic metabolism assumed by class analogy; specific CYP enzymes and metabolites unknown.

4. **LD₅₀ / toxicity** — No animal or human toxicity data for PRO-LAD. Toxic dose genuinely unknown. Seed data correctly flags this.

5. **Niwaguchi 1976 paper** — Referenced in secondary sources as the first description of PRO-LAD-class compounds, but not retrievable through PubMed or OpenAlex. The 1985 Hoffman & Nichols paper is the first verifiable primary publication. **FLAG for editorial review of discovery date.**

6. **Physical properties** — Only melting point (87–88°C) from TiHKAL [Ref 11] available. Solubility, vapor pressure, pKa, and stability data not found in published literature.

7. **"Return of the Lysergamides" series** — No dedicated PRO-LAD paper exists in this series (Parts I–VII cover 1P-LSD, AL-LAD/LSZ, ETH-LAD/1P-ETH-LAD, 1B-LSD, 1CP-LSD, 1V-LSD, 1DD-LSD). PRO-LAD lacks a modern analytical characterization paper.

8. **Forensic detection** — No validated LC-MS/MS or GC-MS method specifically for PRO-LAD in biological matrices has been published.

9. **Lithium interaction** — Lithium + LSD seizure risk is documented class-level data but missing from seed interactions. Recommend adding to interactions table as "dangerous."

### Safety-Critical Flags

- **Dose range (Strong: 200–350 µg, Heavy: 350+ µg):** These values are from community sources only (PsychonautWiki, TiHKAL). TiHKAL [Ref 11] places the upper practical dose at 175 µg; community data extends to 200+ µg. No controlled study has verified safety at 350+ µg. **FLAG: Strong/Heavy dose ranges unverified against published source.**

- **Tramadol "dangerous" classification:** Mechanistically justified but no PRO-LAD-specific published data. **FLAG.**

- **Onset 30–45 minutes:** Community consensus; no controlled study. Consistent with LSD class but unverified for PRO-LAD specifically.

- **Duration 6–8 hours:** Consistent across TiHKAL and community sources; shorter than LSD. Mechanistic basis for shorter duration not characterized. Seed data value appears reliable.

- **Synthesis year discrepancy:** Secondary sources cite either 1984 (Psychedelics Daily, Tripsitter) or 1985 (PMID 4032428 publication date, DOI verified). The Hoffman & Nichols paper was submitted/accepted in 1984 but published 1985. The 1985 date should be used for the publication year; 1984 may refer to the synthesis/submission date.