Pharmacology of tetrahydrocannabinol (THC)

Viola Brugnatelli & Fabio Turco: Principles of Clinical Cannabinology Handbook".

by Gastautor

Viola Brugnatelli & Fabio Turco have written „Principles of Clinical Cannabinology Handbook“. The book was published by CannabiScientia and Prohibition Partners. Below presents to the readers: Chapter 2.3 Pharmacology of Tetrahydrocannabinol (THC). More Infos:

By Viola Brugnatelli & Fabio Turco

Is it possible to separate the side effects from the therapeutic ones?

Tetrahydrocannabinol (THC) is the active ingredient of Cannabis Sativa L. which is responsible for many of its therapeutic effects, but also for the main side effects. Is it possible to separate the desired effects of THC from the undesired ones, so as to have a drug that is even more manageable?

THC [1]

THC is the main phytocannabinoid found in Cannabis Sativa L. plants. Typically, it is found in amounts ranging from 0.5-5% to 25-30%, depending on the variety. Chemically, THC is a compound with a structure resembling that of Anandamide -the amide of bliss-, the first endocannabinoid to be discovered in the 1990s. More specifically, it can be considered a benzopyran derivative with substitutions, including a hydroxide and several methyls. Its structure makes this compound very lipophilic, so it easily passes the blood-brain barrier and distributes well in the brain, where it exerts most of its effects by interacting with CB1 cannabinoid receptors.

The interaction with CB1 makes THC effective in the treatment of various pathological conditions, including:

  • chronic pain;
  • nausea and vomiting;
  • anorexia from chemotherapy or AIDS;
  • spasticity (such as that induced by multiple sclerosis or other pathological conditions);
  • Gilles de la Tourette syndrome;
  • glaucoma;
  • potentially also neurodegenerative diseases (such as Alzheimer’s or Parkinson’s);
  • anxiety or depressive syndromes

The interaction with CB1 receptors in the brain is also responsible for the main side effects of THC:

  • euphoria;
  • nausea;
  • dizziness;
  • dry mouth;
  • reddening of the eye;
  • increased anxiety and stress;
  • impairment of short-term memory;
  • impaired motor coordination;
  • catalepsy (abolition of voluntary muscle movements).

The interaction with CB2 receptors, on the other hand, is mainly responsible for the anti-inflammatory actions of THC.

THC also interacts with other receptors: [2]

  • Transient receptor potential vanilloid channels 2 (TRPV2): agonist;
  • Transient receptor potential ankyrin type 1 (TRPA1): agonist;
  • TRP subfamily M (TRPM8) receptor: antagonist.

Various research has shown that motor impairment and catalepsy are due to the action of THC on a specific area of the brain: the basal ganglia system, rich in CB1 receptors.

Pharmacokinetics of THC

Data on the pharmacokinetics of THC are derived from studies on its synthetic counterpart, dronabinol. [3]


Due to its high solubility, dronabinol is almost completely (90 to 95 %) absorbed after a single oral dose. Due to the combined effects of hepatic first-pass metabolism and high lipid solubility, only 10 to 20 % of the administered dose reaches the systemic circulation. After oral administration, dronabinol has an onset of action of approximately 0.5-1 hour and a peak effect of 2-4 hours. Cmax was 1.32ng/mL with a median Tmax of 1.00 hours.


Dronabinol has a large apparent volume of distribution, about 10 L/kg.

Metabolism and elimination

THC is metabolised mainly in the liver, by cytochrome P450. 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) is the main active metabolite, capable of producing psychological and behavioural effects similar to THC. 11-OH-THC is then metabolised into 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH), the main inactive metabolite of THC. THC and 11-OH-THC are present in plasma in approximately equal concentrations. Concentrations of THC and its metabolite peak approximately 0.5 to 4 hours after oral administration and decrease for several days.

THC is eliminated with urine or faeces. The elimination half-life is about 4 hours, but THC remains in the body for a long time. A single dose can be eliminated even after 36 hours.

The ganglia of the base [3]

The basal ganglia are a grouping of brain neurons that mediate interactions between the cerebral cortex and the thalamus, essential for the control and coordination of motor activity. The central nucleus of the basal ganglia is the striatum.

Neurons of the striatum have the highest levels of CB1 cannabinoid receptor expression in the brain. These neurons can be divided into 2 populations, which form:

  • the indirect striatal pathways, which terminate in the region of the external Globus Pallidus;
  • the direct striatal pathways, which terminate in the region of the Substantia Nigra reticulata.

This latter circuit, called the striatonigral circuit, is a potential target for explaining both the beneficial and deleterious effects of THC, due to its crucial role in regulating motor function and pain transmission.

At the neuronal level, CB1 receptors are mainly associated with the plasma membranes of axon terminals, where they regulate synaptic transmission. However, various studies show that CB1 receptors are also present in intracellular compartments, in particular associated with the mitochondria, organelles present in all animal cells that are responsible for energy production. CB1 receptors are thought to influence memory and sociability at this level by modulating bioenergetic processes.

The existence of different subpopulations of CB1 receptors, located in different cellular compartments, suggests that their activation by cannabinoids could lead to distinct effects within the same circuit.

Separating the therapeutic effects of THC from the side effects [4]

In some cases, at least potentially, it is possible to separate the therapeutic effect of cannabis and THC from the undesirable ones.

This is the conclusion reached by a recent study published in the journal Neuron, entitled Subcellular specificity of cannabinoid effects in striatonigral circuits. [1]

This research work was directed by Giovanni Marsicano and Luigi Bellocchio, researchers at the neuroscientific research centre in Bordeaux, the ‚Neurocentre Magedie‘. For the success of this work, the two researchers collaborated with the Institute of Neurodegenerative Diseases in Bordeaux and also with the University of Bilbao in Spain and the University of Calgary in Canada.

The study was carried out on laboratory animals, combining genetic, pharmacological, biochemical, electrophysiological, imaging and behavioural approaches.

Researchers have shown that the activation of CB1 receptors at different subcellular locations, in the same neuronal circuit, can result in distinct behaviour.

CB1 receptors in the direct striatal pathway are in fact responsible for the multimodal action of THC which, acting on this neuronal circuit, induces both catalepsy and an anti-nociceptive effect (useful in cases of pain). The former effect depends on THC’s interaction with mitochondrial CB1 receptors, while the anti-nociceptive effect is induced by stimulation of membrane CB1 receptors. Thus, by acting on different subcellular signalling pathways in the neurons themselves, the researchers were able to dissociate the analgesic effect from the catalepsy induced by an acute injection of THC or other synthetic cannabinoids.

THC: the conclusions

Every pharmacologically active substance, whether natural or synthetic, induces side effects. Very often it is difficult to separate the therapeutic effects from the undesirable ones, as both result from the interaction of that substance with a specific receptor, or at least are inherent in its mechanism of action.

This was also thought to be the case with cannabis, although recent research seems to cast doubt on this paradigm. Indeed, it appears that the therapeutic and undesired action of the main component of cannabis, THC, depends on the interaction with different subcellular pools of CB1 receptors.

Further supporting the possibility of separating therapeutic effects from side effects, another paper recently published in the Journal of Medical Chemistry, shows that peptide compounds similar to THC are able to induce analgesic effects without causing cognitive impairment. [4]

These results are crucial for a better understanding of the mechanisms of action of cannabis and for the development of new therapeutic strategies, based on its beneficial effects, such as analgesia, while avoiding its deleterious effects (e.g. catalepsy).


[1] Edgar Soria-Gomez, Antonio C Pagano Zottola, Yamuna Mariani, Tifany Desprez, et al.
Subcellular specificity of cannabinoid effects in striatonigral circuits. Neuron. 2021 May 5;109(9):1513-1526.e11.

[2] Chanté Muller, Paula Morales, and Patricia H. Reggio.
Cannabinoid Ligands Targeting TRP Channels.
Front Mol Neurosci. 2018; 11: 487.

[3] Sharma P, Murthy P, Bharath MM.
Chemistry, metabolism, and toxicology of cannabis: clinical implications.
Iran J Psychiatry. 2012 Fall;7(4):149-56.

[4] Maria Gallo, Estefanía Moreno, Sira Defaus, Antonio Ortega-Alvaro.
Orally Active Peptide Vector Allows Using Cannabis to Fight Pain While Avoiding Side Effects.
J Med Chem. 2021 Apr 22.

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