Introduction
Cannabis is gaining traction as a therapeutic agent for a growing list of medical conditions. Within the Cannabis sativa plant, a complex array of over 70 phytocannabinoids exists, each with unique pharmacological potential.1 Among these, delta-9-tetrahydrocannabinol (Delta 9 THC) and cannabidiol (CBD) are the most extensively studied due to their pronounced biological effects. Delta 9 THC is particularly notable as the primary psychoactive component of cannabis. While cannabis remains classified as a Schedule I drug at the federal level in the United States, many states have approved its use for medical and even recreational purposes, highlighting the ongoing debate and evolving legal landscape surrounding cannabis. As of June 2015, 23 states and the District of Columbia had legalized medical cannabis, and a further four states permitted recreational use. This article aims to explore delta 9 THC in detail, examining its effects, mechanisms of action, and interactions, particularly in relation to CBD. We will delve into the science behind how delta 9 THC works within the body and its implications for both therapeutic and recreational cannabis use.
The Endocannabinoid System and Delta 9 THC
To understand “What Is Delta 9 Thc” and its effects, it’s crucial to first understand the endocannabinoid system (ECS). The physiological impact of cannabis is largely mediated by this intricate endogenous system within the human body. The ECS is comprised of cannabinoid receptors, endocannabinoids (naturally produced cannabinoids), and enzymes that synthesize and degrade endocannabinoids. Two primary cannabinoid receptors have been identified in the brain: cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R). CB1 receptors are predominantly found on neurons throughout the central nervous system (CNS) and peripheral nervous system, whereas CB2 receptors are mainly located on glial cells in the CNS, as well as within the immune and enteric nervous systems.2-4 Emerging research suggests other receptors, such as GPR55 and peroxisome proliferator–activated receptor-alpha (PPAR-alpha), also interact with endocannabinoids but are not typically classified as core components of the ECS.5
The psychoactive effects attributed to cannabis, specifically those induced by delta 9 THC, are primarily a result of CB1 receptor activation.6 These CB1 receptors are strategically located on GABAergic and glutamatergic terminals in key brain regions including the basal ganglia, frontal cortex, hippocampus, and cerebellum.7,8 While CB2 receptors are also present in these areas, their expression is significantly less pronounced. The primary endogenous agonists of the ECS are anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG).9 These endocannabinoids are released from postsynaptic neurons “on demand” and exert their effects through retrograde signaling, rapidly influencing CB1 receptors on presynaptic terminals.10,11 Upon binding, these G protein–coupled receptors trigger a cascade of intracellular events, activating inwardly rectifying K+ channels and inhibiting voltage-sensitive N-type and P/Q-type Ca2+ channels. This ultimately leads to a reduction in neurotransmitter release.12 This process of endocannabinoid-mediated reduction of GABA or glutamate release is termed depolarized suppression of inhibition or depolarization of excitation, respectively.13 The breakdown of AEA and 2-AG is primarily facilitated by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. These enzymes are now considered therapeutic targets for pharmaceutical development, aimed at creating novel treatments for conditions like pain, depression, and osteoarthritis.14,15
Delving Deeper: What is Delta 9 THC?
Delta-9-tetrahydrocannabinol (delta 9 THC) is the principal psychoactive constituent of cannabis and is classified as a partial agonist at both CB1 and CB2 receptors. Its interaction with CB1 receptors is the primary driver of the psychotropic effects commonly associated with cannabis use. Binding to CB2 receptors may contribute to other effects, such as immunomodulation or anti-inflammatory actions.1 Delta 9 THC can be administered via various routes, including oral ingestion, sublingual application, topical application, vapor inhalation, smoking, incorporation into food, and infusion in beverages like tea. Research settings have even employed intravenous administration.
The effects of delta 9 THC are multifaceted, encompassing both psychoactive and physiological changes. Undesirable effects can include heightened psychoactive symptoms, cognitive impairment, and elevated heart rate.16 The psychoactive experiences typically manifest as alterations in perception, such as intensified auditory experiences. In higher doses, or in individuals predisposed to psychosis, delta 9 THC can exacerbate psychotic symptoms like delusions and hallucinations. For individuals with schizophrenia, THC can worsen psychotic symptoms, and these effects may not be mitigated by antipsychotic medications.17,18 Furthermore, delta 9 THC can induce anxiety, potentially progressing to paranoia in severe cases.
Cognitively, delta 9 THC is generally associated with acute impairments. Verbal learning deficits, specifically difficulties in encoding new information, are among the most consistently observed cognitive impairments following THC administration.19 The question of whether chronic cannabis use leads to long-term cognitive decline has been a subject of debate. However, emerging evidence suggests that prolonged cannabis use, particularly when initiated during adolescence, is associated with persistent memory deficits. A longitudinal study by Meier et al.20 tracked over 1000 individuals for more than two decades and found that chronic cannabis use starting in adolescence was linked to an approximate 10-point decrease in IQ.20 The most common physiological effect of delta 9 THC is an increase in heart rate. While typically transient, it’s an important consideration, although it usually resolves without significant complications.21
Beyond its psychoactive and potentially negative effects, delta 9 THC also possesses properties that are clinically beneficial. These include antiemetic effects, appetite stimulation, analgesic properties, and potential immunomodulatory actions.22 Dronabinol, a synthetic oral THC product, is approved in the United States for treating chemotherapy-induced nausea and vomiting and as an appetite stimulant. The therapeutic potential of THC has driven the legalization of cannabis in many regions for a broad spectrum of conditions, including chronic pain, seizures, glaucoma, HIV/AIDS, posttraumatic stress disorder, and numerous other chronic illnesses. A meta-analysis by Whiting et al.22 evaluating cannabis and cannabinoid drugs for medical use reviewed 79 trials of adequate quality. The analysis revealed moderate evidence for efficacy in treating chronic pain and spasticity. Limited evidence supported efficacy for other conditions like chemotherapy-induced vomiting and weight gain in HIV. However, the short-term side effect burden was notable. Common adverse events included dizziness (66%), dry mouth (65%), nausea (55%), fatigue (42%), somnolence (49%), euphoria (37%), vomiting (34%), disorientation (27%), drowsiness (20%), confusion (18%), loss of balance (14%), and hallucinations (14%).22 These findings, coupled with other available data,23 raise important questions about the overall wisdom of promoting cannabis as a widespread medical treatment, emphasizing the need for careful consideration of both benefits and risks.
Cannabidiol (CBD) and its Interaction with Delta 9 THC
Research into cannabidiol (CBD) began in the early 1970s, with much of the initial work focused on understanding its interactions with delta 9 THC in both animal and human models. CBD has generally been found to be well-tolerated and exhibits minimal to no psychoactive effects. Sedation is the most commonly reported side effect of CBD.24 The pharmacology of CBD is complex, with over 20 different mechanisms of action described.5 Notably, CBD interacts with both CB1 and CB2 receptors, acting as an antagonist at these sites. Another significant mechanism of action is CBD’s ability to inhibit fatty acid amide hydrolase (FAAH), leading to increased levels of anandamide (AEA) in the body. The clinical applications of CBD are being explored across a wide range of conditions, including epilepsy, anxiety disorders, cancer, inflammatory conditions, and schizophrenia.25
A critical aspect of CBD research is its interaction with delta 9 THC. CBD appears to modulate the effects of THC in significant ways, both by mitigating adverse effects and potentially enhancing therapeutic benefits. Early animal studies, such as those by Karniol and Carlini,26 indicated that CBD could reduce anxiety-related negative effects while simultaneously potentiating the analgesic effects of THC. However, a rodent study by Fernandes et al.27 found that CBD prolonged the effects of THC in mice, suggesting a potentiation of THC’s overall effects. Subsequent human studies have largely supported the anxiety-reducing effects of CBD in combination with THC. Studies have shown that when CBD is administered with THC, participants report reduced anxiety and fewer psychotic symptoms.28,29 Interestingly, an early study, mirroring the findings of Fernandes et al. in rodents,30 demonstrated that smoking cannabis with higher CBD concentrations could prolong the effects of THC. Despite some conflicting findings, the prevailing evidence suggests that CBD generally diminishes many of the psychoactive effects associated with delta 9 THC.
Epidemiological evidence further supports this interaction. A study analyzing hair samples from 120 regular cannabis smokers found that individuals with detectable CBD in their hair reported fewer psychiatric issues compared to those with higher THC concentrations.31 This real-world observation strengthens the laboratory findings that CBD can mitigate the psychotomimetic effects of cannabis by modulating THC’s actions.
Table: Human Studies Evaluating the Effects of Delta-9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD)
The extent to which CBD can influence other clinical effects of THC remains an active area of research. A study involving 46 adults found that oral CBD (600 mg) administered 3.5 hours before intravenous THC (1.5 mg) significantly reduced verbal memory deficits compared to placebo when co-administered with THC. Furthermore, CBD also lessened THC-induced psychotic symptoms as measured by the Positive and Negative Symptom Scale (PANSS).32 Emotional perception, which is often impaired in individuals with cannabis use disorder, is also influenced by the THC-CBD interaction. Hindocha et al.33 conducted a randomized, crossover, double-blind study over four days, examining the effects of oral THC (8 mg), oral CBD (16 mg), and placebo in 48 participants on their ability to recognize emotional facial expressions. While participants reported no difference in feeling “stoned” between THC alone and THC combined with CBD, the THC-only condition resulted in more errors in facial emotion recognition, and these errors were corrected when CBD was given concurrently.33 The researchers concluded that CBD effectively reverses the deficits in emotional processing caused by THC.
The mechanism underlying this attenuation of THC effects by CBD is not fully elucidated. It is debated whether it is solely due to pharmacodynamic interactions or if pharmacokinetic effects are also involved. Blood THC concentrations do not appear to be altered by CBD, but CBD may interfere with the metabolic conversion of THC into a more psychoactive metabolite, 11-hydroxy-THC.34 Functional magnetic resonance imaging (fMRI) studies have provided further insights. Bhattacharyya et al.35 used fMRI to examine brain activity in 15 individuals performing cognitive tasks after receiving oral THC, CBD, or placebo on separate study days. They observed opposing neurobiological effects of THC and CBD on blood oxygen level–dependent responses. CBD generally increased brain activation relative to placebo, whereas THC typically decreased activation. In a subsequent phase of the study, they administered oral CBD or placebo to six participants before intravenous THC on two different test days. Consistent with previous findings, CBD reduced the psychotomimetic effects of THC. Several follow-up imaging studies from the same research group have consistently demonstrated opposing biological effects of CBD and THC in the brain,36 strongly suggesting that pharmacodynamic interactions play a significant role in their interplay.
Nabiximols (Sativex®): A THC and CBD Combination Therapy
Nabiximols, marketed as Sativex®, represents a pioneering medication combining THC and CBD, and is approved in numerous European countries for the symptomatic relief of moderate to severe spasticity in adult patients with multiple sclerosis.37 The pharmaceutical industry has been actively pursuing the development of selective CB2 agonists for therapeutic applications in analgesia, inflammation, and cancer. Given that THC acts as an agonist at both CB1 and CB2 receptors, carrying the risk of CNS-mediated side effects, CBD was incorporated into Nabiximols as a CB1 receptor antagonist. This strategic combination is intended to neutralize the adverse CNS effects associated with THC, effectively allowing the product to function more like a selective CB2 receptor agonist.38
Nabiximols is formulated as an oromucosal spray, with each 100 mL spray delivering 2.7 mg of THC and 2.5 mg of CBD. Patients initiating Nabiximols treatment undergo a titration period of approximately 14 days to reach their optimal dose. Clinical trials have indicated an average therapeutic dose of 8 sprays per day, administered in two divided doses.37 The maximum recommended dose is 12 sprays per day in two divided doses, although studies have explored doses up to 48 sprays per day.37 Once the desired daily dose is achieved, patients can distribute individual sprays throughout the day based on their individual tolerance and response. Nabiximols is available in presentations of three 10-mL spray bottles or four 5.5-mL spray bottles, providing total quantities of 30 mL and 22 mL, respectively. These quantities are designed to supply approximately 25 and 18 days of medication at the maximum recommended dosage of 12 sprays per day. Currently, Nabiximols is in phase 3 clinical trials in the United States for the treatment of cancer pain, though regulatory approval for multiple sclerosis spasticity has not yet been sought in the US.
Conclusion: The Therapeutic Potential of Delta 9 THC and CBD
Over the past quarter-century, our understanding of the endocannabinoid system and the roles of phytocannabinoids like delta 9 THC and CBD has significantly advanced. Accumulating evidence suggests that CBD, when co-administered with THC, can effectively mitigate THC-induced psychoactive symptoms through both pharmacodynamic and potentially pharmacokinetic interactions. Importantly, while diminishing the psychoactive effects, CBD appears to preserve the therapeutic potential of THC across various disease states. These findings are driving the development of innovative medications that combine delta 9 THC and CBD to harness their synergistic clinical benefits. Further research into the intricate interplay between these compounds promises to unlock even greater therapeutic applications and optimize the use of cannabis-based medicines.
Footnotes
Disclosures: Dr. Ranganathan has received research support from Insys Therapeutics. The other authors declare no conflicts of interest.
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