Cannabinoids

Cannabinoids are produced by the body itself (endocannabinoids), by plants (phytocannabinoids) and can be produced artificially (synthetic cannabinoids).
Cannabinoids act as neurotransmitters and are closely linked to the dopamine system.

• 1. Cannabinoids
  • 1.1. Endocannabinoids
    • 1.1.1. Known endocannabinoids
    • 1.1.2. AEA (anandamide, N-arachidonoylethanolamine)
      • 1.1.2.1. Synthesis of AEA
      • 1.1.2.2. AEA and blood-brain barrier
      • 1.1.2.3. AEA receptor binding
      • 1.1.2.4. Reduction of AEA
      • 1.1.2.5. Effects of AEA
      • 1.1.2.6. AEA (anandamide) for ADHD and other disorders
    • 1.1.3. 2-AG (2-arachidonylglycerol)
      • 1.1.3.1. Synthesis of 2-AG:
      • 1.1.3.2. 2-AG receptor binding
      • 1.1.3.3. Effect of 2-AG
      • 1.1.3.4. Reduction of 2-AG
    • 1.1.4. PEA (palmitoylethanolamide)
      • 1.1.4.1. Synthesis of PEA
      • 1.1.4.2. PEA receptor binding
      • 1.1.4.3. Reduction of PEA
      • 1.1.4.4. Effect of PEA
  • 1.2. Phytocannabinoids (plant cannabinoids)
    • 1.2.1. Cannabinoids from the hemp plant
      • 1.2.1.1. Tetrahydrocannabinoids
      • 1.2.1.2. CBD-type cannabinoids (cannabidiols)
      • 1.2.1.3. CBC-type cannabinoids (cannabichromenes)
      • 1.2.1.4. CBCN-type cannabinoids (cannabichromanones)
      • 1.2.1.5. CBL-type cannabinoids (cannabicyclols)
      • 1.2.1.6. CBE-type cannabinoids (cannabielsoins)
      • 1.2.1.7. CBN-type cannabinoids (cannabinols)
      • 1.2.1.8. CBT-type cannabinoids (cannabitriols)
      • 1.2.1.9. CBND-type cannabinoids (cannabinodiols)
      • 1.2.1.10. CBG-type cannabinoids (cannabigerols)
      • 1.2.1.11. Unclear to which type
    • 1.2.2. Cannabinoids from other plants
  • 1.3. Synthetic cannabinoids (cannabinoid mimetics)
  • 1.4. Endocannabinoidome: the extended cannabinoid system

1. Cannabinoids¶

1.1. Endocannabinoids¶

Endocannabinoids are cannabinoids produced by the body itself. Endocannabinoids are bioactive lipids and consist of two structurally different classes of fatty acid derivatives, the acylethanolamides (AEs) and the monoacylglycerols (MAGs).
Endocannabinoids are synthesized on demand by dopaminergic neurons of the VTA and released postsynaptically. From there, they bind to presynaptic¹² cannabinoid receptors on nearby GABAergic (inhibitory) and glutamatergic (activating) neurons³

1.1.1. Known endocannabinoids¶

Endocannabinoids are:

• Omega-6 endocannabinoids (ω-6 endocannabinoids)⁴
  • Anandamide, AEA (see below for details)
  • 2-AG (see below for details)
  • PEA (see below)
• Omega-3 endocannabinoids (ω-3 endocannabinoids)
  • DHEA (docosahexaenoyl ethanolamide, DHA-EA, synaptamide)⁵⁴⁶
    • GPR110 ligand⁴
    • Degradation by FAAH to DHA⁴
  • 2-Docosahexaenoyl glycerol (2-DHG)⁴
  • DHA-serotonin (DHA-5HT, endocannabinoid-like substance)⁴
  • DHA-dopamine (DHA-DA, endocannabinoid-like substance)⁴
  • EPA-EA, EPEA (EPA ethanolamide)⁴
  • DHG (DHA glycerol)⁴
  • EPG (EPA glycerol)⁴
• NADA (N-arachidonoyldopamine)⁷
  • NADA increased the permeability of the blood-brain barrier through a cytotoxic mechanism⁸
  • TRPV1 agonist
  • acts on CB1R, but atypically and causes a slight reduction in activated CB1R⁹
• γ-Linolenoylethanolamide¹⁰
• DEA (docosatetraenoylethanolamide)¹⁰
• Noladinether (2-arachidonylglyceryl ether)¹¹
• Virodhamin (O-arachidonylethanolamide)¹¹
  • partial CB1R antagonist¹²
• OEA (oleoylethanolamide)¹³
  • PPAR-α agonist (PPAR-α: peroxisome proliferator-activated receptor alpha)¹⁴
  • GPR-119 agonist¹⁵
  • does not bind to CB1R¹⁶
  • conveys a feeling of satiety¹⁷
  • has an antidepressant effect¹⁴
    • via PPAR-α and histamine
  • Reduction via FAAH and FAAH-2 (equally strong)¹⁸
    • FAAH2 only in primates, not in rodents¹⁸
  • is freely available as a dietary supplement
• NAGly (N-arachidonylglycine)¹¹
• Oleic acid amide, oleamide ((Z)-octadec-9-enamide)¹¹
  • Carboxylic acid amide of oleic acid
  • CB1R agonist
  • TRPV1 agonist
  • sleep inducing
  • Dismantling by FAAH
• Stearylethanolamide¹⁰

It is assumed that AEA represents more of a “tonic” mechanism and 2-AG more of a “burst-like” mechanism for CB1R activation¹⁹

DHA (docosahexaenoic acid) reduces the gene expression of endocannabinoids.²⁰
Endocannabinoids can influence the gene expression of dopamine receptors.

• THC during birth caused²¹²²
  • in the neonatal period
    • delayed appearance of neonatal reflexes
    • increased DRD2 mRNA
    • 2-AG brain levels decreased, which persisted into adulthood
  • in adult rats
    • increased CNR1 expression (the gene that codes for CB1R) (only) in the PFC
    • increased DRD2 expression (only) in the PFC
    • increased DRD3 expression (only) in the PFC
    • consistent reduction of DNA methylation in the DRD2 regulatory region
    • social withdrawal
    • cognitive impairments
    • which was reversed by cannabidiol treatment

1.1.2. AEA (anandamide, N-arachidonoylethanolamine)¶

• occurs in large quantities in the CNS
• Ethanolamine derivative of arachidonic acid
• is an acylethanolamide

1.1.2.1. Synthesis of AEA¶

There are several alternative synthesis pathways of AEA, which may be preferred depending on the brain region or for different physiological and pathophysiological processes.²³

• First step: Synthesis of NAPE
  • Phosphatidylethanolamine is converted to NAPE (N-acyl-phosphatidylethanolamine (N-arachidonoylphosphatidylethanolamine)) by N-acylation with N-acyltransferase¹³²⁴
    OR
    • Arachidonic acid (a polyunsaturated omega-6 fatty acid, PUFA) is converted from the sn-1 position of phosphatidylcholine to N-arachidonoylphosphatidylethanolamine (NAPE) by transacylase
• Second step: NAPE becomes anandamide
  • NAPE is hydrolyzed to anandamide by phospholipase D (NAPE-PLD)^13242526
    OR
  • NAPE is produced by sequential deacylation by phospholipase B (alpha,beta-hydrolase 4, ABHD4) and subsequent cleavage of glycerophosphate to AEA (in around 60 minutes)²⁵
    OR
  • NAPE is hydrolyzed by phospholipase C to phosphoanandamide²⁵
    OR
  • NAPE is dephosphorylated by phosphatases (e.g. the tyrosine phosphatase PTPN22 and the inositol 5’-phosphatase SHIP1) (in less than 10 minutes)²⁵

1.1.2.2. AEA and blood-brain barrier¶

Anandamide can cross the blood-brain barrier. Thus, blood AEA could be a reservoir for the brain and blood AEA deficiency or excess could maintain a similar imbalance of AEA levels in the brain as has been demonstrated in Huntington’s disease, Parkinson’s disease, multiple sclerosis, ADHD, schizophrenia, depression and headache.²⁷²⁸ Consequences could be that dysfunctions of endocannabinoid signaling in the brain are mirrored by elements of the peripheral endocannabinoid system. It may be possible to diagnose and treat neurological disorders using blood endocannabinoids (e.g. anandamide).²⁷

A study on healthy adults found higher AEA levels in women than in men. 2-AG was not independent of gender. AEA and 2-AG concentrations were independent of age, education, BMI, caffeine and alcohol consumption²⁹

1.1.2.3. AEA receptor binding¶

AEA binds to a striking number of different receptors:³⁰

• CB1R (partial agonist)²⁷
  • AEA probably binds to CB1R at low AEA concentrations, to TRPV1 only at high concentrations³¹
  • It is possible that AEA only acts as a partial CB1R agonist without 2-AG and as a competitive antagonist in the presence of 2-AG ³²
  • With low receptor density or a limited number of post-receptor effectors, AEA (like THC) can antagonize the CB1R signals triggered by 2-AG.^23333435
• CB2R (partial agonist)²⁷ significantly weaker than at CB1R¹⁰
• TRPV1 receptor (full agonist, weak binding)²⁷ (partial agonist)³⁶
  • AEA probably only binds to TRPV1 at high concentrations, but to CB1R even at low AEA concentrations³¹
  • vasodilatory, among other things
• SCP-2 (sterol carriere protein 2, a lipid transport protein) with moderate affinity (Ki = 0.68)³⁷³⁸
• Glycine receptors in the VTA³⁹
• nicotinic acetylcholine receptors (nAChR)³⁹
• Adenosine receptor A3⁴⁰
• muscarinic acetylcholine receptor M1⁴⁰
• muscarinic acetylcholine receptor M4⁴⁰
• 5-HT1A⁴⁰
• 5-HT2A⁴⁰
• 5HT3A (antagonist)⁴¹

The differences in the binding affinity of AEA to CB1R and TRPV1 could mean that³¹

• low AEA levels preferentially bind CB1 receptors, while
• higher concentrations affect TRPV1 channels

1.1.2.4. Reduction of AEA¶

• enzymatic hydrolysis to ethanolamine and arachidonic acid by
  • FAAH (fatty acid amide hydrolase , N-arachidonoylethanolamine amidohydrolase)²⁷
  • FAAH-2 (weak degradation)¹⁸
    • only in primates, not in rodents¹⁸
  • NAAA (N-acylethanolamine acid amidase, NAE-hydrolyzing acid amidase)⁴²⁴³⁴⁴
• P450 enzymes, including⁴⁵⁴⁶
  • CYP2D6
  • CYP3A4
  • CYP4F2
  • CYP4X1
• Oxidation through⁴⁷
  • COX-2 (cyclooxygenase-2) to prostaglandins⁴⁸
    • selective COX-2 inhibitors
      • have an anxiolytic effect due to AEA degradation inhibition⁴⁹
      • have an anti-inflammatory effect by reducing prostaglandins
      • Substrate-selective COX-2 inhibitors can leave prostaglandin synthesis unaffected⁴⁹⁵⁰
      • have an analgesic effect
      • may only be taken for a short time
  • 12-Lipoxygenases
  • 15-Lipoxygenases

AEA has a very short half-life as it is rapidly taken up with high affinity by the AEA membrane transporter in neurons and glia.⁵¹ Although AEA binds to the CB1R like THC, it has little psychoactive effect, presumably because it is rapidly broken down.⁵²

1.1.2.5. Effects of AEA¶

• Inhibits neuropathic pain when injected into the hippocampus⁵³
  • Possibly through desensitization of TRPV1
• Increases adenosine⁵⁴
  • Adenosine increases ADHD symptoms. More on this at Adenosine In the section Neurotransmitters in ADHD in the chapter Neurological aspects.
• Regulates social reward⁵⁵
  • Elevated AEA levels correlate with a lower preference for affective touch in relation to social processing. The AEA level was independent of the evaluation of affective pictures.
• Low AEA administration increased sexual behavior in male rats⁵⁶
• Inhibits depressive symptoms⁵⁷ via CB2R⁵⁸
  • Depressed women showed reduced peripheral AEA and 2-AG levels⁵⁹
  • Depressed suicide victims showed increased CB1R expression dlPFC⁶⁰
  • People with ADHD and depression are more likely to have CB1R polymorphisms⁵⁷
  • The CB1R antagonist rimonabant increases symptoms of depression and anxiety⁶¹
  • The effect of conventional antidepressants (including fluoxetine) is dependent on endocannabinoid signaling⁶², including PPARα⁶³

• Increased AEA (by an AEA uptake inhibitor and AEA degradation inhibitor) normalized the impairment of contextual fear conditioning of the SHR⁶⁴
• reduces endocrine stress reactions of the HPA axis⁶⁵
• AEA (as well as the endocannabinoid-like oleoylethanolamide, OEA) reduced the permeability of the blood-brain barrier, i.e. increased its resistance, via CB2R (in astrocytes), TRPV1 receptor, calcitonin gene-regulated peptide receptor (CGRP) (anandamide only) and PPARα receptor (OEA only)⁸

• Enhances NMDA-induced excitation of locus coeruleus neurons via CB1R⁶⁶

• Partial agonist of TRPV1 (as well as methanandamide and AM404)⁶⁷
• AEA reduces 2-AG via TRPV1.⁶⁸
  • AEA administration such as inhibition of AEA degradation reduced 2-AG levels, 2-AG metabolism and 2-AG effects in the striatum
  • The stable AEA analog methanandamide had a comparable effect
  • Inhibition of TRPV1 prevented the effect on 2-AG

1.1.2.6. AEA (anandamide) for ADHD and other disorders¶

• AEA is elevated in ADHD⁶⁹
• AEA reduced blood pressure in SHR^{7071 72} and anesthetized guinea pigs⁷³, but not in rats without hypertension⁷⁴
• Reduced AEA degradation (by a FAAH inhibitor) normalized blood pressure in SHR⁷⁵⁷⁶
• AEA reduces hyperactive behavior⁷⁷ in SHR⁷⁸⁷⁹
• AEA caused bradycardia (rapid heartbeat) only in SHR⁷⁴

In relapsing-remitting MS, AEA (but not 2-AG) was elevated in the cerebrospinal fluid. At the same time, AEA was increased in peripheral lymphocytes, resulting in increased synthesis and decreased degradation. Increased AEA synthesis, decreased AEA degradation and increased AEA concentrations were also found in the brains of MS model mice during acute MS relapses.⁸⁰ Endocannabinoids have a tonic effect on spasticity in MS.⁸¹

1.1.3. 2-AG (2-arachidonylglycerol)¶

2-AG is an ester of arachidonic acid (a polyunsaturated omega-6 fatty acid, PUFA) and glycerol.
2-AG is found in the brain in 170 times the amount of AEA.⁸² unlike AEA, 2-AG is not present in the striatum⁸²

1.1.3.1. Synthesis of 2-AG:¶

De novo synthesis.

Most of the 2-AG seems to be generated by²³

• Arachidonoyl-containing PIP2 (often 1-stearoyl-2-arachidonoyl-sn-glycerol is hydrolyzed to diacylglycerol by a PLCβ
• An increase in intracellular calcium leads to the activation of sn-1-specific diacylglycerol lipase-α and -β.
• Diacylglycerol is hydrolyzed to 2-AG by diacylglycerol lipase (DAGL)⁸³⁸⁴
  • DAGLα appears to be responsible for the majority of 2-AG production and to contribute to synaptic plasticity in the adult CNS.⁸⁵⁸⁶⁸⁷ DAGLβ appears to contribute to synaptic 2-AG under certain conditions and plays an important role in the formation of 2-AG during immune responses.²³
  • DGLα is expressed in
    • of the plasma membrane at the dendritic spines of the MSN of the NAc after the CB1 receptor-expressing terminals.³⁶
    • VTA⁸⁸
  • The diacylglycerol lipase inhibitor DO34 reduces the biosynthesis of 2-AG⁸⁹ and the response to / effect of alcohol in mice.

This synthesis pathway is stimulated by receptors that activate PLC, e.g.

• group I metabotropic glutamate receptors
• M1 muscarinic receptors
• M3 muscarinic receptors
• Orexin A

A secondary route for 2-AG synthesis could be:²³

• Cleavage of the phosphatidyl inositol precursor by a phospholipase A
• Hydrolysis of the phosphate ester bond by a lyso-phospholipase C

A study in healthy adults found no gender-dependent differences in 2-AG levels, while AEA was elevated in women. AEA and 2-AG concentrations were independent of age, education, BMI, caffeine and alcohol consumption²⁹

1.1.3.2. 2-AG receptor binding¶

2-AG binds to a striking number of different receptors:³⁰

• CB1R and CB2R full agonist⁹⁰
  • 2-AG binds to both in approximately equal strength¹⁰
  • 2-AG binds to both much more strongly than AEA¹⁰
• GPR 55 and GPR 119¹⁰
• TRPv1 (vanilloid receptor type 1) as an agonist¹⁰
  • this was still seen differently in 2012³⁰
• SCP-2 (sterol carrier protein 2, a lipid transport protein) with moderate affinity (Ki = 0.37)³⁷
• GABA-A receptors⁹¹

1.1.3.3. Effect of 2-AG¶

The 2-AG level is determined by the balance between postsynaptic production by DAGLα and presynaptic degradation by MAGL.³⁶

• Fear
  • 2-AG induced anxiety-like responses through the activation of CB1R⁹² and CB2R in the dorsolateral periaqueductal gray.⁹³
• Reward⁸⁸
  • Stimuli are classified as rewarding and motivating by phasic dopaminergic activity⁹⁴⁹⁵
    • Rewards promote the phasic activity of dopaminergic neurons, which correlates with the release of dopamine in the nucleus accumbens
    • aversive stimuli inhibit the phasic activity of dopaminergic neurons
  • WIN 55,212-2 (cannabinoid antagonist) acts via CB1R
    • a release of dopamine in the nucleus accumbens shell⁹⁶
    • an increase in the basal tonic firing rate⁹⁷
    • an increase in the burst frequency of VTA dopamine neurons⁹⁷
  • increased reward behavior correlates with increased 2-AG levels (but not AEA) in the VTA [87]
  • cB1R blockade in the VTA, PFC and nucleus accumbens reduces reward behavior [87], [88].
• 2-AG (as well as noladinether and oleamide) showed no influence on the permeability of the blood-brain barrier⁸

1.1.3.4. Reduction of 2-AG¶

2-AG is 85 % degraded by MAGL and 15 % by ABHD6 and ABHD12.⁹⁸

• quick dismantling due to⁹⁹
  • Uptake into the cells
  • enzymatic hydrolysis to ethanolamine and arachidonic acid by
    • MAGL (monoacylglycerol lipase / monoacylglycerol lipase)⁴²
      • MAGL is localized at the presynaptic membrane¹⁰⁰
    • ABDH6 (α,β-hydrolase domain-containing 6)⁴
    • ABDH12 (α,β-hydrolase domain-containing 6)⁴
    • FAAH (fatty acid amide hydrolase, N-arachidonoylethanolamine amidohydrolase)²⁷ (subordinate)
    • NAAA (N-acylethanolamine amidase)⁴² (subordinate)
• Oxidation through⁴⁷
  • Cyclooxygenase-2⁵⁰
  • 12-Lipoxygenases
  • 15-Lipoxygenases

Which influences 2-AG, among other things:

• Sustained elevation of neuregulin-1 (a common hallmark of schizophrenia) impairs endocannabinoid-mediated synaptic regulation¹⁰¹
  • Neuregulin-1 increased AG-2 degradation in the hippocampus in vitro by increasing the expression of the 2-AG degradation enzyme MAGL
  • shortened depolarization-induced 2-AG signaling reduced the 2-AG-dependent long-term depression of inhibitory synapses
• 2-AG is increased by masturbation and orgasm.¹⁰²

1.1.4. PEA (palmitoylethanolamide)¶

PEA (palmitoylethanolamide), formerly also known as LG 2110/1¹⁰³, is one of the most common N-acylethanolamines together with AEA and OAE.¹⁰⁴

1.1.4.1. Synthesis of PEA¶

The structure, synthesis and degradation of PEA is similar to AEA.⁸⁸

1.1.4.2. PEA receptor binding¶

PEA binds to:

• PPARα agonist (PPARα: peroxisome proliferator-activated receptor alpha)¹³⁸⁸ , the main pathway of action of PEA
  • EC50 = 3.1 μM¹⁰⁵
• GPR55 selective agonist¹⁰⁶ non-selective¹⁰⁷
  • EC50 = 4 nM¹⁰⁸
• CB1R
  • weak agonist¹⁰⁷⁸⁸
  • EC50 = 19,800 nM¹⁰⁸
• CB2R
  • weak agonist¹⁰⁷⁸⁸
  • EC50 over 30,000 nM¹⁰⁸
  • causes indirect CB2R upregulation¹⁰⁹

Uptake in cells / reuptake in cells

PEA crosses the blood-brain barrier.¹¹⁰

The main receptor of PEA, PPAR-Alpha, is found inside cells. PEA must therefore first be taken up by the cell.¹⁰⁴
To date, no cell membrane transporter has been discovered for PEA, as exists for the closely related AEA.¹⁰⁴ In particular, PEA is not reabsorbed by the AEA transporter, but enters the cell interior by other mechanisms.¹¹¹

Around half of the uptake of PEA in cells occurs through a temperature-dependent process. Endogenous and plant cannabinoids such as AEA, 2-AG, arachidonic acid, R1-methanandamide, Δ9-THC and CBD inhibited uptake¹¹²
The other half appears to occur by diffusion through the cell membrane. The uptake of PEA into the cell is not affected by FAAH (unlike AEA).¹¹³

1.1.4.3. Reduction of PEA¶

Reduction of PEA:
Hydrolysis to palmitic acid and ethanolamine¹⁰⁴

• primarily through N-acylethanolamine-hydrolyzing acid amidase (NAAA)¹¹⁴
  • NAAA breaks down PEA much more effectively than AEA¹⁰⁴⁴⁴
  • NAAA breaks down PEA primarily in the large intestine¹⁰⁴
• also by FAAH¹¹⁵ and FAAH2¹⁰⁴
  • both break down AEA faster than PEA¹⁰⁴
  • FAAH breaks down PEA primarily in the brain and liver¹⁰⁴

1.1.4.4. Effect of PEA¶

• anti-inflammatory¹¹⁶¹¹⁷
  • via PPAR-δ (Delta) and PPAR-γ (Gamma)¹¹⁸
• inhibits mast cell activation¹¹⁹
• antimicrobial¹¹⁷
• immunomodulatory¹¹⁷
• neuroprotective¹¹⁷
  • via PPAR-δ (Delta) and PPAR-γ (Gamma)¹¹⁸
• pain-relieving
  • for rodents^{120121117122123}
  • in humans
    • affirmed for lumboischialgia in two RCTs¹²⁴¹²⁵
      • Number Needed to Treat (NNT) for ≥50% pain relief¹²⁶¹⁰⁴
        • 300 mg: 9
        • 600 mg: 1.7
        • for comparison: TZA: 3.5, pregabailin: 7.7; cannabinoids: no better than placebo
    • affirmative for knee osteoarthritis¹²⁷
    • affirmative for migraine¹²⁸
    • negative for long-term severe neuropathic pain^{129130 124}
    • greater pain relief than CBD or THC¹³¹
    • possibly more effective in men than in women¹³²
• antidepressant^120121107123
  • especially for men¹³³
  • a single dose of PEA induced prolonged stress-induced depression and PTSD in the socially isolated mouse, an animal model for prolonged stress-induced depression and PTSD:^134135136137
    • Allopregnanolone increased in PFC, amygdala, hippocampus and olfactory bulb
    • aggressive behavior weakened
    • Depression symptoms reduced
    • Reduced anxiety symptoms
• increased BDNF¹³⁸¹²⁰
• anxiety-relieving¹²³
• regulates HPA axis¹¹⁰
• Blood pressure lowering in SHR¹³⁹ SHR are the main model animal for elevated blood pressure and ADHD.
• unchanged AEA blood levels in humans and rodents - at least when taken orally¹⁴⁰, AEA also remains unchanged in the gut (as does OEA)¹⁴¹, whereby PEA is primarily degraded in the gut by NAAA and in the brain and liver by FAAH, which also degrades AEA¹⁰⁴. We therefore see an option that PEA could increase AEA in the brain because it competes directly with AEA for FAAH as a degradation enzyme. AEA only increased with intraperitoneal administration in rodents.¹⁴²
• 2-AG increased¹⁴⁰
• very good tolerance¹¹⁷¹⁴³ , non-toxic even at high doses¹⁴⁴
• short bioavailability¹¹⁷
  • sustained release products have been developed that may allow for lower dosing¹¹⁷
  • Absorption is improved by (ultra) micronization (very fine components)
  • Half-life
    • approx. 25 minutes¹⁴⁵
    • 2 hours¹⁴⁰
  • 300 mg of ultramicronized PEA orally led to a doubling of plasma lipid levels in humans after two hours, which returned to normal levels after 4 and 6 hours¹⁴⁰
    • we suspect that multiple doses throughout the day are necessary to compensate for the short bioavailability
  • in rats, around 1% of the orally ingested amount reached the brain, primarily in the hypothalamus and pituitary gland, as well as peripherally in the adrenal glands¹¹⁰
  • very poorly soluble in water
• is marketed as a “dietary food for special medical purposes”
  • recommended dose is generally 1200 mg/day¹⁴⁶

PEA appears to be reduced in Huntington’s disease¹⁴⁷ and multiple sclerosis⁸¹.⁴⁴

1.2. Phytocannabinoids (plant cannabinoids)¶

Phytocannabinoids are phenolic terpenoids.¹⁴⁸

1.2.1. Cannabinoids from the hemp plant¶

The best-known (phyto)cannabinoids are those from the hemp plant. The botanical classification of hemp is¹⁴⁹

• Department: Tracheophyta
• Subdivision: Pteropsida
• Class: Angiospermae
• Order: Urticales
• Subclass: Dicotyledoneae
• Family: Cannabaceae
• Genus: Cannabis
• Species: sativa and indica. Possibly also ruderalis

in 2024, 113 cannabinoids from cannabis plants were known.¹⁵⁰

1.2.1.1. Tetrahydrocannabinoids¶

1.2.1.2. CBD-type cannabinoids (cannabidiols)¶

1.2.1.3. CBC-type cannabinoids (cannabichromenes)¶

1.2.1.4. CBCN-type cannabinoids (cannabichromanones)¶

1.2.1.5. CBL-type cannabinoids (cannabicyclols)¶

1.2.1.6. CBE-type cannabinoids (cannabielsoins)¶

1.2.1.7. CBN-type cannabinoids (cannabinols)¶

1.2.1.8. CBT-type cannabinoids (cannabitriols)¶

1.2.1.9. CBND-type cannabinoids (cannabinodiols)¶

1.2.1.10. CBG-type cannabinoids (cannabigerols)¶

1.2.1.11. Unclear to which type¶

1.2.2. Cannabinoids from other plants¶

1.3. Synthetic cannabinoids (cannabinoid mimetics)¶

Cannabinoids can also be produced synthetically.¹⁸⁰ Several hundred SC are known, belonging to different chemical classes. They can be non-selective or highly selective agonists at the CB1 or CB2 receptor or both. As a rule, they are lipophilic molecules, almost all of which have a much greater binding affinity to the CBR than THC or endocannabinoids.¹⁸¹ Due to the strong CB1R binding and the resulting psychoactive effect, synthetic cannabinoids are not useful for medical purposes.¹⁰

Between 2005 and 2023, synthetic cannabinoids accounted for the largest share of new psychoactive substances reported for the first time in the EU, at 28%.¹⁸² They are also known as synthetic cannabinoid receptor agonists. “Spice” and “K2” are representatives of this group.
Synthetic cathinones (a class of β-keto-phenethylamine derivatives) accounted for the second largest proportion at 18%. These are derived from S-cathinone, an alkaloid from khat (Catha edulis), and have structural and pharmacological similarities to amphetamine.¹⁸² Both groups represent a relevant proportion of synthetic drugs.
In view of the considerable effects and side effects, including deaths, even in clinical studies, the risk of uncontrolled intake can barely be overestimated.
The use of synthetic cannabinoids is associated with much more frequent hospitalizations and deaths due to the much stronger CB1R effect than THC. Common side effects are¹⁸¹

• Panic attacks
• States of anxiety
• Paranoia
• Hallucinations
• Psychoses
• Depression
• Impairment of executive functions
• reduced density of gray matter
• Impairment of the working memory
• High blood pressure
• Hypotension
• Bradycardia
• Tachycardia
• Restlessness
• Nausea, vomiting
• Stroke
• Myocardial infarction
• Cardiomyopathy
• Cardiac arrhythmia
• Cardiac arrest

Synthetic cannabinoids include:¹⁰

• Dronabinol
  • Agonist
• Nabilon
  • Agonist
• Rimonabant, SR141716A, Acomplica (5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)
  • selective CB1R antagonist
  • acts like an inverse agonist, which is often associated with side effects, as is also the case here¹⁸³
• 2-isopropyl-5-methyl-1-[2,6-dihydroxy-4-(1,2-dimethylheptyl)phenyl]cyclohex-1-ene
  AB-FUBINACA (N-[(2S)-1-amino-3-methyl-1-oxo-2-butanyl]-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide), an indazole carboxamide derivative¹⁸¹
• AM-2201 (AM: developed by Alexandros Makriyannis)
• AM-2233
• CRB-913
  • CB1R inverse agonist¹⁸⁴
• CP-47,497
• CP-55940
  • CB1R agonist
• HU-210 ((6aR)[-trans-3-(1,1-dimethylheptyl)-6a, 7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6Hdibenzo[b,d]pyran-9-methanol), a cyclohexylphenol¹⁸¹
  • more than 100 times greater binding affinity to CB1R and CB2R than THC
• JWH-018 (-pentyl-3-(1-naphthoyl)indole), an aminoalkylindole; (JWH: developed by John W. Huffman)¹⁸¹
• JWH-073
• JWH-122
• JWH-210¹⁸¹
• WIN 55,212,2, WIN2 ((R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanon)¹⁸⁵
  • Agonist
• XLR-144
• ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol)¹⁸⁵
  • Agonist

1.4. Endocannabinoidome: the extended cannabinoid system¶

In addition to the cannabinoid system in the narrower sense, an extended cannabinoid system consisting of endocannabinoid-like mediators has been described. This so-called endocannabinoidome comprises more than 100 lipid mediators, 20 enzymes and 20 receptors.¹⁵³¹⁸⁶ These include several long-chain fatty acid amides and fatty acid amide esters:

• the N-acylethanolamines, NAEs (related to anandamide)
• the 2-acylglycerols, 2-AcGs (related to 2-AG)
• the N-acyl amino acids
• acylated neurotransmitters such as N-acyl dopamine and N-acyl serotonin
• the primary fatty acid amides.

These lipid mediators often bind to other receptors such as

• Transient receptor channel type 1, type 2 and type 4 (TRPV1, TRPV2, TRPV4)
• Orphan G-Protein-coupled Receptors (GPR18, GPR55, GPR110, GPR119)
• ligand-activated ion channels
• Peroxisome proliferator-activated nuclear receptors (PPAR-α, PPAR-γ)