Cannabinoid reuptake and degradation

• 1. Reuptake by cannabinoid transporters
  • 1.1. Cannabinoid transporter
  • 1.2. Cannabinoid reuptake inhibitors
• 2. Cannabinoid degradation
  • 2.1. Cannabinoid degradation enzymes
    • 2.1.1. FAAH
    • 2.1.2. MAGL
    • 2.1.3. FLAT
  • 2.2. Cannabinoid enzyme degradation inhibitors
    • 2.2.1. FAAH inhibitors
    • 2.2.2. MAGL inhibitors
    • 2.2.3. FLAT inhibitors
  • 2.3. Further decomposition paths

1. Reuptake by cannabinoid transporters¶

1.1. Cannabinoid transporter¶

The cannabinoid membrane transporter takes cannabinoids back into the nerve cell. The endocannabinoids then hydrolyze immediately.¹

1.2. Cannabinoid reuptake inhibitors¶

Cannabinoid reuptake inhibitors are among others:

• AM404²³⁴
  • active metabolite of paracetamol
    • AM-404 such as paracetamol prevent dyskinesia triggered by dopamine D2 receptor antagonists (antipsychotics such as haloperidol)⁵
    • binds to Transient Receptor Potential Vanilloid 1 (TRPV1)⁵
    • prevented the haloperidol-induced decrease in c-Fos+preproenkephalin+striatal neurons in wild-type mice, but not in TRPV1-deficient mice⁵
    • has an analgesic effect via 5-HT1A receptors⁶
    • reduces alcohol self-administration in mice⁷⁸
    • had an antidepressant, anticompulsive effect and enhanced the effect of fluoxetine⁹¹⁰
    • binds to TRPV1 via the vanilloid binding site; TRPV1 is the main receptor for AM404 in DRG neurons¹¹
  • pain-relieving
  • anxiety-relieving¹²
• AM1172¹³¹⁴
• Guinean¹⁵
• Linvanil³
• LY-2183240¹⁶¹⁷
• O-2093, O-2247, O-2248, O-3246, O-3262¹⁸
• OMDM-2
  • reduced social isolation¹⁹
• Olvanil²⁰
• RX-055
• SYT-510
• UCM-707 (N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide)²¹
• VDM-11²²
• WOBE437²³²⁴
• OMDM-1²⁵²⁶

2. Cannabinoid degradation¶

2.1. Cannabinoid degradation enzymes¶

Endocannabinoids are primarily degraded by FAAH, FLAT and MAGL.

2.1.1. FAAH¶

FAAH (fatty-acid amide hydrolase 1, N-arachidonoylethanolamine amidohydrolase, fatty acid amidohydrolase, also oleamide hydrolase, anandamide amidohydrolase) degrades:

• AEA²⁷²⁸ on arachidonic acid and ethanolamide²⁹³⁰
  • AEA degradation by FAAH predominantly in the postsynapse³¹
• 2-AG²⁸
  • this is contradicted by the fact that the FAAH inhibitor URB597 only increased AEA in the hypothalamus, but not 2-AG³²
• Oleamide (cis-9,10-octadecenoamide), a sleep-inducing lipid³³
  • unclear whether oleamide interacts with FAAH³⁴
• N-acyltaurine³⁵
• N-acylethanolamine
  • N-oleoylethanolamine
  • N-palmitoylethanolamine

The degradation of AEA by FAAH appears either to serve other pathways or to be significantly stronger than the degradation by reuptake. In any case, FAAH inhibitors show different or stronger effects than AEA reuptake inhibitors.²¹

In Alzheimer’s disease, FAAH appears to be increased overall³⁶ but decreased in PFC²⁹.

2.1.2. MAGL¶

MAGL, monoacylglycerol lipase²⁹ metabolizes 2-AG to arachidonic acid and glycerol.
Degradation of 2-AG by MAGL in the presynapse.³¹

2-AG is 85 % degraded by MAGL and 15 % by ABHD6 and ABHD12.³⁷

2.1.3. FLAT¶

FLAT (FAAH-like anandamide transporter) is a truncated and catalytically inactive(r) variant of FAAH.³⁸

• binds anandamide with low micromolar affinity²⁵
• facilitates its transfer into the cells²⁵
• is blocked by the anandamide transporter inhibitors AM404 and OMDM-1²⁵
• the phthalazine derivative ARN272 is a competitive antagonist of the interaction of anandamide with FLAT and prevented the uptake of anandamide into cells²⁵
• pharmacological inhibition of FLAT enhanced AEA signaling and its antinociceptive effect³⁸
• not yet detected in any tissue³⁸
• is primarily localized at intracellular membranes³⁸
• shows no contact with the plasma membrane³⁸
  • Enhancement of AEA uptake therefore due to enzymatic action rather than transport activity

2.2. Cannabinoid enzyme degradation inhibitors¶

Inhibition of the degradation of cannabinoids is also of particular pharmacological interest.
A degradation inhibitor is

• AACOCF3³⁹
• VDM-11²²

2.2.1. FAAH inhibitors¶

Synthetic FAAH inhibitors showed massive to fatal side effects, especially with long-term use, such as impairment of cognitive and motor functions and increased risk of psychosis⁴⁰ (however, we were unable to verify the sources cited). Testing of the synthetic FAAH inhibitor BIA 10-2474 in humans showed no side effects with a single dose in 86 subjects. In a subsequent phase of daily oral administration, however, one subject was hospitalized after a few days and died shortly thereafter due to brain death; 4 of 5 other subjects suffered severe bleeding and dying tissue in the brain with presumably irreversible impairments.⁴¹
Even if this is a very rare accident in a phase 1 trial, it should be a clear warning against carrying out self-experiments with untested substances.
Biological FAAH should not have these side effects.⁴⁰

Organophosphates inhibit FAAH, which degrades the CB1R and CB2R agonist anandamide (AEA), leading to ADHD symptoms in mice. Excessive FAAH inhibition increases AEA to such an extent that it has a neurotoxic effect.⁴²

Other FAAH inhibitors:⁴³

• biological FAAH inhibitors⁴⁰
  • Biochanin A (flavonoid in red clover; Trifolium pretense)
  • Daidzein (flavonoid in red clover; Trifolium pretense)
  • Formononetin (flavonoid in red clover; Trifolium pretense)
  • Genistein (flavonoid in red clover; Trifolium pretense)
  • Guineensine (alkaloid in monk’s pepper; Piper longum)
  • Kaempferol⁴⁴⁴⁵ (broccoli, Brussels sprouts, tomatoes, grapes, green tea, delphinium, witch hazel, grapefruit, red grapes, ginkgo, grapefruits, passionflower, daphne, apples, potatoes, onions, pumpkin, cucumber, lettuce, green beans, peach, Blackberries, raspberries, spinach, hops, aloe vera, Coccinia grandis, Cuscuta chinensis, Euphorbia pekinensis, Glycine max, Hypericum perforatum, Pinus sylvestris, Moringa oleifera, rosemary, Sambucus nigra, Toona sinensis, holly, endive, spice lily)
  • (N-BenzylOctadeca-9Z, 12Z-dienamide) (Maca, Lepidium meyenii)
  • N-Benzylstearamide (Maca, Lepidium meyenii)
  • Macamide (Maca, Lepidium meyenii)
  • Myristicin (nutmeg, aniseed, parsley, dill),
  • Pelargonidin (all berries, plums, pomegranates)
• synthetic FAAH inhibitors⁴⁰
  • AA5HT (N-[2-(5-Hydroxy-1H-indol-3-yl)ethyl]-5,8,11,14-eicosatetraenamid)⁴⁶
  • BIA 10-2474⁴¹
    • Severe side effects: acute and rapidly progressive neurological symptoms, such as headache and impaired consciousness. Brain death in one patient, presumably due to overdose⁴⁷
  • JNJ-42165279
  • JZL195 (also MAGL inhibitor)
  • LY-2183240
  • PF-04457845⁴⁸
  • URB597 (KDS-4103, Cyclohexyl carbamic acid 3’-carbamoyl-biphenyl-3-yl ester)²¹
    • potentiated the ability of anandamide to increase dopamine levels in the nucleus accumbens shell²¹
    • increased FAAHs also in the brain when administered subcutaneously or intraperitoneally⁴⁹
    • increased AEA in the hypothalamus, but not 2-AG³²
• unknown whether natural or synthetic FAAH inhibitor
  • 4-Nonylphenylboronic acid
  • (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one⁵⁰
  • MK-4409⁵¹
  • N-arachidonoyl serotonin⁴⁷
  • Piperazine carboxamides are inhibitors of FAAH and MAGL⁵²
  • Piperazine carbamates are inhibitors of FAAH and MAGL⁵²
  • Piperidine carboxamides are inhibitors of FAAH and MAGL⁵²
  • Piperidine carbamates are inhibitors of FAAH and MAGL⁵²
  • PF-622 (N-phenyl-4-(quinolin-2-ylmethyl)piperazine-1-carboxamide)⁵³
  • PF-750 (N-phenyl-4-(quinolin-3-ylmethyl)piperidine-1-carboxamide)⁵³
  • PF3845⁵⁴
  • SA-57 (also MAGL inhibitor)⁵⁵
  • ST4070⁵⁶⁴⁷
  • SSR411298⁴⁷
  • URB597⁴⁷
  • URB694⁴⁷

FAAH inhibitors also appear to act as TRPV1 agonists.⁵⁷

2.2.2. MAGL inhibitors¶

MAGL breaks down 2-AG. MAGL is inhibited by:

• JZL184
  • MAGL inhibitor⁷
  • increased alcohol self-administration in mice⁷
• JZL195
  • FAAH and MAGL inhibitor⁴³
• KML29⁴⁷
• MJN110⁵⁸
  • Piperazine carboxamides are inhibitors of MAGL and FAAH⁵²
  • Piperazine carbamates are inhibitors of MAGL and FAAH⁵²
  • Piperidine carboxamides are inhibitors of MAGL and FAAH⁵²
  • Piperidine carbamates are inhibitors of MAGL and FAAH⁵²
• SA-57
  • fAAH inhibitor at the same time

2.2.3. FLAT inhibitors¶

Guineensin is said to act as a FLAT inhibitor.⁵⁰

2.3. Further decomposition paths¶

Endocannabinoids can be broken down by oxidation of:⁵⁹⁶⁰

• Cyclooxygenase-2
• Lipoxygenases
• Cytochrome P450
  • CYP2J2⁶⁰