Medical Cannabis as an Opiate Alternative: A Prospective Observational Cohort Study

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“Opioid use for chronic pain has contributed to an epidemic of overdoses and deaths in the United States.

Some clinical studies suggest that medical cannabis may help alleviate pain and improve quality of life. However, cost can be a barrier to patients accessing medical cannabis.

This is the first prospective observational study evaluating medical cannabis as an alternative to opioids in a setting where cost was removed as a major barrier.

Methods: Twenty-nine patients were recruited from a university-based outpatient chronic pain clinic. Each patient underwent monthly pain assessments using the Numeric Pain Rating Scale (NRS). Daily opioid use, measured in morphine milligram equivalents (MMEs), was recorded and monitored over five months. Pain-related quality of life was assessed using the SF-36 Health Survey at baseline, and again at two and five months.

Results: Daily opioid use decreased from baseline to one month (from 46.8 MMEs to 16.2 MMEs, a 65% reduction), and this reduction was maintained through five months. The mean NRS score decreased by two points from baseline to one month (from 7.03 to 5.07; p < 0.0001), and this improvement was sustained at five months. The SF-36 Physical Functioning score increased from 15.3 at baseline to 21.4 at one month and was maintained at five months (p < 0.03 for both comparisons).

Conclusion: These results suggest that medical cannabis may be a useful adjunct therapy for reducing opioid use, relieving chronic pain, and improving health-related quality of life.”

https://pubmed.ncbi.nlm.nih.gov/42153072

“Opioids are associated with serious adverse events, including death, particularly at higher dosages or when used in combination with benzodiazepines.

In contrast, medical cannabis has not been associated with mortality from overdose. When used under appropriate medical supervision, medical cannabis may represent an effective adjunctive strategy for reducing opioid use among patients receiving long-term opioid therapy.

“Although cannabis has historically been characterized as a potential “gateway drug,” it may also serve as a harm-reduction tool for some patients seeking to reduce reliance on higher-risk opioid medications.”

https://www.cureus.com/articles/432327-medical-cannabis-as-an-opiate-alternative-a-prospective-observational-cohort-study#!

Whole Plant Cannabinoid Nonpharmaceutical Treatment Protocols for a Young Male With Dravet Syndrome

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“Objective: This case report describes the outcomes of a novel, conservative approach for a young male patient with Dravet syndrome, which is a genetic epileptic encephalopathy resulting in frequent and recalcitrant seizures and developmental delays.

Clinical features: A male infant began to experience seizures before 7 months of age, and genetic testing revealed an SCN1A mutation, confirming the diagnosis of Dravet syndrome. At age 7, despite standard polypharmacy consisting of antibiotics, steroids, and antiepileptic drugs, he continued to suffer from approximately 25 to 28 daily tonic-clonic refractory seizures.

Intervention and outcome: The clinical objective was to restore the function of the endocannabinoid system by integrating very low-dose, whole-plant extracted, naturally chiral, hemp-derived phytocannabinoid formulations, and broad environmental and dietary modifications. Within the first week of treatment, the patient had only 1 to 2 mild seizures per day. Four years later, all pharmaceuticals were discontinued, and by age 12, the patient’s daily hemp formulation was reduced to as-needed status. At the time of this writing, the patient was 16 years of age and had an average of 7 to 10 very mild petit mal seizures per month. The whole plant hemp formulations generated no observable side effects.

Conclusion: This case study demonstrates conservative comanagement of a patient with a catastrophic seizure disorder using novel nonpharmaceutical comanagement strategies.”

https://pubmed.ncbi.nlm.nih.gov/42152927

“The objective of this case report is to describe 10 years of treatment effects of whole plant hemp cannabidiol (CBD) extracts in a young male patient with Dravet syndrome, who was responding poorly to the standard polypharmacy approach.”

“Chronic seizure activity in a young male patient was reduced after the introduction of whole plant extracted hemp and diet modifications”

https://www.sciencedirect.com/science/article/abs/pii/S1556370725000379

Feasibility, Safety and Preliminary Efficacy of 1:1 THC:CBD Cannabis Oil for Fibromyalgia Symptoms: Results From a Randomised, Double-Blind, Placebo-Controlled Pilot Trial

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“Fibromyalgia is a chronic disorder characterised by widespread pain and other symptoms that substantially impact the quality of life.

This double-blind, randomised, placebo-controlled trial primarily assessed feasibility (procedures and intervention adherence) and safety/tolerability of a 1:1 delta-9-tetrahydrocannabinol:cannabidiol (THC:CBD) cannabis oil (10 mg/mL each) in 24 adults with fibromyalgia, with secondary, preliminary assessment of efficacy across symptom domains.

Participants completed a 4-week dose titration followed by 12 weeks of stable dosing. Of 77 prescreened individuals, 24 were randomised, yielding a screening-to-enrolment ratio of approximately 3:1 (31.2%). Recruitment reached 66.7% of the target (24/36); the shortfall was mainly due to geographic and legal barriers. Retention was 91.7% (22/24) and adherence was high, with all participants taking ≥ 90% of the prescribed doses.

The study medication was well tolerated in this small sample, with adverse events mostly mild and no serious events observed.

Secondary outcomes suggested medium to large between-group effects favouring cannabis for pain reduction, improved sleep quality, and reduced fibromyalgia impact (FIQR), but findings should be interpreted cautiously given the small sample.

Clinically meaningful FIQR improvement (predefined MCID 45.5%) occurred in 40% of the cannabis-treated participants versus 10% with placebo.

For pain, 70% of the cannabis group reported ≥ 30% reduction post-titration and at Week 12 (Placebo 20% and 40%, respectively). Fatigue and anxiety/depression showed no significant changes.

A randomised trial of 1:1 THC:CBD oil appears feasible with excellent retention and adherence, though recruitment barriers need addressing. Preliminary safety and efficacy signals warrant confirmation in larger, adequately powered trials.”

https://pubmed.ncbi.nlm.nih.gov/42142029

“In recent years, medicinal cannabis has emerged as a potential therapeutic option for fibromyalgia, with increasing patient interest in new treatment approaches [5]. Given fibromyalgia’s complexity and diverse manifestations, investigating multifaceted therapies such as medicinal cannabis is well justified.”

“Cannabis sativa L. is a plant with a long history of medicinal use, containing over 100 phytocannabinoids, including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) [6]. These compounds interact with the endocannabinoid system, which plays a critical role in modulating pain, mood and sleep—key domains affected in fibromyalgia [7–9]. Consequently, cannabis is being investigated as a potential therapeutic agent for fibromyalgia, with several studies suggesting it may help reduce pain, improve sleep and enhance the quality of life, although findings to date remain mixed and optimal dosing strategies, including the THC:CBD ratio and routes of administration, still require further investigation.”

https://onlinelibrary.wiley.com/doi/10.1155/prm/7311235


Effect of cannabidiol, cannabinol and tetrahydrocannabivarin in managing inflammatory pain

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“Current medications used to treat the inflammatory pain either have limited effectiveness or may be associated with serious side effects. Non-psychoactive phytocannabinoids may have a better safety profile and could be used as an alternative approach to treat this condition.

The aim of this study was to test the potential of three phytocannabinoids, cannabinol (CBN), tetrahydrocannabivarin (THCV) and cannabidiol (CBD), in treating inflammatory pain.

The inflammatory pain was triggered in male rats by a single intra-articular knee injection of the complete Freund’s adjuvant (CFA). One week later, rats were given four daily administrations of ibuprofen, CBN, THCV or CBD. Our data demonstrated that CFA injection triggered an inflammatory response expressed as damage of the synovial tissue, reduced locomotor activity, increased mechanical and, to a lesser extent, thermal pain sensitivity, and loss of body weight.

All phytocannabinoids reduced mechanical hyperalgesia and had no or a minor effect on locomotor activity.

Treatment with CBN also lowered thermal hypersensitivity. Treatment with CBN and THCV recovered the body weight of CFA-injected rats. However, administration of CBD reduced body weight and elevated blood monocyte and granulocyte levels above those of the CFA-injected control animal group.

We conclude that CBN and THCV may have potential in managing inflammatory pain.”

https://pubmed.ncbi.nlm.nih.gov/42151379

https://www.nature.com/articles/s41598-026-51275-7

Assessing the Efficacy of Cannabinoid Compositions for Treating 3 Classes of Chronic Pain: A Real-World Evidence Study

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“Purpose: Cannabis has been determined to be effective at treating chronic pain, although research on the effects of specific cannabinoids, especially for different mechanisms of chronic pain, is limited. This study examined therapeutic efficacy for combinations of intoxicating and nonintoxicating cannabinoids for symptoms of 3 different types of chronic pain conditions.

Methods: We recruited adult California residents diagnosed with fibromyalgia (n = 64), rheumatoid arthritis (n = 25), and osteoarthritis of the knee and/or hip (n = 75). Participants in each group were randomly assigned to receive a 12-week supply of oral capsules with 3 different cannabinoid compositions: product 1-12.5 mg cannabidiol (CBD) and 12.5 mg tetrahydrocannabinol (n = 45); product 2-10 mg tetrahydrocannabinolic acid, 10 mg cannabidiolic acid (CBDa), 5 mg cannabigerol, and 3 mg cannabichromene (n = 57); and product 3-10 mg CBD and 10 mg CBDa (n = 62). Participants completed validated self-report questionnaires assessing pain characteristics, mental health and cognitive functioning, and physical functioning at baseline and 12-week timepoints.

Findings: Of 276 individuals recruited, 168 (60.9%) completed all survey questionnaires. Four individuals who completed the questionnaires but discontinued study product use were removed from the dataset. Per-protocol analyses identified significant improvements across all symptoms except cognitive function abilities. Effects ranged from small to large; most did not differ in magnitude across product or type of chronic pain. Products differed in effectiveness for sleep disturbance, and participants taking product 2 reported reductions in neuropathic pain intensity.

Implications: These findings suggest that various cannabinoid combinations may have beneficial effects across 3 different types of chronic pain. Nonintoxicating cannabinoids such as CBD and CBDa may provide relief from pain and related symptoms and may be utilized when cannabis intoxication is undesirable or problematic.”

https://pubmed.ncbi.nlm.nih.gov/42140793

“Various cannabinoid combinations may have therapeutic benefits across 3 different types of chronic pain.”

https://www.clinicaltherapeutics.com/article/S0149-2918(26)00136-0/abstract

Cell-Free Synthesis of Cannabistilbene I: A Dual Acting Anti-Inflammatory from Cannabis sativa

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“Despite the potential of Cannabis bibenzyls to remedy acute and chronic inflammation, their relative scarcity, in planta, has hindered applications for them in mainstream therapeutic efforts.

Here, we describe the biocatalytic synthesis of cannabistilbene I (1), a prototypical Cannabis bibenzyl, and demonstrate its utility as an anti-inflammatory agent.

A Cannabis O-methyltransferase (CsOMT1) was first identified that catalyzes the 3-hydroxymethylation of dihydroresveratrol (2) to produce pinobistilbene (3). Structural characterization of CsOMT1 revealed that the substrate-binding pocket requires the ethyl bridge on 2 to twist with a dihedral angle of -110°, thereby explaining why less flexible aromatics such as stilbenes serve as poor enzymatic substrates.

Next, a prenyltransferase (CloQ) from the Gram-positive bacterium Streptomyces was shown to prenylate the 3′-position of the B-ring on 3 into 1. Using these two enzymes, a cell-free method was then developed to synthesize 1 and the compound was shown to inhibit both microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase enzyme activity, in vitro, more effectively than the leading commercially available inhibitors.

Together, these results establish a platform for producing cannabistilbene I (1) that circumvents the challenges of traditional “chemical synthesis”, and which is amenable to produce similar value-added compounds that are not easily accessible from nature.”

https://pubmed.ncbi.nlm.nih.gov/42139234

“The widespread use of Cannabis sativa as a natural product therapeutic has been well documented since time immemorial.”

“In this study, we hereby add cannabistilbene I (1) to this list of prenylated aromatics from C. sativa that act as “dual-acting inhibitors” of the pro-inflammatory pathway. Strikingly, in our in vitro assays, cannabistilbene I (1) was ∼3× and ∼20× more potent than the leading commercially available inhibitors of mPGES-1 and 5-LOX, respectively.”

https://pubs.acs.org/doi/10.1021/acs.jnatprod.6c00318

Cannabidiol-Induced Tumor Cell Death: Molecular Mechanisms and Translational Perspectives in Cancer Therapy

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“Background: Cannabidiol (CBD), a major non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention as a potential anticancer agent because of its pleiotropic biological activities and favorable safety profile. However, the mechanisms by which CBD regulates tumor cell death and their therapeutic relevance remain incompletely understood.

Methods and results: This review summarizes current evidence on the molecular mechanisms by which CBD regulates tumor cell death across different cancer models. Available studies indicate that CBD exerts antitumor effects through multi-target and multi-pathway mechanisms involving oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, calcium homeostasis imbalance, and modulation of signaling networks such as PI3K/Akt/mTOR, MAPK, NF-κB, and PPARγ. Through these interconnected processes, CBD can induce apoptosis, autophagy, ferroptosis, pyroptosis, and cell cycle arrest in a context-dependent manner. Notably, CBD may activate multiple regulated cell death pathways simultaneously or sequentially within the same tumor model, reflecting a broader stress-response network rather than a single cytotoxic mechanism.

Therapeutic implications: By coordinately engaging multiple cell death pathways and modulating the tumor microenvironment, CBD provides mechanistic insights and potential opportunities for the development of novel anticancer strategies. However, current evidence remains predominantly preclinical, while challenges related to oral bioavailability, pharmacokinetic variability, dose optimization, and potential drug interactions continue to limit translational progress.

Conclusion: Collectively, available evidence suggests that CBD functions as a pleiotropic modulator of tumor cell fate rather than a classical single-target cytotoxic agent. Further mechanistic, pharmacological, and clinical studies are required to support the rational development of CBD-based anticancer therapies.”

https://pubmed.ncbi.nlm.nih.gov/42137120

“Cannabidiol (CBD), a major non-psychoactive phytocannabinoid derived from Cannabis sativa, has attracted increasing attention as a potential anticancer agent due to its multimodal capacity to induce tumor cell death.”

“In conclusion, current evidence indicates that cannabidiol exerts antitumor effects through pleiotropic and context-dependent regulation of multiple cell death programs, including apoptosis, autophagy, ferroptosis, pyroptosis, and cell cycle arrest. By integrating oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, calcium imbalance, and diverse signaling networks, CBD reshapes tumor cell fate and provides a mechanistic basis for potential anticancer intervention.”

https://www.dovepress.com/cannabidiol-induced-tumor-cell-death-molecular-mechanisms-and-translat-peer-reviewed-fulltext-article-DDDT

Cannabis for Harm Reduction: Exploring Mental Health and Other Motivational Factors among Adults at Risk for Alcohol Use Disorder in Florida

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“Background: Prior research has suggested that cannabis may serve as a safer alternative to alcohol, this study examined “marijuana” (THC-dominant cannabis) and cannabidiol (CBD) use as strategies to reduce alcohol consumption among adults who report harmful levels of drinking.

Method: Online surveys were distributed to 451 Florida adults (≥18 years) who consumed ≥5 alcoholic drinks weekly and reported any lifetime cannabis use. Measures included comorbid health conditions, alcohol use severity (Alcohol Use Disorder Identification Test [AUDIT]), depressive symptoms (PHQ-8), anxiety (GAD-7), post-traumatic stress symptoms (primary care post-traumatic stress disorder [PC-PTSD]), childhood trauma (Adverse Childhood Experience Questionnaire [ACE-Q]), and readiness to change (Readiness to Change Questionnaire [RCQ-12]). Chi-square and ANOVA examined differences across alcohol use risk groups; logistic regression identified factors associated with marijuana and CBD use for alcohol reduction.

Results: High (AUDIT scores ≥16) were found in 61.4% of males and 40.9% of females. Higher alcohol use risk was significantly associated with younger age, higher PHQ-8 and GAD-7 scores, greater ACE-Q scores, PTSD positivity, more health conditions, and higher readiness to change (p < 0.001). Marijuana (37.9%) and CBD (32.2%) were the most frequently reported alcohol-reduction strategies; higher alcohol use severity was linked to greater perceived effectiveness. Factors associated with marijuana use for alcohol reduction included higher PTSD scores (OR = 1.76), more comorbid conditions (OR = 1.17), action-stage readiness to change (OR = 1.47), and higher AUDIT scores (OR = 1.83). Factors associated with CBD use for alcohol reduction included higher ACE-Q scores (OR = 1.14), more comorbid conditions (OR = 1.18), action-stage readiness (OR = 1.50), and higher AUDIT scores (OR = 1.95).

Conclusion: These findings identify key clinical and motivational correlates of cannabis use for alcohol harm reduction, informing future intervention development.

Plain language summary

“This study found that individuals with severe alcohol problems, especially those with trauma and mental health conditions, frequently use cannabis to reduce drinking. Many perceive these strategies as effective, particularly when traditional treatments are inadequate or inaccessible. Public health efforts should recognize this growing interest in cannabis-based harm reduction and address the unmet needs of individuals who wish to reduce alcohol consumption, exploring alternative, evidence-based strategies to improve outcomes for high-risk groups and reduce the broader burden of alcohol-related harm.”

https://www.tandfonline.com/doi/full/10.1080/10826084.2026.2670620

Cannabidiol and other non-psychotropic cannabinoids from Cannabis sativa as therapeutics for microglial-mediated neuroinflammation and neurodegeneration

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“Non-psychotropic phytocannabinoids produced by Cannabis sativa, including cannabidiol, cannabigerol, cannabichromene and their varin and acidic analogs, are emerging as promising modulators of neuroinflammation, particularly through actions on microglia, the brain’s resident immune cells.

These compounds engage numerous receptors, ion channels, and intracellular signaling systems in microglia associated with neuroinflammation, and therefore are promising therapeutic candidates to treat chronic microglial inflammation-mediated neurodegenerative disorders.

Despite substantial public and scientific interest, comprehensive evaluation of their mechanistic diversity, disease-relevant potential, and translational gaps across neurodegenerative disorders remains limited. Commonly, gaps also exist between cannabis breeders’ and cultivators’ knowledge of phytocannabinoid diversity and translational scientists’ understanding of therapeutic potential.

In this review, we first provide an in-depth overview of the main non-psychotropic phytocannabinoids, their biosynthesis, and the genetics that control their production in cannabis. We then summarize the known mechanisms of action for each cannabinoid in microglial-expressed molecular targets and signaling pathways relevant to neuroinflammation.

Lastly, we review the effects of non-psychotropic phytocannabinoids in pre-clinical models and clinical trials of four neuroinflammation-associated neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Huntington’s disease.

Current evidence supports meaningful biological activity and complex cannabinoid-specific polypharmacology, yet substantial gaps persist, especially for cannabinoids other than cannabidiol; addressing these gaps in disease-relevant models will be essential for translating these compounds into future therapeutic strategies. Further, we anticipate the summarized information will foster collaboration between cannabis breeders/cultivators and applications scientists for therapeutic evaluation and development of emerging non-psychotropic phytocannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/42121212

https://link.springer.com/article/10.1186/s42238-026-00445-5

Cannabidiol triggers fatty acids β-oxidation mediated by Stat2 to facilitate intestinal stem cells regeneration post radiation

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“The development of compounds triggering intestinal stem cells (ISCs) proliferation represents a promising strategy to alleviate irradiation (IR)-induced gastrointestinal syndrome.

Here, cannabidiol (CBD)-a nonpsychotomimetic phytocannabinoid derived from the Cannabis sativa plant-was found to dramatically improve body weight loss of mice and stimulate Lgr5+ ISCs proliferation upon a lethal dose of IR.

Using absolute quantitative lipidomics, we found that the dysregulation of fatty acids in crypts induced by IR was rescued by CBD, which was indispensable for ISCs regeneration. Integrative analysis of transcriptome and lipidomics unveiled the critical role of PPARα in regulating fatty acid β-oxidation (FAO) by transcriptionally upregulating Slc27a2 and Acox1.

Further experiments showed that CBD could trigger the enrichment of Stat2 on the promoter region of Pparα, ultimately facilitating the FAO program and subsequent ISCs proliferation following IR exposure. In addition,THOC3 was identified as a direct target of CBD, which stabilized the THOC3 protein and substantially alleviated the IR-induced blockade of Stat2 mRNA nuclear export.

This study reveals a connection between CBD-driven ISCs proliferation and the FAO program during IR damage, providing a promising avenue for IR-induced gastrointestinal syndrome treatment. The binding of CBD to THOC3 maintains its radiation stability, which then supports the nuclear export of Stat2 mRNA for the subsequent transactivation of Pparα. The upregulation of PPARα will ultimately stimulate the FAO program, thereby facilitating ISCs regeneration during IR exposure.”

https://pubmed.ncbi.nlm.nih.gov/42120478

“Cannabidiol (CBD) is a nonpsychotomimetic phytocannabinoid derived from the Cannabis sativa plant, which possesses many therapeutic properties.”

“The potent radioprotective effect and very low toxicity of CBD point to its promise as a radioprotective agent for further development.”

https://www.nature.com/articles/s12276-026-01711-5