From Jerusalem To Your Brain: What Cannabis Research Reveals

Global Cannabis Research Roundup: Why Experts Say It’s The Key To Better Health

Key Points

Research suggests that cannabinoid deficiency, specifically clinical endocannabinoid deficiency (CED), may be linked to certain diseases, though this is still a theory under investigation.
The evidence leans toward migraine, fibromyalgia, and irritable bowel syndrome (IBS) being associated with CED, based on studies showing deficits in the endocannabinoid system.
Other conditions like PTSD, multiple sclerosis, and depression might also be related, but the connections are less clear and require more research.
This is a debated topic, as CED is not yet a widely accepted medical diagnosis, and more studies are needed to confirm these links.
Research suggests that laws significantly restrict research on cannabis and Clinical Endocannabinoid Deficiency (CED), impacting our understanding and treatment options.
Legal barriers, like cannabis being a Schedule I drug in the US, limit access to research-grade cannabis and funding, slowing progress.
State and federal law conflicts creating challenges, but recent changes, like the 2018 Farm Bill, offer some relief for hemp research.

Cannabinoid deficiency refers to a potential lack of function in the body’s endocannabinoid system (ECS).

The ECS helps regulate various processes like pain, mood, and digestion.

The concept of clinical endocannabinoid deficiency (CED) suggests that a deficiency in this system could contribute to certain diseases.

While research is ongoing, some conditions have been more strongly associated with CED than others.

Below, we explore the main diseases linked to this theory and provide a detailed survey of the evidence.

Background On Clinical Endocannabinoid Deficiency (CED)

Cannabinoids are chemical compounds that interact with the body’s endocannabinoid system (ECS), which is involved in regulating processes such as pain, mood, appetite, and immune response.

The theory of clinical endocannabinoid deficiency (CED) was first proposed by Dr. Ethan Russo in 2004.

Russo suggests that a deficiency in the ECS—either through reduced endocannabinoid levels (e.g., anandamide [AEA] and 2-arachidonoylglycerol [2-AG]) or impaired receptor function—could contribute to various diseases.

This theory draws parallels with other neurotransmitter deficiencies, such as dopamine in Parkinson’s disease, and posits that similar deficits in the ECS might manifest in predictable clinical features.

Despite being discovered nearly 30 years ago, the ECS is still not widely taught in medical curricula, leading to a knowledge gap among healthcare providers.

This lack of awareness, potentially due to the association with cannabis, has slowed the integration of ECS research into mainstream medicine, as noted in discussions by Dr. Russo and others.

Diseases Strongly Associated With CED

The most commonly discussed diseases linked to CED are migraine, fibromyalgia, and irritable bowel syndrome (IBS), supported by research showing deficits in endocannabinoid levels or function:

The PubMed article, published in 2016 and frequently cited, provides robust evidence for the association of CED with the following diseases.

Migraine

Research shows statistically significant differences in cerebrospinal fluid (CSF) anandamide levels, with advanced imaging studies indicating ECS hypofunction.

For instance, CSF AEA levels in 15 chronic migraineurs were significantly lower than in 20 controls (p<0.0001), and migraine affects 14% of Americans, costing $20 billion annually (Clinical Endocannabinoid Deficiency Reconsidered).

Fibromyalgia

There is a high comorbidity with migraine, with 97% of 201 fibromyalgia patients also having primary headaches.

Central sensitization and hyperalgesia are noted, with 35.6% of 101 chronic daily headache subjects fitting fibromyalgia criteria.

Irritable Bowel Syndrome (IBS)

Characterized by GI pain, spasm, and altered bowel movements, IBS shows visceral hypersensitivity and genetic variations affecting endocannabinoid metabolism.

Prevalence is 10–15% in the Western world, with a 3.5-fold elevation in TRPV1-immunoreactive nerve fibers in IBS sufferers compared to controls (p<0.0001).

These conditions are highlighted as the primary focus of the CED theory, with specific statistical evidence supporting their association.

Disease/Condition	Evidence Supporting CED	Specific Findings/Statistics
Post-Traumatic Stress Disorder (PTSD)	Serum 2-AG reduced in PTSD victims, especially with direct exposure, PET study showing higher CB1 receptor availability	Serum 2-AG reduced in 46 WTC attack survivors with PTSD vs. without, p=0.001, 19.5% higher CB1 V_T in PTSD vs. controls
Multiple Sclerosis (MS)	Direct assays show significant deficits in CSF AEA and 2-AG, particularly in secondary progressive cases	Significant deficits in CSF AEA and 2-AG in MS patients vs. controls, affirmed as functional disease marker
Huntington’s Disease (HD)	Widespread impairment of endocannabinoid function, loss of CB1 immunoreactivity, PET study showing decreased receptor availability	15–25% reduction in CB1 receptor availability in HD vs. controls, p<0.0001, across cerebellum to frontal cortex
Parkinson’s Disease (PD)	CSF AEA levels doubled in untreated patients, posited as compensatory mechanism for dopamine depletion	CSF AEA levels doubled in PD patients vs. age-matched controls, p<0.001, irrespective of disease stage
Motion Sickness	Significant reductions in AEA and 2-AG in blood during acute episodes, correlated with nausea scores	7/21 adults developed motion sickness with significant AEA reduction, p=0.04, 2-AG reduction, p=0.01, nausea scores negatively correlated with AEA, p=0.02
Anorexia Nervosa	Increased global CB1 receptor availability, posited as response to ECS hypoactivity, elevated peripheral serum AEA	Increased CB1 availability in cortical and subcortical areas in anorexia vs. controls, p=0.0003, insula p=0.01
Schizophrenia	CSF AEA levels eightfold higher in untreated acute cases, negatively correlated with psychotic symptoms	CSF AEA eightfold higher in schizophrenics vs. controls, p=0.000, negatively correlated with psychotic symptoms, p=0.001
Major Depression	Linked to CNS plasticity, inflammatory component, posited as degenerative disease with endocannabinoid deficiency	No specific statistics, but linked to ECS deficiency in discussion
Diabetic Neuropathy	Rat model showed reduced rostroventromedial medullary AEA levels, TRPV1 desensitizer capsaicin decreased nociceptive signs	No human statistics, animal model findings discussed
Autistic Spectrum Disorders	Genes regulating ECS function impaired, suggesting therapeutic approaches	Neuroligin-3 mutations in mice impaired tonic endocannabinoid signaling, no human statistics

Broader Perspectives From Other Sources

The Neurocenter NJ blog post provides a broader perspective, suggesting that deficient endocannabinoid tone may increase the risk for chronic conditions, including neurological disorders like dementia and epilepsy.

It lists a wide range of diseases potentially influenced by the ECS, such as.

ADD/ADHD
Alzheimer’s
ALS
Asthma
Bipolar
Cancer
Chronic fatigue
Crohn’s
Diabetes
Epilepsy
Migraine
Multiple sclerosis
Nausea
Neuropathy
Rheumatoid arthritis
Stroke
Tourette
Spasms

This list is more speculative and includes conditions where the ECS may play a role, but it does not provide specific evidence for deficiency.

It also notes that cannabinoid receptor polymorphisms are associated with conditions like addictions, schizophrenia subtypes, central obesity, hyperlipidemia, and cyclic vomiting syndrome, which may indicate overactivity rather than deficiency in some cases.

Therapeutic Implications And Research Gaps

Modulating the ECS is suggested to have therapeutic potential for a wide array of diseases.

Diseases including obesity/metabolic syndrome, diabetes and diabetic complications, pain, neurodegenerative diseases, inflammatory disorders, cardiovascular disorders, hepatic disorders, gastrointestinal and skin diseases, psychiatric disorders, cachexia, cancer, and chemotherapy-induced nausea/vomiting, as cited in Pacher et al. (2013) in the FEBS Journal.

However, the origin of cannabinoid deficiencies remains unknown, with suggestions of genetic reasons, disease, or injury, and the validity of these findings is still debated due to limited research.

Dr. Russo has emphasized the need for further studies, particularly looking at the ECS’s relationship with the gut microbiome, noting a significant knowledge deficit in medical education regarding the ECS.

This gap hinders the ability to treat patients effectively, as highlighted in discussions on platforms like Labroots.

Strategies For Prevention And Management

To address CED-related ailments, both endo-cannabinoids and plant-based cannabinoids can be leveraged, along with other substances interacting with the ECS.

Endo-Cannabinoids: Naturally produced, their levels can be increased by inhibiting FAAH and MAGL. FAAH inhibitors, like JNJ-42165279, have shown efficacy in social anxiety disorder by elevating AEA levels, while MAGL inhibitors, like LEI-515, increase 2-AG in peripheral organs, showing promise in pain and inflammation (The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279, A monoacylglycerol lipase inhibitor showing therapeutic efficacy). These inhibitors offer a way to enhance ECS function without direct cannabinoid administration.
Plant-Based Cannabinoids: Compounds like THC and CBD from cannabis can activate CB1 and CB2 receptors, compensating for ECS deficits. CBD, for instance, has shown anti-inflammatory and analgesic properties, potentially beneficial for fibromyalgia and IBS, while THC may help with pain and nausea in migraine (Clinical Evidence of Cannabinoids in Migraine).
Other Substances: Beyond cannabinoids, substances like montelukast and repaglinide, identified as repurposable FAAH inhibitors, and NSAIDs like sulindac, which also inhibit FAAH, could support ECS function, offering dual benefits in pain and inflammation (Identifying FAAH Inhibitors as New Therapeutic Options, Assessment of NSAIDs as potential inhibitors).

Emerging Research from Leading Institutions

The Multidisciplinary Center on Cannabinoid Research at the Hebrew University of Jerusalem, launched in 2017, is led by figures like Professor Raphael Mechoulam, who pioneered cannabinoid research.

Their focus includes cancer, pain, inflammation, immunity, metabolism, drug delivery, pharmaceutical chemistry, neuroscience, and plant science and genetics, aiming to uncover therapeutic potentials (Hebrew University Launches Multidisciplinary Center).

The International Cannabinoid Research Society (ICRS), established in 1992, supports global research with over 650 members, holding annual symposia (e.g., ICRS2024 in Salamanca, Spain).

Their scope includes biochemical, chemical, and physiological studies of the ECS.

Insights From Dr. Tashkin And Dr. Allen

Dr. Donald P. Tashkin

A pulmonologist at UCLA, has conducted over 30 years of research on cannabis’s lung effects.

His 2006 case-control study found no increased lung cancer risk among heavy marijuana users, contrasting with tobacco, which is an unexpected finding given public health concerns.

Tashkin found.

No increased risk of lung or head/neck cancers in marijuana-only smokers.
No excess decline in lung function.
No consistent evidence of increased COPD risk, even in long-term and heavy users.
Despite airway changes, lung function tests (spirometry) remained normal in marijuana smokers.

This is relevant for CED patients considering cannabis-based treatments, suggesting lower respiratory risks.

Dr. David Allen

Dr. David Allen, a retired cardiac surgeon and ICRS member and IRCS member, emphasizes the ECS’s role in homeostasis, describing it as a critical medical discovery.

He advocates for cannabinoids to “feed” the ECS, potentially offering broad therapeutic benefits for CED-related conditions, highlighting its significance in future medicine.

Allen’s current role is a cannabinoid research scientist and member of the International Cannabinoid Research Society (ICRS).

He advocates for cannabinoids to “feed” the ECS, potentially offering broad therapeutic benefits for CED-related conditions, highlighting its significance in future medicine.

Cannabinoids interact with the ECS, potentially offering therapeutic benefits.

Dr. Allen suggests that introducing cannabinoids can support the ECS, promoting overall health and aiding in disease management.

Legal Barriers And Their Impact On CED Research

The legal status of cannabis varies globally, with significant implications for research, particularly in the United States, where it is classified as a Schedule I drug under the Controlled Substances Act (CSA).

This classification, which denotes a high potential for abuse and no accepted medical use, imposes strict controls on possession, manufacturing, distribution, and dispensing, making research challenging.

Key Legal Challenges

From the review, several specific challenges emerge.

Limited Access to Research-Grade Cannabis: In the US, the only legal source of research-grade cannabis is from the University of Mississippi, which contracts with the National Institute on Drug Abuse (NIDA) to cultivate cannabis for research purposes (Challenges and Barriers in Conducting Cannabis Research). This single-source system limits the variety of cannabis available, often providing products of lower potency and quality compared to state-regulated markets, which can affect the external validity of research findings.
Quality Issues: The cannabis provided by NIDA has been criticized for potential contamination, such as mold, and inconsistent quality, further complicating research (The State of Cannabis Research Legislation in 2020). This is particularly problematic for studies requiring high-quality, standardized materials.
Regulatory Barriers: The Schedule I status requires researchers to obtain multiple approvals, including DEA Schedule I registrations and state research licenses, which are sequential and time-consuming (Legal and Regulatory Issues Governing Cannabis and Cannabis-Derived Products in the United States). This process can delay or prevent studies from starting, as seen with Dr. Ethan Russo’s attempt to study cannabis for migraines, approved by the FDA in 1999 but never conducted due to political opposition (The Latest Medical Cannabis Research: Dr. Ethan Russo Discusses Neurological Research, Dosing, and More).
Funding Challenges: Federal funding for Schedule I substance research is restricted, making it difficult to secure grants for cannabis studies. This is particularly true for therapeutic research, with the NIH cannabis research portfolio growing but still limited compared to other areas (Challenges for Clinical Cannabis and Cannabinoid Research in the United States).
State vs. Federal Law Conflicts: The discrepancy between state laws (where many states have legalized medical or recreational cannabis) and federal law creates legal risks for researchers. Institutions can lose federal funding if they obtain cannabis from state-legal sources, deterring research (The cannabidiol and marijuana research expansion act: Promotion of scientific knowledge to prevent a national health crisis).

Impact On CED Research

Research into CED benefits from a deeper understanding of the ECS, which often involves studying both endo-cannabinoids and plant-based cannabinoids.

The legal restrictions on plant-based cannabinoids can indirectly affect CED research in several ways.

Limited Study of Plant-Based Cannabinoids: Since plant-based cannabinoids like THC and CBD are used to study and potentially treat CED, legal barriers limit their availability for research. This restricts the ability to explore how these compounds can augment ECS function in CED patients, potentially slowing the development of treatments.
Indirect Effect on ECS Understanding: Even though CED research can focus on the body’s own endocannabinoids, understanding how to treat it often involves studying how external cannabinoids interact with the system. Legal restrictions hinder this, as seen in the lack of data on how daily cannabis use and abstinence alter endocannabinoid levels, which is critical for guiding therapeutic use (Cannabis Use and the Endocannabinoid System: A Clinical Perspective).
Personal Accounts from Researchers: Dr. Ethan Russo, a key figure in CED research, has highlighted the political and institutional opposition as a major challenge, noting that his planned study on migraines was never conducted due to legal hurdles. This illustrates how legal barriers can personally affect researchers working on CED-related topics (Meet the Experts: Interview with Dr. Ethan Russo).

Recent Developments and Potential Changes

Despite these challenges, there have been some positive developments in the legal landscape.

2018 Farm Bill: This legislation removed hemp (defined as cannabis with ≤0.3% THC on a dry weight basis) from the CSA, facilitating research on CBD and other non-THC cannabinoids (FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)). This has streamlined processes for researchers studying hemp-derived products, offering a partial relief for CED research involving non-psychoactive compounds.
Efforts to Reschedule Cannabis: There are ongoing legislative efforts, such as the Cannabidiol and Marijuana Research Expansion Act (S.253), passed by the US Senate in March 2022, aimed at accelerating research by reducing regulatory barriers (The cannabidiol and marijuana research expansion act: Promotion of scientific knowledge to prevent a national health crisis). These efforts could potentially ease restrictions on THC research, benefiting CED studies.
Growing State-Level Research: Some states have their own laws allowing more flexibility for cannabis research, but federal law still poses significant hurdles for interstate research and funding, creating a complex landscape for researchers.

Broader Implications

The legal restrictions not only slow down scientific progress but also affect patients who might benefit from cannabis-based treatments for CED-related conditions.

The lack of research limits the evidence base needed for regulatory approval of new therapies, leaving many patients with treatment-resistant conditions without options.

Moreover, the stigma associated with cannabis, partly due to its legal status, can deter researchers and institutions from pursuing this field, further hindering progress.

Overcoming these legal barriers is essential for advancing our understanding of CED and developing effective treatments, ensuring better health outcomes for those affected.

Final Thoughts On Clinical Endocannabinoid Deficiency

In summary, the diseases most commonly associated with cannabinoid deficiency, specifically CED, are migraine, fibromyalgia, and irritable bowel syndrome, supported by research showing deficits in endocannabinoid levels or function.

Other conditions like PTSD, multiple sclerosis, and depression may also be linked, but the evidence is less conclusive.

The broader list from Neurocenter NJ suggests potential influences on many other conditions, but these are less directly tied to deficiency.

Given that CED is still a theory and not a recognized diagnosis, ongoing research is crucial to clarify these associations and their implications for treatment.

Laws significantly impact research into cannabis and CED, creating barriers such as limited access to research-grade cannabis, quality issues, regulatory hurdles, funding challenges, and conflicts between state and federal laws.

These restrictions indirectly affect CED research by limiting the study of plant-based cannabinoids, which are crucial for understanding and treating the condition.

Recent developments, like the 2018 Farm Bill and efforts to reschedule cannabis, offer hope, but significant challenges remain.