Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker

Posted on August 14, 2025 by David

“Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD).

Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics.

Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology.

In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity.

Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders.

Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use.”

https://pubmed.ncbi.nlm.nih.gov/40806766/

“Alcohol, methamphetamine, and opioids consistently elicited Tau hyperphosphorylation in cortical and subcortical regions tied to executive function, reward processing, and memory. In contrast, certain cannabinoids and psychedelics demonstrated potential neuroprotective properties, modulating Tau-related signaling in ways that reduced aberrant phosphorylation and enhanced synaptic resilience in preclinical models. “

https://www.mdpi.com/1422-0067/26/15/7638

Opioid reduction in patients with chronic non-cancer pain undergoing treatment with medicinal cannabis

Posted on August 11, 2025 by David

“Introduction: Opioid sparing by co-prescription of cannabinoids may enable patients to reduce their opioid consumption prescribed for chronic benign pain.

Methods: One cohort attending a small private pain clinic (N = 102), already taking opioids, was co-prescribed cannabinoids and another cohort (N = 53) attending a separate pain clinic nearby received only opioids. The two groups were studied prospectively for a year before their drug consumption was assessed.

Results: At baseline, median opioid consumption was 40 mg/day in both cohorts. Medicinal cannabis was administered daily in an oil formulation usually starting at 2.5 mg/day and was titrated to maximize benefits. At 12 months, the median dose contained 15 mg delta-9-tetrahydrocannabinol and 15 mg cannabidiol. At one-year follow-up, 46 of 102 cases had dropped out compared with only one of 53 controls. Opioid consumption had decreased significantly at one-year follow-up, the final median dose being lower in cases (2.7 mg/day) than controls (42.3 mg/day) (p < 0.05 in an intention-to-treat analysis). Disability and insomnia had also decreased in cases.

Conclusion: The introduction of cannabinoids can produce useful reductions in opioid consumption in real-world settings, with additional benefits for disability and insomnia. However, this treatment is tolerated by only a subgroup of patients.”

https://pubmed.ncbi.nlm.nih.gov/40788193/

“Plain language summary

Morphine-like drugs (opioids) decrease pain but can cause severe breathing problems and death if these drugs are consumed in excessive amounts. Stopping these drugs suddenly (going “cold turkey”) can cause severe adverse effects and, as time goes on, increasing amounts may be required to reduce pain. It might be possible to reduce opioid consumption by also taking medicinal cannabis; otherwise, reduction can be difficult to achieve. Cannabis treatment is safe when the hallucinatory component of cannabis is kept to low levels, causing minimal euphoric effects (a “stoned” sensation).In this study, two groups of patients with chronic pain were studied. Both were taking opioid drugs, but one group also took medicinal cannabis. About half of the medicinal cannabis group were not able to keep taking it due to unpleasant side effects. In the remainder, opioid consumption decreased significantly after both 6 and 12 months. Physical activity and sleep also improved. These findings indicate that medicinal cannabis can help patients to reduce their opioid consumption and improve their physical activity and sleep.”

“These findings indicate that medicinal cannabis can help patients to reduce their opioid consumption and improve their physical activity and sleep.”

https://www.tandfonline.com/doi/full/10.1080/17581869.2025.2544511

NON-PSYCHOACTIVE CANNABIS EXTRACT PROMOTES EXTINCTION AND REDUCES REINSTATEMENT BY PRIMING DOSE IN SMOKED COCAINE-INDUCED CONDITIONED PLACE PREFERENCE

Posted on August 5, 2025 by David

“The therapeutic potential of Cannabis sativa L. and cannabidiol (CBD) for substance use disorders is being actively investigated using murine addiction models. However, the efficacy of cannabis or its constituents in attenuating dependence indicators associated with smoked cocaine consumption remains unclear.

This study employed a Conditioned Place Preference (CPP) paradigm using anhydroecgonine methyl ester and cocaine (AEME-COC) as the reinforcing agent to model smoked cocaine consumption in mice.

The model was utilized to evaluate the preclinical efficacy of a non-psychoactive cannabis extract (NPCE) and CBD on extinction parameters and reinstatement induced by stress and priming doses. Experiment 1 compared conditioning phase (Cond) and extinction times between subjects administered cocaine and those receiving AEME-COC. Experiment 2 investigated the effects of CBD and NPCE on extinction latency in AEME-COC-induced CPP. Experiment 3 examined the competitive 5-HT1A receptor antagonist WAY-100135 and CB2 receptor inverse agonist AM630 on NPCE-mediated inhibition of stress-induced and priming-induced reinstatement of AEME-COC-induced CPP.

The results showed that subjects administered cocaine exhibited greater exploration of the conditioned compartment during Cond compared to those administered AEME-COC, with the latter group displaying prolonged extinction latency (Experiment 1).

NPCE, but not CBD, significantly reduced the extinction latency of AEME-COC-induced CPP (Experiment 2). In Experiment 3, NPCE selectively inhibited priming-induced reinstatement but did not affect stress-induced reinstatement. The 5-HT1A receptor attenuated NPCE’s inhibitory effects on priming-induced reinstatement, whereas the CB2 receptor had no significant modulatory impact on this indicator.

These findings suggest that NPCE influences smoked cocaine dependence indicators primarily through serotonergic receptor modulation.”

https://pubmed.ncbi.nlm.nih.gov/40752858/

https://www.sciencedirect.com/science/article/pii/S0031938425002495?via%3Dihub

Cannabidiol mitigates alcohol dependence and withdrawal with neuroprotective effects in the basolateral amygdala and striatum

Posted on July 11, 2025 by David

“Alcohol use disorder (AUD) remains a pervasive public health issue with limited effective treatments. Cannabidiol (CBD), a non-psychotropic constituent of cannabis, shows promise in modulating addictive behaviors.

This study investigated the effects of chronic CBD administration on alcohol dependence, withdrawal symptoms, and neurodegeneration using two complementary rodent models: chronic intermittent ethanol (CIE) exposure, which models established alcohol dependence, and ethanol vapor self-administration (EVSA), which captures the volitional aspects of alcohol intake. In the CIE model, CBD reduced alcohol self-administration during acute withdrawal without affecting alcohol metabolism or locomotor activity.

CBD decreased motivation for alcohol, somatic withdrawal signs, withdrawal-induced anxiety-like behaviors, and mechanical sensitivity. During extinction, CBD attenuated alcohol-seeking behavior and stress-induced reinstatement. Electrophysiological recordings revealed that CBD reversed alcohol-induced decreases in neuronal excitability in the basolateral amygdala, suggesting a mechanism involving normalization of neural function. In the EVSA model, CBD reduced voluntary alcohol intake during the escalation phase, impacting voluntary alcohol intake. This effect was specific to alcohol-related behaviors, as it did not affect saccharin self-administration.

Immunohistochemical analyses showed that CBD prevented alcohol-induced neurodegeneration in the nucleus accumbens shell and dorsomedial striatum, regions implicated in the volitional control of alcohol consumption. These findings indicate that chronic CBD administration attenuates both behavioral and neurobiological facets of alcohol dependence by modulating neuronal excitability and preventing neurodegeneration, supporting its therapeutic potential for AUD and providing mechanistic insights for future research.”

https://pubmed.ncbi.nlm.nih.gov/40640509/

“In conclusion, chronic CBD administration mitigates key behavioral and neurobiological features of alcohol dependence by reducing withdrawal symptoms, lowering relapse risk, restoring BLA neuronal excitability, and preventing neurodegeneration in striatal regions. Together, these findings highlight CBD’s capacity to preserve functional integrity in neural circuits underlying emotional regulation, reward processing, and habit formation.”

https://www.nature.com/articles/s41386-025-02164-6

Cannabidiol attenuates methamphetamine-induced oxidative neurotoxicity via regulating transient receptor potential vanilloid type 1

Posted on July 1, 2025 by David

“Background: The prevalence of methamphetamine (METH) abuse has significantly escalated in many regions worldwide. Despite this increase, the complexity of neurotoxicity associated with METH is inadequately understood. Cannabidiol (CBD), a non-addictive plant ingredient in cannabis, has been used in preclinical and clinical studies for treating various neuropsychiatric disorders, but the mechanism by which CBD exerts therapeutic effects is still unclear.

Purpose: This work aims to explore the mechanism of transient receptor potential vanilloid type 1 (TRPV1) mediates oxidative neurotoxicity in the context of METH exposure and reveal the therapeutic target of CBD for METH-induced oxidative neurotoxicity.

Results: In the hippocampus and medial prefrontal cortex of METH users, overactivation of TRPV1, intracellular Ca²⁺ overload, increased oxidative stress, and elevated apoptosis were observed compared to control individuals. Molecular docking and surface plasmon resonance (SPR) detection results indicated that CBD binds to human TRPV1. In addition, METH induced Ca²⁺ influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells, which were mitigated by TRPV1 knockdown or CBD pretreatment. CBD pretreatment also blocked TRPV1 agonist capsaicin-induced Ca²⁺ influx, oxidative stress, cell damage, and TRPV1 activation in HT-22 cells. Furthermore, METH triggered stereotyped behavior, spatial memory impairment, TRPV1 activation, Ca²⁺ overload, apoptosis, and oxidative stress in the hippocampus, which were attenuated by CBD pretreatment in mice. Finally, hippocampal TRPV1 knockdown reduced METH-induced stereotyped behavior and spatial memory impairment in mice, blocked METH-induced apoptosis and oxidative stress in the hippocampus of mice.

Conclusion: METH induces oxidative neurotoxicity via activating TRPV1-dependent Ca²⁺ influx, oxidative stress, and apoptosis, while CBD inhibits METH-induced oxidative neurotoxicity by regulating TRPV1. This study establishes CBD as a therapeutic intervention for METH use disorders.”

https://pubmed.ncbi.nlm.nih.gov/40582208/

“In summary, our results suggest that METH induced oxidative neurotoxicity by activating TRPV1-dependent Ca²⁺ influx, oxidative stress, and apoptosis, while CBD pretreatment inhibited METH-induced oxidative neurotoxicity by regulating TRPV1.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711325006543?via%3Dihub

Omega-3 Fatty Acids Mitigate Long-Lasting Disruption of the Endocannabinoid System in the Adult Mouse Hippocampus Following Adolescent Binge Drinking

Posted on June 28, 2025 by David

“Adolescent binge drinking has lasting behavioral consequences by disrupting the endocannabinoid system (ECS) and depleting brain omega-3.

The natural accumulation of omega-3 fatty acids in cell membranes is crucial for maintaining the membrane structure, supporting interactions with the ECS, and restoring synaptic plasticity and cognition impaired by prenatal ethanol (EtOH) exposure. However, it remains unclear whether omega-3 supplementation can mitigate the long-term effects on the ECS, endocannabinoid-dependent synaptic plasticity, and cognition following adolescent binge drinking.

Here, we demonstrated that omega-3 supplementation during EtOH withdrawal increases CB1 receptors in hippocampal presynaptic terminals of male mice, along with the recovery of receptor-stimulated [³⁵S]GTPγS binding to Gαi/o proteins. These changes are associated with long-term potentiation (LTP) at excitatory medial perforant path (MPP) synapses in the dentate gyrus (DG), which depends on anandamide (AEA), transient receptor potential vanilloid 1 (TRPV1), and N-methyl-D-aspartate (NMDA) receptors. Finally, omega-3 intake following binge drinking reduced the time and number of errors required to locate the escape box in the Barnes maze test.

Collectively, these findings suggest that omega-3 supplementation restores Barnes maze performance to levels comparable to those of control mice after adolescent binge drinking. This recovery is likely mediated by modulation of the hippocampal ECS, enhancing endocannabinoid-dependent excitatory synaptic plasticity.”

https://pubmed.ncbi.nlm.nih.gov/40564971/

“In summary, omega-3 intake mitigates some of the adverse effects of adolescent binge drinking on Barnes maze performance.”

“Omega-3 supplementation has also been shown to reverse synaptic plasticity impairments caused by prenatal EtOH exposure.”

https://www.mdpi.com/1422-0067/26/12/5507

“Hemp (Cannabis sativa L.) is a valuable source of omega-3 fatty acids.”

The effect of cannabidiol on neurometabolite levels in alcohol use disorder

Posted on June 25, 2025 by David

“Background and aims: Preclinical research demonstrates that cannabidiol (CBD) attenuates alcohol-seeking behaviour and may have a neuroprotective effect against adverse alcohol consequences on the brain. This preliminary clinical study aimed to examine the effect of CBD on modulating neurometabolites in individuals with Alcohol Use Disorder (AUD).

Methods: Twenty-two non-treatment seeking participants were randomized to receive 800 mg CBD or matched placebo/day in a crossover double-blind, randomized trial. Presence of GABA+, NAA, Glx, Cho, and glutathione (GSH) in the dorsal anterior cingulate cortex was measured using in vivo proton magnetic resonance spectroscopy (1H-MRS) in each session.

Results: There were no significant treatment effects across each of the neurometabolites (p’s ≥ .28) but post hoc analyses revealed significant treatment effects when considering recent alcohol consumption. Specifically, CBD sessions were associated with significantly higher GSH (P < .001) and GLx (p = .001) concentrations relative to placebo sessions for participants who consumed alcohol the previous day while this effect was not observed in those who were abstinent. Similarly, GABA concentrations were significantly higher during CBD sessions and lower during placebo sessions for participants who consumed alcohol the previous day and this relationship was not observed for individuals who were abstinent the previous day (P = .0024).

Conclusion: The effect of CBD on modulating levels of neurometabolites may be contingent on recent alcohol consumption. These preliminary results suggest that CBD may regulate abnormal neurometabolite concentrations the day following alcohol consumption and thus may have a role in management of AUD.”

https://pubmed.ncbi.nlm.nih.gov/40551671/

Combination of Cannabidiol and Low-Dose Buprenorphine Suggests Synergistic Analgesia and Attenuates Buprenorphine-Induced Respiratory Depression

Posted on June 5, 2025 by David

“Introduction: As opioid-related drug overdoses remain a public health crisis, there is a critical need for innovative approaches to developing safer analgesics with improved safety profiles. BDH-001 is a fixed-dose combination of low-dose buprenorphine (BUP) and cannabidiol (CBD) being developed as a safer analgesic than currently available opioids. The purpose of this study was to examine the analgesic and opioid-sparing effects of BDH-001 and to complete an in vivo safety assessment in rats.

Methods: Analgesic effect of BDH-001 was assessed using the chronic constriction injury model of chronic neuropathic pain with pain threshold assessed via Von Frey testing. Drug-drug interaction effects on pharmacokinetic (PK) parameters were assessed in a single dose PK study in rodents. The effects on respiratory depression were also assessed and confirmed in two separate rodent studies performing blood gas analysis and measuring O₂ saturation.

Results: BDH-001 (combination of subanalgesic BUP dose and CBD) resulted in statistically significant increases in pain threshold compared to saline (p < 0.001), CBD alone (p < 0.01), and BUP alone (p < 0.05). The half-life of BUP was significantly shorter in the presence of CBD compared to BUP alone (p = 0.008), with no significant changes in any other BUP pharmacokinetic parameter assessed. CBD was found to attenuate BUP-induced respiratory depression in rats when assessing blood gases (p < 0.05) and O₂ saturation (p < 0.05) over several time bins.

Conclusions: Data obtained in the present study indicate the addition of CBD to BUP was opioid-sparing and attenuated BUP- but not morphine-induced respiratory depression. There was no evidence these findings were the result of a PK interaction. Results support the hypothesis that BDH-001, a fixed-dose combination of BUP and CBD, may provide effective analgesia with a more favorable safety profile.”

https://pubmed.ncbi.nlm.nih.gov/40468945/

https://www.liebertpub.com/doi/10.1089/can.2025.0004

“Buprenorphine is a medication that plays a crucial role in treating opioid use disorder (OUD), also known as opioid addiction. It works by partially activating the same receptors in the brain as opioids, helping to reduce withdrawal symptoms and cravings without producing the intense euphoria or dangerous side effects associated with full opioid agonists like heroin or fentanyl.”

Cannabidiol dose dependently reduces alcohol intake in mice via a non-5-HT1A receptor mechanism: Exploration of other potential receptor targets

Posted on May 28, 2025 by David

“Background and purpose: Binge drinking is a risky pattern of alcohol intake and a major predictor of alcohol use disorder (AUD). Current AUD medications have limited efficacy and poor patient compliance, calling for more effective therapeutics. Cannabidiol (CBD), a non-intoxicating component of cannabis, has emerged as a potential novel therapeutic. However, receptor mechanisms in CBD’s alcohol-related effects have not been investigated comprehensively.

Experimental approach: Using the murine drinking-in-the-dark model of binge drinking, our research aimed to confirm a reduction of alcohol consumption with CBD (7.5, 15, 30, 60, 120 mg kg^-1) in male and female mice. Behavioural pharmacological approaches were used to explore CBD interactions with identified target mechanisms: serotonin-1A receptor (5-HT_1AR) and peroxisome proliferator-activated receptor-gamma (PPARɣ), and the novel targets, chemokine receptor type-4 (CXCR4) and neuropeptide S receptor (NPSR).

Key results: Acute CBD dose dependently suppressed binge-like drinking and blood ethanol concentration. The effect was not driven by locomotor impairments and was maintained across sub-chronic treatment. Blockade of 5-HT_1AR and PPARɣ had no impact on CBD’s reduction of alcohol consumption. Co-administration of subthreshold CBD doses and a NPSR antagonist implicated NPSR blockade as a potential mechanism contributing to CBD’s effect, whereas co-administration of CBD and a CXCR4 antagonist suggested CXCR4 was not involved. However, the potent and selective CXCR4 antagonist AMD3100 reduced ethanol consumption.

Conclusions and implications: CBD represents a promising candidate to reduce voluntary alcohol consumption. Mechanisms driving CBD’s alcohol-related effects remain unclear and may involve polypharmacology, including actions at the NPSR identified in the present study.”

https://pubmed.ncbi.nlm.nih.gov/40432283/

“These experiments consistently showed a dose-dependent suppression of alcohol consumption by CBD.”

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70070

Effects of legal access versus illegal market cannabis on use and mental health: A randomized controlled trial

Posted on May 10, 2025 by David

“Aims: We measured the effects of public health-oriented cannabis access compared with the illegal market on cannabis use and related mental health outcomes in adult cannabis users.

Design: This was a two-arm, parallel group, open-label, randomized controlled trial. Follow-up outcome measurement took place after 6 months.

Setting: The study was conducted in Basel-Stadt, Switzerland.

Participants: A total of 378 adult (aged ≥18 years) cannabis users were enrolled and randomized between August 2022 and March 2023, although only 374 users who completed baseline measures could be included.

Intervention and comparator: Participants were randomly assigned to the intervention group with public health-oriented recreational cannabis access in pharmacies (regulated cannabis products, safer use information, voluntary counseling, no advertisement; 189/188) or the illegal market control group (continued illicit cannabis sourcing; 189/186).

Measurements: The primary outcome was self-reported severity of cannabis misuse after 6 months, as measured by the Cannabis Use Disorders Identification Test – Revised (range 0-32). Secondary outcomes involved depressive, anxiety, and psychotic symptoms, cannabis consumption amount, alcohol, and drug use.

Findings: Ten participants were not followed (2.7%). Primary analysis included those with complete data (182 vs. 182). There was some evidence of a difference in cannabis misuse between the legal cannabis intervention group (mean [M] = 10.1) and the illegal market control group (M = 10.9; β = -0.69, 95% confidence interval [CI] = -1.4 to 0.0, P = 0.052). These results were supported by an intention-to-treat multiple imputation analysis (n = 374). Additional sub-group analysis by whether the participant used other drugs or not suggested that any reduction in cannabis misuse was confined to those in the legal cannabis intervention group who used other drugs (P_Interaction < 0.001). We found no statistically significant changes in any of the secondary outcomes.

Conclusions: Public health-oriented recreational cannabis access may decrease cannabis use and cannabis-related harms, especially among those using other drugs.”

https://pubmed.ncbi.nlm.nih.gov/40289676/

“Our results indicate that public health-oriented RCL could be an effective policy model to make cannabis safer without increasing cannabis use and cannabis-related harms.”

https://onlinelibrary.wiley.com/doi/10.1111/add.70080

“Cannabis study finds legalization reduces problematic consumption, especially among those using other drugs”

https://medicalxpress.com/news/2025-05-cannabis-legalization-problematic-consumption-drugs.html

“Researchers uncover causal evidence that cannabis legalization reduces problematic consumption”

Researchers uncover causal evidence that cannabis legalization reduces problematic consumption

“Legal Cannabis Linked to Less Problematic Use, Better Mental Health”

Legal Cannabis Linked to Less Problematic Use, Better Mental Health

www.thctotalhealthcare.com

Category Archives: Addiction