Do tobacco and cannabis use and co-use predict lung function: A longitudinal study

Respiratory Medicine | Journal | by Elsevier

“Background: Use of tobacco and cannabis is common and has been reported to predict lung function. Less is known about co-use of tobacco and cannabis and their impact on changes in lung function to early adulthood.

Research question: The study examines whether cigarette smoking or cannabis use and co-use are each associated with lung function in a population sample of young adults.

Study design and methods: Data are from a prospective cohort study of cigarette smoking, cannabis use and co-use at 21 and 30 years of age and lung function (FVC, FEV1, FEV1/FVC) measured at 30 years. Lung function results are transformed using Global Lung Function Formulae. Subjects are the children of pregnant women who were recruited into the cohort study over the period 1981-3. Respondents were administered a spirometry assessment at 21 and 30 years of age. These respondents completed a smoking and cannabis use questionnaire at 21- and 30-year follow-ups.

Results: Cigarette smoking (with or without cannabis use) is associated with reduced airflow. There is no consistent association between cannabis use and measures of lung function. The co-use of tobacco and cannabis appears to entail no additional risk to lung function beyond the risks associated with tobacco use alone.

Interpretation: Persistent cigarette smoking is associated with reduced airflow even in young adults. Cannabis use does not appear to be related to lung function even after years of use.”

“•Cigarette smoking and cannabis use and co-use are risk factors for impaired lung function.

By 30 years, those who have smoked cigarettes since adolescence already show evidence of impairment of lung function.

By 30 years, those who used cannabis since the adolescent period do not appear to have evidence of impaired lung function.

Co-use of tobacco and cannabis does not appear to predict lung function beyond the effects of tobacco use alone.”

“Smoking Cannabis Not Associated With Impaired Lung Functioning In Latest Study”

Changes in Prescribed Opioid Dosages Among Patients Receiving Medical Cannabis for Chronic Pain, New York State, 2017-2019

JAMA editors name the journal's best articles of the decade | American  Medical Association

“Importance: Patients with chronic pain often receive long-term opioid therapy (LOT), which places them at risk of opioid use disorder and overdose. This presents the need for alternative or companion treatments; however, few studies on the association of medical cannabis (MC) with reducing opioid dosages exist.

Objective: To assess changes in opioid dosages among patients receiving MC for longer duration compared with shorter duration.

Design, setting, and participants: This cohort study of New York State Prescription Monitoring Program data from 2017 to 2019 included patients receiving MC for chronic pain while also receiving opioid treatment. Of these, patients receiving LOT prior to receiving MC were selected. Individuals were studied for 8 months after starting MC. Data were analyzed from November 2021 to February 2022.

Exposures: Selected patients were divided into 2 groups based on the duration of receiving MC: the nonexposure group received MC for 30 days or fewer, and the exposure group received MC for more than 30 days.

Main outcomes and measures: The main outcome was opioid dosage, measured by mean daily morphine milligram equivalent (MME). Analyses were conducted for 3 strata by opioid dosage prior to receiving MC: MME less than 50, MME of 50 to less than 90, and MME of 90 or greater.

Results: A total of 8165 patients were included, with 4041 (median [IQR] age, 57 [47-65] years; 2376 [58.8%] female) in the exposure group and 4124 (median [IQR] age, 54 (44-62) years; 2370 [57.5%] female) in the nonexposure group. Median (IQR) baseline MMEs for the exposure vs nonexposure groups were 30.0 (20.0-40.0) vs 30.0 (20.0-40.0) in the lowest stratum, 60.0 (60.0-70.0) vs 60.0 (60.0-90.0) in the middle stratum, and 150.0 (100.0-216.2) vs 135.0 (100.0-218.0) in the highest stratum. During follow-up, significantly greater reductions in opioid dosage were observed among the exposure group. A dose-response association of patients’ opioid dosage at baseline was observed with the differences in the monthly MME reductions between exposure and nonexposure groups, with a difference of -1.52 (95% CI, -1.67 to -1.37) MME for the lowest stratum, -3.24 (95% CI, -3.61 to -2.87) MME for the middle stratum, and -9.33 (95% CI, -9.89 to -8.77) MME for the highest stratum. The daily MME for the last month of the follow-up period among patients receiving longer MC was reduced by 48% in the lowest stratum, 47% in the middle stratum, and 51% in the highest stratum compared with the baseline dosages. Among individuals in the nonexposure group, daily MME was reduced by only 4% in the lowest stratum, 9% in the middle stratum, and 14% in the highest stratum.

Conclusions and relevance: In this cohort study of patients receiving LOT, receiving MC for a longer duration was associated with reductions in opioid dosages, which may lower their risk of opioid-related morbidity and mortality.”

“This cohort study found that receiving MC for longer was associated with opioid dosage reductions. The reductions were larger among individuals who were prescribed higher dosages of opioids at baseline. These findings contribute robust evidence for clinicians regarding the potential benefits of MC in reducing the opioid burden for patients receiving LOT and possibly reduce their risk for overdose.”

“State DOH: Medical cannabis may reduce opioid burden in managing chronic pain”

Inhaled Δ9-tetrahydrocannabinol does not enhance oxycodone-induced respiratory depression: randomised controlled trial in healthy volunteers

British Journal of Anaesthesia | The Royal College of Anaesthetists

“Background: In humans, the effect of cannabis on ventilatory control is poorly studied, and consequently, the effect of Δ9-tetrahydrocannabinol (THC) remains unknown, particularly when THC is combined with an opioid. We studied the effect of THC on breathing without and with oxycodone pretreatment. We hypothesised that THC causes respiratory depression, which is amplified when THC and oxycodone are combined.

Methods: In this randomised controlled crossover trial, healthy volunteers were administered inhaled Bedrocan® 100 mg (Bedrocan International B.V., Veendam, The Netherlands), a pharmaceutical-grade high-THC cannabis variant (21.8% THC; 0.1% cannabidiol), after placebo or oral oxycodone 20 mg pretreatment; THC was inhaled 1.5 and 4.5 h after placebo or oxycodone intake. The primary endpoint was isohypercapnic ventilation at an end-tidal Pco2 of 55 mm Hg or 7.3 kPa (VE55), measured at 1-h intervals for 7 h after placebo/oxycodone intake.

Results: In 18 volunteers (age 22 yr [3]; 9 [50%] female), oxycodone produced a 30% decrease in VE55, whereas placebo was without effect on VE55. The first cannabis inhalation resulted in VE55 changing from 20.3 (3.1) to 23.8 (2.4) L min-1 (P=0.06) after placebo, and from 11.8 (2.8) to 13.0 (3.9) L min-1 (P=0.83) after oxycodone. The second cannabis inhalation also had no effect on VE55, but slightly increased sedation.

Conclusions: In humans, THC has no effect on ventilatory control after placebo or oxycodone pretreatment.”

“In pain management, the use of THC or its combination with an opioid can be advantageous, as the combination has an opioid-sparing effect.

However, this is only of advantage provided the combination of these two drug classes does not exacerbate opioid-induced respiratory depression.

In this study, we examined the effect of inhaled medicinal-grade cannabis, containing a high THC dose, on ventilatory control in healthy human volunteers with placebo or oxycodone pretreatment. 

THC has no effect on ventilatory control after placebo or oxycodone pretreatment.

In summary, in human volunteers, THC has no significant effect on ventilatory control after placebo or oxycodone pretreatment.”

Recreational cannabis and opioid distribution

“Twenty-one U.S. states have passed recreational cannabis laws as of November 2022. Cannabis may be a substitute for prescription opioids in the treatment of chronic pain. Previous studies have assessed recreational cannabis laws’ effects on opioid prescriptions financed by specific private or public payers or dispensed to a unique endpoint.

Our study adds to the literature in three important ways: by (1) examining these laws’ impacts on prescription opioid dispensing across all payers and endpoints, (2) adjusting for important opioid-related policies such as opioid prescribing limits, and (3) modeling opioids separately by type. We implement two-way fixed-effects regressions and leverage variation from eleven U.S. states that adopted a recreational cannabis law (RCL) between 2010 and 2019.

We find that RCLs lead to a reduction in codeine dispensed at retail pharmacies. Among prescription opioids, codeine is particularly likely to be used non-medically. Thus, the finding that RCLs appear to reduce codeine dispensing is potentially promising from a public health perspective.”

“When recreational cannabis is legal, codeine demand drops”

Cannabidiol repairs behavioral and brain disturbances in a model of fetal alcohol spectrum disorder

Pharmacological Research

“Fetal alcohol spectrum disorder (FASD) includes neuropsychiatric disturbances related to gestational and lactational ethanol exposure. Available treatments are minimal and do not modulate ethanol-induced damage. Developing animal models simulating FASD is essential for understanding the underlying brain alterations and searching for efficient therapeutic approaches. The main goal of this study was to evaluate the effects of early and chronic cannabidiol (CBD) administration on offspring exposed to an animal model of FASD. Ethanol gavage (3g/kg/12h, p.o.) was administered to C57BL/6J female mice, with a previous history of alcohol consumption, between gestational day 7 and postnatal day 21. On the weaning day, pups were separated by sex, and CBD administration began (30mg/kg/day, i.p.). After 4-6 weeks of treatment, behavioral and neurobiological changes were analyzed. Mice exposed to the animal model of FASD showed higher anxiogenic and depressive-like behaviors and cognitive impairment that were evaluated through several experimental tests. These behaviors were accompanied by alterations in the gene, cellular and metabolomic targets. CBD administration normalized FASD model-induced emotional and cognitive disturbances, gene expression, and cellular changes with sex-dependent differences. CBD modulates the metabolomic changes detected in the hippocampus and prefrontal cortex. Interestingly, no changes were found in mitochondria or the oxidative status of the cells. These results suggest that the early and repeated administration of CBD modulated the long-lasting behavioral, gene and protein alterations induced by the FASD model, encouraging the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.”

“The results of the present study reveal that the early and chronic administration of CBD repairs the emotional and cognitive alterations observed in male and female mice exposed to the animal model of FASD. Likewise, CBD modulates sex-dependently the gene expression changes and metabolomic targets affected by the model exposure. Interestingly, the data suggest the absence of mitochondrial and oxidative targets in CBD-induced modulation, pointing out that lipid and protein metabolism could be another pathway involved in the cellular reparation observed after CBD chronic administration. The modulation of Pparβ/δ gene expression could be one of the multiple targets involved in CBD’s induced cellular reparation and behavioral modulation. However, further studies are required to explore the real implication of this target in CBD’s mechanism of action in this model of FASD. Taken together, these results strongly stimulate the possibility of performing clinical trials to evaluate the effects of CBD in children affected with FASD.”

Cannabidiol Reduced the Severity of Gastrointestinal Symptoms of Opioid Withdrawal in Male and Female Mice

View details for Cannabis and Cannabinoid Research cover image

“Introduction: Opioid withdrawal is a powerful driver of drug-seeking behavior as relief from this aversive state through drug-taking is a strong negative reinforcer. There are currently limited treatment options available for opioid withdrawal and cannabidiol (CBD) has been identified as a potential novel therapeutic. This study explored the efficacy and dose dependency of CBD for reducing the severity of naloxone-precipitated and spontaneous oxycodone withdrawal (PW and SW, respectively) in male and female mice. 

Methods: Mice were administered saline or escalating doses of oxycodone, whereby 9, 17.8, 23.7, and 33 mg/kg oxycodone IP was administered twice daily on days 1-2, 3-4, 5-6, and 7-8, respectively. On the 9th day, a single 33 mg/kg dose of oxycodone (or saline) was administered. To precipitate withdrawal, on day 9, mice in the withdrawal conditions were administered an IP injection of 10 mg/kg naloxone 2 h after the final oxycodone injection and immediately before withdrawal testing. To elicit SW, a separate group of mice underwent withdrawal testing 24 h after their final oxycodone injection. Mice were treated with an IP injection of 0, 10, 30 or 100 mg/kg of CBD 60 min before testing. Withdrawal symptoms examined included gastrointestinal symptoms (fecal boli, diarrhea, and body weight loss), somatic symptoms (paw tremors), and negative affect (jumping). 

Results: A robust PW syndrome was observed in both male and female mice, whereas only male mice displayed an SW syndrome. CBD dose dependently reduced gastrointestinal symptoms during both PW and SW in male mice and during PW in female mice. CBD had no effect on PW- or SW-induced jumping in male mice. However, in female mice, the PW-induced increase in jumps was less pronounced in CBD-treated mice. The highest dose of CBD inhibited paw tremors during PW, but not SW, in male mice. Neither PW- nor SW-induced paw tremors were observed in female mice. 

Conclusions: The magnitude of effects on the gastrointestinal symptoms, their consistency across PW and SW, and both sexes, alongside the availability of CBD for clinical use, suggest further exploration of the potential for CBD to treat these symptoms could be justified.”

Drug-Drug Interaction Between Orally Administered Hydrocodone-Acetaminophen and Inhalation of Cannabis Smoke: A Case Report

SAGE Journals Home

“Objective: To determine if a 2-day protocol measuring pharmacokinetic and pharmacodynamic characteristics can demonstrate drug-drug interactions when smoked cannabis is added to orally administered hydrocodone/acetaminophen combination products.

Case summary: A 51-year-old non-Hispanic white male with chronic pain diagnoses participated in a 2-day pilot protocol. The participant attended two 7-hour in-lab days where he received 10 blood draws each day and completed self-administered pain and anxiety surveys. For both days, the participant took his prescribed dose of hydrocodone/acetaminophen (1/2 tablet of 7.5 mg/325 mg combination product) with the addition of 1 smoked pre-rolled marijuana cigarette (labeled as 0.5 g; 22.17% Δ9-tetrahydrocannabinol; 0.12% cannabidiol) on Day 2. Blood specimens were analyzed using mass spectrometry to quantify the difference of plasma hydrocodone levels between Day 1 and Day 2.

Results: Compared to Day 1, lower levels of pain and anxiety were reported during Day 2 with the addition of cannabis to oral hydrocodone/acetaminophen. Day 2 pharmacokinetic analysis also revealed more rapid absorption and overall lower levels of hydrocodone in plasma.

Discussion: Lower hydrocodone plasma levels in Day 2 may indicate cannabis’s effect on metabolism and reduce the risk of opioid toxicity. The quicker absorption rate of hydrocodone could explain lower pain and anxiety scores reported on the second day.

Conclusion and relevance: A 2-day protocol was able to capture differences across time in pharmacokinetic and pharmacodynamic measurements. Larger studies can be designed to better characterize the potential drug-drug interaction of cannabis and opioids.”

Cannabinoids inhibit ethanol-induced activation of liver toxicity in rats through JNK/ERK/MAPK signaling pathways

“Cannabinoids (CBs) are psychoactive compounds, with reported anticancer, anti-inflammatory, and anti-neoplastic properties. The study was aimed at assessing the hepatoprotective effects of CB against ethanol (EtOH)-induced liver toxicity in rats. The animals were divided into seven groups: control (Group I) and Group II were treated with 50% ethanol (EtOH 5 mg/kg). Groups III, IV, and VI were treated with (EtOH + CB 10 mg/kg), (EtOH + CB 20 mg/kg), and (EtOH + CB 30 mg/kg), respectively. Groups V and VII consisted of animals treated with 20 and 30 mg/kg, of CB, respectively. Biochemical analysis revealed that Group IV (EtOH + CB 20 mg/kg) had reduced levels of ALT-alanine transferase, AST-aspartate aminotransferase, ALP-alanine peroxidase, MDA-malondialdehyde and increased levels of GSH-reduced glutathione. Histopathological analysis of liver and kidney tissues showed that EtOH + CB (20 and 30 mg/kg) treated animal groups exhibited normal tissue architecture similar to that of the control group. ELISA revealed that the inflammatory markers were reduced in the animal groups that were treated with EtOH + CB 20 mg/kg, in comparison to the animals treated only with EtOH. The mRNA expression levels of COX-2, CD-14, and MIP-2 showed a remarkable decrease in EtOH + CB treated animal groups to control groups. Western blot analysis revealed that CB downregulated p38/JNK/ERK thereby exhibiting its hepatoprotective property by inhibiting mitogen-activated protein kinase pathways. Thus, our findings suggest that CB is a potential candidate for the treatment of alcohol-induced hepatotoxicity.”

Alleviation of opioid withdrawal by cannabis and delta-9-tetrahydrocannabinol: A systematic review of observational and experimental human studies

Drug and Alcohol Dependence

“Background: While six U.S. states have already officially authorized cannabinoids to substitute opioids and treat opioid use disorder, the therapeutic benefits of cannabinoids remain unclear, especially when weighted against their adverse effects.

Methods: We conducted a systematic review of studies examining the association between opioid withdrawal and cannabis use or delta-9-tetrahydrocannabinol (THC) administration. We searched multiple databases from inception to July 30, 2022, and assessed study quality.

Results: Eleven studies were identified, with a total of 5330 participants, of whom 64 % were male. Nine observational studies examined the association between cannabis use and opioid withdrawal. Two randomized, placebo-controlled clinical trials (RCTs) investigated the withdrawal-alleviating effects of dronabinol, a synthetic form of THC. Four observational studies found an association between cannabis use and the alleviation of opioid withdrawal; one reported exacerbation of opioid withdrawal symptoms; and four reported no association. RCTs reported that THC alleviated opioid withdrawal, albeit with dose-dependent increases in measures of abuse liability, dysphoria, and tachycardia. There was high heterogeneity in measurements of opioid withdrawal and the type and dose of opioid at baseline.

Conclusions: Although there is preliminary evidence that cannabis and its main psychoactive constituent, THC, may alleviate opioid withdrawal, these effects are likely to have a narrow therapeutic window. Further, the potential of cannabinoids to alleviate opioid withdrawal is determined by complex interactions between patient characteristics and pharmacological factors. Collectively, these findings have clinical, methodological, and mechanistic implications for treating opioid withdrawal during cannabinoid use, and for efforts to alleviate opioid withdrawal using non-opioid therapeutics.”

A 1:1 ratio of cannabidiol: tetrahydrocannabinol attenuates methamphetamine conditioned place preference in mice: A prospective study of antidopaminergic mechanism

Brain Research Bulletin

“A 1:1 ratio of cannabidiol to tetrahydrocannabinol (CT) was suggested to be safer for therapeutic purposes in many illnesses. However, CT effects on methamphetamine (METH) conditioned place preference (CPP) remained largely unexplored. This study aimed to examine the effects of CT on METH CPP mice evaluated by animal behaviors accompanied by local field potential (LFP) signals analysis. Male ICR mice were implanted with the LFP electrode in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Animals were next subjected to induce METH CPP by peritoneal injection with 1mg/kg METH and 0.9% NaCl on an alternate day for ten sessions and confined to the corresponding compartment for 30min meanwhile control mice were given normal saline all day for both compartments. On testing day, either 10mg/kg CT or 20mg/kg bupropion (BP), a dopamine reuptake inhibitor, and VTA GABAergic suppressor were orally administered before CPP testing. The results exposed that CPP scores elevation was observed in the METH+vehicle and METH+BP mice, but this was reversed by CT treatment. Although both METH+vehicle and METH+BP enhanced the VTA delta power, NAc gamma I power, NAc delta-gamma coupling, and VTA-NAc gamma I coherence, changes in opposite trends of all mentioned parameters were seen by CT application. These improvements were postulated to involve the antidopaminergic effects of CT via modulations of neural signaling in the VTA and NAc. Altogether, the evidence-based study may suggest the using CT in alternative drugs for METH-seeking and craving therapy.”

“From the encouraging results, the CT would be developed and deployed as a novel drug for the treatment of METH dependence.”