Delta-9 and the Endocannabinoid System: Beyond the Science

Delta-9-tetrahydrocannabinol, or Delta 9-THC, is the main psychoactive compound in cannabis. It interacts with the body and brain via attaching to the endocannabinoid system (ECS), a natural cell-signaling pathway that controls pain, mood, metabolism, and immune system function. Discovered in the late 1900s, the ECS is responsible for many basic bodily functions. Research has shown that Delta 9-THC does so by activating two types of receptors: CB1 (mainly in the brain) and CB2 (mainly in immune-associated tissues). However, there is a great deal more to learn regarding the broader impact of Delta 9-THC—its medical uses, social and economic effects, and moral implications—because this data is dispersed across various fields of research.

This review will highlight recent scientific findings from neuroscience, medicine, and social policy to provide an overview of current research into Delta-9-THC’s potential roles. We discuss:

• How the endocannabinoid system (ECS) metabolizes Delta-9-THC and responds to it.
• Research investigating Delta-9-THC’s possible relevance to brain diseases, mental health conditions, and chronic illnesses.
• Ongoing debates surrounding drug policy, public health, and cannabis regulation.
• Future research directions aimed at translating scientific discoveries into potential therapeutic applications.

Follow along with us as we highlight cannabis science to practical application, addressing some of the most important questions that still need to be answered.

Introduction to the Endocannabinoid System

The endocannabinoid system (ECS) is a fundamental discovery in contemporary neurobiology, representing a ubiquitous signaling system that keeps the body in balance (Russo, 2016; PMC6007535). Initially discovered in the 1990s when investigating how Delta 9-THC functions, the ECS is made up of three main components:

• Endocannabinoids (such as anandamide [AEA] and 2-arachidonoylglycerol [2-AG])

• Receptors (CB1 and CB2, which are coupled to G proteins)

• Enzymes (FAAH and MAGL, which degrade endocannabinoids)

It contributes to most bodily functions such as brain plasticity, endocrine functions, and the immune response.

Delta 9-THC weakly activates CB1 receptors (with 20-40% efficacy relative to full agonists) and weakly stimulates CB2 receptors (Pertwee, 2008; Marijuana and Madness, Cambridge). Unlike CBD, Delta-9 THC promotes potent psychoactive experiences. Due to its solubility in fats, it readily crosses the blood-brain barrier, resulting in its psychoactive effects by affecting dopamine and glutamate activity within the brain. It also impacts the immune system by modifying cytokine release and immune cell migration.

Even with increased research on cannabis, Delta 9-THC is still controversial. Research indicates that it can be beneficial for conditions such as chemotherapy-induced nausea and muscle spasms in multiple sclerosis. Yet, excessive use of cannabis has been associated with adverse effects, such as mental health consequences and addiction. This paradox points to knowledge gaps regarding optimal dosing, interindividual variability, and long-term brain alterations.

How Delta-9-THC Interacts with Cannabinoid Receptors

CB1 receptors are primarily located in nerve cells that regulate signals in the brain. When Delta-9-THC acts on them, it alters the way these cells communicate, resulting in:

• Changes in Dopamine Levels: In the brain reward system (VTA), Delta-9-THC decreases inhibition on cells releasing dopamine, elevating dopamine in crucial regions by 30-50% (Psychopharmacology, 2013). The increase is associated with pleasure but also with risk of addiction.

• Altered Glutamate & GABA Activity: In the hippocampus, Delta-9-THC suppresses memory-associated signals by lowering glutamate. Simultaneously, in the amygdala, it influences the level of anxiety—low doses (2.5-5 mg) potentially decrease anxiety by soothing some regions of the brain, and high doses (>10 mg) potentially heighten anxiety by overstimulating some regions (AJP, 2021).

CB2 Receptor Effects in Peripheral Tissues

The CB2 receptor is located on immune cells (e.g., microglia and macrophages). Upon activation by Delta 9-THC it can result in reduced inflammation-producing molecules by up to 60% in models of autoimmune conditions (Cells, 2024). Such an immune-modulating action may be useful in treating diseases such as multiple sclerosis and rheumatoid arthritis.

Alternative Signaling Pathways

At higher concentrations (greater than 1 μM), Delta 9-THC acts on TRPV1 channels and PPARγ receptors, which could be involved in its analgesic and anti-cancer activities reported in certain studies (PMC8221009).

How Cannabis Impacts the Brain and Body: From Cells to Entire Systems

Short-Term Impact on the Brain

• Thinking and Memory: A single dose of Delta 9-THC of 10 mg is enough to degrade working memory by 25-40%, increasing the difficulty of tasks such as recalling sequences. Brain scans reveal decreased activity in regions that handle concentration and decision-making (PubMed, 2013). This is due to THC interfering with communication between centers for memory and reasoning in the brain.

• Balance and Movement: THC acts on brain areas responsible for controlling movement, most notably the cerebellum. Higher dosage (20 mg) impairs balance further, 200% raising unsteadiness in tests.

Long-Term Effects of Regular Use

Brain Development Risks: Adolescents who begin consuming cannabis prior to age 16 are likely to have smaller centers of memory (hippocampus) and thinner layers in the brain (cortex) than non-consumers. Individuals with genetic susceptibility to mental illness are greater than twice more likely to create illnesses such as schizophrenia (Marijuana and Madness, Cambridge). This can occur because THC blocks normal brain “pruning” during adolescence.

Tolerance and Withdrawal: Repeated use of cannabis can render the brain less sensitive to THC, needing 2-4 times the initial dose to achieve the same effect. Abrupt cessation after prolonged use can cause withdrawal symptoms (mood changes, sleep disturbances) within 1-2 days as the brain grapples with rebalancing its chemistry (Biological Psychiatry, 2016).

Comparative Pharmacology: Delta 9-THC vs. Other Cannabinoids

Data synthesized from Psychiatry Online (2021) and PMC8221009

Laws and Public Opinion Worldwide

Research Barriers

• U.S. Regulations: Federal legislation deems cannabis a high-risk drug, requiring scientists to employ low-potency Delta 9-THC (less than 12%), whereas dispensaries distribute significantly more potent drugs (90% maximum). This renders it difficult to examine actual-world impacts (PMC6007535).

• International Examples: As of early 2023, Israel had approximately 123,000 registered medical cannabis patients. This number increased to over 137,940 by December 2023, making Israel one of the countries with the highest per capita rates of medical cannabis use. (Endocannabinoid Medicine, 2023).

Evolutionary Perceptions

• Decreasing Stigma: A 2022 Gallup poll indicated that Americans are evenly split on marijuana’s effect on society, with 49% considering it positive and 50% negative

Health & Wellness Impacts and Considerations

• Nerve Stimulation: A multicenter study of 172 patients with chronic central neuropathic physical discomfort and fibromyalgia gave an average of 7.5 mg/day of Delta-9-THC for several months. The trial showed significant reduction in discomfort intensity, improvement in quality of life, and decrease in opioid consumption. Nevertheless, approximately 25% of the patients were intolerant to the treatment because of side effects such as drowsiness and dizziness.

• Combination with Opioids: a systematic review and meta-analysis suggested that the combination of Delta-9-THC with opioids may decrease the dose of morphine needed by about 3.5 times to produce equivalent analgesia in preclinical models. Clinical trials have provided inconsistent results, with some demonstrating benefits and others failing to show significant effects.​
  
• PTSD: Low doses of Delta 9-THC (2.5 mg twice a day) when combined with therapy reduced PTSD symptomatology by 40% relative to placebo, probably through an effect on fear-related pathways in the brain (AJP, 2021).
  
• Parkinson’s: A 2022 systematic review and meta-analysis assessed the impacts of cannabinoids on PD animal models. It revealed that cannabinoid-treated mice had better motor performance, as assessed by the rotarod test, with a mean increase in performance time of about 31.63 seconds compared to controls.
  
• Multiple Sclerosis (MS): In animal research, Delta-9 THC lowered MS-like symptoms by 40% by soothing hyperactive immune cells. Clinical trials in humans indicate it alleviates muscle stiffness (30% improvement) but does not markedly slow disease progression. (Haddad, 2022)

Important Disclaimer: The information above is presented for educational and informational purposes only. It is based on independent third-party research and publicly available studies. We make no claims regarding the health benefits, therapeutic effects, or medical uses of Delta-9-THC. None of the information provided is intended to diagnose, treat, cure, or prevent any disease or health condition. Always consult with a qualified healthcare professional before using any cannabinoid product.

Future Directions in Cannabinoid Research and Treatment 

The future of Delta 9-THC-based medicine involves tailoring treatments to individual differences in genetics, metabolism, and biochemistry. Key developments include: 

• Genetic Testing for Drug Response: Variations in the CNR1 gene (which produces CB1 receptors) can affect how sensitive a person is to Delta 9-THC. For instance, those with the rs2023239 variant may experience stronger effects, including higher dopamine release and a greater risk of addiction. Similarly, mutations in the FAAH gene can delay the breakdown of anandamide (a natural cannabinoid), making some people more prone to anxiety from Delta 9-THC.
  
• The future of cannabis research is rapidly evolving, driven by advances in personalized medicine, genetic testing, and new delivery technologies. Scientists are also exploring rare cannabinoids like CBN, known for its sedative properties, and THCP, a potent compound with up to 30 times stronger receptor affinity than Delta-9-THC. As understanding deepens, these discoveries could unlock new therapeutic applications while reshaping how cannabis-based treatments are developed and prescribed.

• Metabolism-Based Dosing: The liver enzymes CYP2C9 and CYP3A4 break down Delta 9-THC. 5–10% of Caucasians may carry genetic variants like CYP2C92 or CYP2C93, which are associated with reduced enzyme activity and slower metabolism of THC (Cannabis Pharmacogenomics, 2023). Genetic testing before treatment could help adjust doses, especially for older adults or those taking multiple medications. 

• Biomarkers for Better Treatment: Measuring levels of natural cannabinoids (like anandamide and 2-AG) in the blood may help identify patients with “endocannabinoid deficiency”—a condition linked to migraines, fibromyalgia, and IBS. Research suggests these patients may benefit most from Delta 9-THC therapy. 

Advanced Cannabinoid Treatments 

To reduce the unwanted effects of Delta 9-THC (such as euphoria and memory problems), scientists are working on new solutions.  Packaging Delta 9-THC in tiny fat-based particles (nanoparticles) makes it 3x more effective and directs it to inflamed areas, minimizing side effects. 

Changing Laws and More Research 

New cannabis policies worldwide are speeding up scientific progress: 

• Germany (2024 Cannabis Act): Legalizes small personal possession (25g) and home growing (3 plants). Adults under 21 years old are limited to receiving up to 25 grams per day and a maximum of 30 grams per month from cannabis clubs. 
• Thailand’s Medical Program: After legalizing medical cannabis in 2022, In 2024, Thailand announced plans to reclassify cannabis as a narcotic, requiring permits for its medical and research use. This policy reversal aims to curb recreational use and regulate the industry more strictly.   
• U.S. Rescheduling Plans: The DEA may reclassify THC as a Schedule III drug (2024), allowing pharmaceutical development while keeping recreational use restricted. 

Final Thoughts: Delta-9 and the Endocannabinoid System

Delta-9-THC has both therapeutic and hazardous potentials, and healthcare and society need to consider this with care. Studies need to investigate how various doses impact brain function, particularly in illnesses such as psychosis, and long-term safety needs to be followed up in medical cannabis consumers for 10+ years. Smart regulation, such as Canada’s approach of taxing high-potency products to deter abuse, is crucial, in addition to ensuring that clinical trials enroll diverse populations to help correct disparities in arrests and access to medical care.

Overall, to maximize the benefits of Delta-9-THC while minimizing harm, scientists, policymakers, and healthcare providers must collaborate. By striking a balance between innovation and safety, we can advance personalized cannabinoid treatments toward a healthier future.

Legal Disclaimer:
By reading this information presented, you agree to release the author of any liability that comes from using this data. This post contains no legal advice. Claims about cannabinoids have not yet been approved by the FDA. Read the full legal disclaimer here.

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