The Basic Pharmacology of Major Cannabinoids

Understanding the pharmacology of major cannabinoids, such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), is paramount in inferring their diverse effects on the human body.  

Cannabis, derived from the Cannabis sativa plant, has been the subject of intense scientific scrutiny due to its therapeutic potential and widespread recreational use. THC not only elicits euphoria and altered perception but also holds promise for medicinal applications.  

Similarly, CBD, another prominent cannabinoid, has received considerable attention for its potential therapeutic benefits. While CBD lacks the psychoactive effects of THC, its pharmacology is complex and diverse, influencing various physiological processes.  

Recommended course: Medicinal Cannabis: An Interdisciplinary Approach – Clinical Applications 

Understanding THC and its pharmacological targets 

THC interacts primarily with the endocannabinoid system, particularly with cannabinoid receptors CB1 and CB2. CB1 receptors, located predominantly in the central nervous system, are associated with THC’s psychoactive effects, including euphoria, altered perception, and memory impairment. CB2 receptors, found mainly in peripheral tissues and immune cells, are implicated in THC’s anti-inflammatory and immunomodulatory effects. 

Beyond the endocannabinoid system, THC also interacts with other molecular targets, such as 5-HT3A receptors (involved in anti-emetic effects), cyclooxygenase (COX) enzymes (implicated in inflammation), and potentially with carboxylesterase 1 (CES1), influencing the metabolism of various medications. 

How the pharmacology of THC relates to its common effects 

Understanding THC’s pharmacology is pivotal in elucidating its various effects, including neuropsychiatric, cognitive, cardiovascular, and immunological responses. Below is an overview of how THC’s pharmacology influences its effects, providing valuable insights for clinicians and researchers alike. 

Neuropsychiatric effects 

THC’s interaction with the endocannabinoid system, particularly with CB1 receptors in the central nervous system, underlies its neuropsychiatric effects. CB1 receptor activation by THC leads to alterations in neurotransmitter release, resulting in euphoria, altered perception, and memory impairment. However, THC’s partial agonist activity at CB1 receptors can also precipitate adverse neuropsychiatric effects, including exacerbation of mania, depression, and psychosis.  

Cognitive impairment 

THC-induced cognitive impairment stems from its actions on various brain regions involved in memory, attention, and executive function. By interacting with CB1 receptors in the hippocampus and prefrontal cortex, THC disrupts synaptic transmission and neuronal signaling, leading to deficits in learning, memory consolidation, and decision-making. Also, THC’s influence on glutamatergic and GABAergic neurotransmission contributes to cognitive impairment.  

Cardiovascular effects 

Activation of CB1 receptors in the cardiovascular system leads to alterations in heart rate, blood pressure, and vascular tone. While THC-induced tachycardia and vasodilation are typically transient, individuals with pre-existing cardiovascular conditions may be at increased risk of adverse events, including myocardial ischemia or arrhythmias.  

Immunomodulatory properties 

THC’s immunomodulatory effects are mediated through its interaction with CB2 receptors expressed on immune cells. THC activation of CB2 receptors exerts anti-inflammatory and immunosuppressive effects, attenuating cytokine production and immune cell activation. While these properties hold promise for conditions characterized by excessive inflammation, such as autoimmune disorders, caution is needed, particularly in immunocompromised individuals.  

Understanding CBD and its pharmacological targets 

Cannabidiol (CBD), a phytocannabinoid derived from cannabis, has received considerable attention for its potential therapeutic benefits. CBD interacts with many molecular targets, although its direct effects on cannabinoid receptors, particularly CB1 and CB2, appear limited.  

While it may indirectly modulate CB1 receptors, CBD’s primary mechanisms of action involve other receptors, such as transient receptor potential vanilloid (TRPV) channels and serotonin (5-HT1A) receptors. TRPV1 is crucial in mediating CBD’s potential therapeutic effects, including neuroprotection, anti-seizure, antipsychotics, and immunomodulation. CBD also acts as an agonist at 5-HT1A receptors, which are implicated in anxiety, depression, and stress responses.  

How the pharmacology of CBD relates to its common effects 

Research shows that CBD interacts with multiple molecular targets to exert its effects. Notably, CBD inhibits fatty acid amide hydrolase (FAAH), leading to increased levels of anandamide (AEA), a neurotransmitter involved in mood regulation. Moreover, CBD facilitates serotonergic neurotransmission via the 5-HT1A receptor, activating the transient receptor potential vanilloid type 1 (TRPV1). These interactions modulate dopamine and serotonin signaling pathways, potentially mitigating positive symptoms, negative symptoms, and cognitive impairment associated with schizophrenia. 

Anxiety 

CBD’s anti-anxiety effects may stem from its ability to inhibit AEA inactivation and interact with 5-HT1A receptors, which play a crucial role in mood regulation. Clinical studies have shown that CBD administration leads to reduced subjective anxiety levels, accompanied by alterations in regional cerebral blood flow, particularly in brain regions implicated in emotional processing. 

Epilepsy/seizures 

CBD antiepileptic effects are mediated through various molecular mechanisms, including modulation of transient receptor potential vanilloid (TRPV) channels, T-type calcium channels, serotonin receptors (5-HT1A and 5-HT2A), and opioid receptors. Clinical trials have demonstrated the safety and efficacy of CBD in reducing seizure frequency, offering hope for patients with refractory epilepsy. 

Insomnia 

CBD’s influence on the endocannabinoid system, particularly its inhibition of fatty acid amide hydrolase (FAAH), may promote sleep stability by modulating levels of endogenous cannabinoids such as AEA. Studies suggest CBD enhances slow-wave sleep, potentially through interactions with inhibitory GABAA receptors. However, further clinical research is needed to elucidate CBD’s effects on sleep architecture in individuals with chronic insomnia. 

Cardiovascular system 

While preclinical studies have demonstrated beneficial cardiovascular effects, clinical trials have yielded mixed results regarding CBD’s impact on resting blood pressure and heart rate. CBD shows potential in modulating cardiovascular responses to stress stimuli via interaction with cannabinoid receptors (CB1, CB2), transient receptor potential vanilloid 1 (TRPV1), peroxisome proliferator-activated receptors (PPARs), and serotonin receptors (5-HT1A) 

Diabetes 

CBD’s anti-inflammatory and antioxidant properties offer potential benefits in attenuating autoimmune-mediated beta-cell destruction and mitigating hyperglycemia. Clinical trials investigating CBD and its analog, tetrahydrocannabivarin (THCV), in patients with Type 2 diabetes have yielded promising results. However, further research should be done to elucidate CBD’s optimal dosing and long-term effects on diabetes management. 

Pain management 

CBD’s analgesic effects are mediated through multiple mechanisms, including modulation of CB1 and CB2 receptors, inhibition of mast cell degranulation, and interaction with serotonin receptors (5-HT1A). Clinical evidence suggests that CBD, alone or in combination with THC, offers effective pain relief in various conditions, including cancer-related pain. 

Other effects 

Furthermore, CBD has shown promising results in the treatment of cancer and COVID-19. CBD exerts antiproliferative, pro-apoptotic, and anti-metastatic effects across different cancer types. Studies have also demonstrated CBD’s efficacy in reducing emotional exhaustion among frontline healthcare professionals and inhibiting SARS-CoV-2 infection.  

Factors that affect the impact of THC and CBD 

Understanding the significance of various factors such as route of administration, dose, and individual characteristics is paramount in assessing the effect of THC and CBD on the human body. 

Route of administration 

Different routes of administration offer distinct pharmacokinetic profiles, affecting the effects’ onset, duration, and intensity. Cannabis can be consumed through various routes, including inhalation, oral ingestion, sublingual absorption, and topical application.  

Inhalation, typically through smoking or vaping, allows cannabinoids to rapidly enter the bloodstream through the lungs, resulting in quick onset but shorter duration of effects. Conversely, oral ingestion leads to slower absorption through the digestive system, resulting in delayed onset but prolonged duration. Sublingual administration, such as sprays, offers a middle ground, with cannabinoids absorbed directly into the bloodstream through the mucous membranes under the tongue. 

Dose 

Dosing plays a critical role in determining the therapeutic efficacy and safety of cannabis. THC and CBD exhibit biphasic dose-response curves. Low to moderate doses may produce desired therapeutic effects, while higher doses can lead to adverse reactions or diminished efficacy. Tailoring doses to individual needs and tolerances is crucial to optimizing therapeutic outcomes while minimizing risks. 

Other factors influencing the pharmacology of major cannabinoids 

Beyond the route of administration and dose, several other factors influence the effects of THC and CBD: 

  1. Individual variability: Genetic factors, endocannabinoid system functioning, and prior cannabis exposure contribute to individual variability in response to cannabinoids. 
  1. Product composition: Cannabis products vary in cannabinoid content, with differing ratios of THC to CBD and the presence of other cannabinoids and terpenes. This variability affects therapeutic effects and adverse reactions. 
  1. Combination therapy: The synergistic interactions between cannabinoids, known as the entourage effect, suggest that combining THC and CBD may enhance therapeutic outcomes while mitigating adverse effects. 
  1. Medical conditions: The presence of underlying medical conditions such as multiple sclerosis, neuropathic pain, or psychiatric disorders can influence the therapeutic effects of cannabinoids. 
  1. Contraindications and drug interactions: Certain medical conditions and medications may contraindicate or interact with cannabinoids, necessitating careful evaluation and monitoring.