The DOI matches its Crossref record; 72 of the 72 references it cites were found in a registry or an index; none of the 40 sources its claims cite is checked for support yet.
Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis
Open accessAbstract
Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED 50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED 50 of morphine alone. In addition, the ED 50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED 50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.
Overview
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Written from the paper’s full text.
TL;DR
This systematic review and meta-analysis found robust preclinical evidence that cannabinoids, especially delta-9-THC, can reduce opioid doses needed for equivalent antinociception, but clinical evidence for an opioid-sparing effect was very limited and low quality. The authors conclude that high-quality controlled clinical trials are needed.
Key findings
- Nineteen preclinical and nine clinical studies met inclusion criteria; 17 of 19 preclinical studies provided evidence of synergistic opioid–cannabinoid effects.
- Meta-analysis of preclinical studies found the median effective dose (ED50) of morphine co-administered with delta-9-THC was 3.6 times lower than morphine alone (95% CI 1.95, 6.76; n = 6), and the ED50 of codeine co-administered with delta-9-THC was 9.5 times lower than codeine alone (95% CI 1.6, 57.5; n = 2).
- Among clinical studies, one case series (n = 3) provided very low-quality evidence of reduced opioid requirements with cannabinoid co-administration; larger controlled studies rarely reported opioid dose changes and showed mixed findings for analgesia.
- GRADE ratings of clinical studies were: one very low, three low, two moderate, and three high quality; none of the high-quality studies provided evidence of an opioid-sparing effect.
Methods
- Systematic review conducted according to PRISMA, searching Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase on October 29, 2015, with no date limits; eligible studies included human or animal studies with outcomes of pain/analgesia or opioid requirements from concurrently administered opioids and cannabinoids, including controlled clinical studies and case series.
- Preclinical studies were narratively reviewed; six studies with sufficient data were meta-analyzed for morphine and two for codeine, using log10 ED50 values, inverse variance, and a random effects model because of heterogeneity; a funnel plot assessed publication/small study bias.
- Clinical studies were heterogeneous and not suitable for meta-analysis, so a narrative synthesis was conducted with quality scored using GRADE criteria.
Limitations
- The paper states that preclinical studies used a range of animal populations, antinociceptive assays, opioids, and cannabinoids, often with small numbers of animals per group, resulting in statistical heterogeneity; funnel plot interpretation was limited because fewer than 10 studies were included.
- The paper states that no studies examined the opioid-sparing effect of cannabidiol alone, delta-9-THC:CBD outside a 1:1 ratio, or other cannabinoids, and that the lack of high-quality human studies means evidence for opioid-sparing is largely limited to preclinical studies.
- Clinical limitations stated in the paper include lack of placebo control, difficulty extrapolating from experimental to clinical pain, use of single doses, small sample sizes, mixed study design quality, subtherapeutic morphine doses in one study, fixed cannabinoid dose ranges, and discouraging opioid dose reduction in another study; evident from the text, only one very low-quality clinical study directly showed an opioid-sparing effect.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, while one of the nine clinical studies identified provided very low-quality evidence of such an effect.”
- Also stated in: § Discussion · plain
“An opioid-sparing effect of cannabinoids in chronic pain patients was observed in only one very low-quality clinical study.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED 50 ) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% CI 1.95, 6.76; n = 6) than the ED 50 of morphine alone.”
- Also stated in: § Meta-Analysis of Pre-Clinical Studies · hedged
“When back-transformed to the original units, the response ratio was 3.6 (95% CI 1.95, 6.76), indicating that the median effective dose (ED 50 ) of morphine was 3.6 times lower when given in combination with delta-9-THC compared to when morphine was administered alone.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Meta-Analysis of Pre-Clinical Studies · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration.”
- Also stated in: § Summary of Pre-Clinical Studies · boosted
“Most studies (17 of the 19) demonstrated that combining a cannabinoid with an opioid resulted in a synergistic effect on analgesia compared to the analgesic effects of the individual drugs.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Summary of Pre-Clinical Studies · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“One case series (n = 3) provided very low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration.”
- Also stated in: § Discussion · plain
“One case series provided very low-quality evidence of a reduction in opioid dose requirements with cannabinoid co-administration (Lynch et al, 2003).”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
What the sources say
- Not checked yetcites Lynch et al, 2003 source
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, the ED 50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n = 2) than the ED 50 of codeine alone.”
- Also stated in: § Meta-Analysis of Pre-Clinical Studies · hedged
“When back-transformed to the original units, the response ratio was 9.5 (95% CI 1.6, 57.5), indicating that the ED 50 of codeine was 9.5 times lower when given in combination with delta-9-THC compared to when codeine was administered alone.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Meta-Analysis of Pre-Clinical Studies · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nineteen pre-clinical and nine clinical studies met the search criteria.”
- Also stated in: § Results · plain
“The initial searches identified 3019 records after duplicates were removed, with 19 pre-clinical and nine clinical studies identified for inclusion in the final review”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Results · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nine clinical studies with 750 participants provided data relevant to the research question (Table 2); however, the heterogeneous nature of the studies precluded meta-analysis.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Results from Clinical Studies
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- Probably not a substantial claim. 18
- It may state two separate claims as one. 24
- The quote only partly states this claim. 3
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Despite the growing body of relevant literature, to date no systematic review has focused on the opioid-sparing effects of cannabinoids.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Introduction
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The nine clinical studies identified were heterogeneous in design and outcomes, and therefore not suitable for meta-analysis.”
- Also stated in: § Results from Clinical Studies · plain
“Nine clinical studies with 750 participants provided data relevant to the research question (Table 2); however, the heterogeneous nature of the studies precluded meta-analysis.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Clinical studies
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Results from Clinical Studies · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Authors of the other studies were contacted in an attempt to include additional studies in the meta-analysis; however, no additional data were identified to enable the inclusion of any additional studies.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Pre-clinical studies
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The initial searches identified 3019 records after duplicates were removed, with 19 pre-clinical and nine clinical studies identified for inclusion in the final review (see Figure 1 for the PRISMA diagram).”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The clinical studies were rated using the GRADE criteria.One study provided very low-quality evidence, three studies provided low-quality evidence, two studies provided moderate-quality evidence, and three randomized controlled trials provided high-quality evidence.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Quality Ratings of Clinical Studies
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All data were extracted by one of the authors (SN, PS, or JT) and checked by a second author (SN, PS, or JT).”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Data Extraction and Outcomes
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Titles were screened by two authors (SN and PS).Where inconsistencies were identified, the authors were able to reach consensus on each occasion.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Search
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“When required data were missing, attempts were made to contact authors of published reports to collect additional information.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Data Extraction and Outcomes
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“We conducted a systematic search of the literature in accordance with recommendations by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al, 2009).”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Search
What the sources say
- Not checked yetcites Moher et al, 2009 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Thus, a narrative synthesis was conducted instead, with all studies scored for quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (Guyatt et al, 2008).”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Clinical studies
What the sources say
- Not checked yetcites Guyatt et al, 2008 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“When calculating the continuous outcome of an equally effective opioid dose (e.g. the log 10 ED 50 for morphine when administered alone versus when administered with a cannabinoid), the inverse variance statistical method and random effects model were used to compensate for study heterogeneity.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Pre-clinical studies
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“A funnel plot was produced to examine publication bias and small study effects in the pre-clinical studies included in the meta-analysis.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Assessment of bias in pre-clinical studies
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While the outcomes of pre-clinical studies are often consistent with clinical studies, pre-clinical studies may overrepresent effects.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the findings from clinical trials are inconsistent, with some studies found to have important limitations such as a lack of placebo control.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Pre-treatment with CP 55,940 resulted in a mean leftward shift to of -6.73-fold.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Pugh 1996 source
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Greater than additive effect observed, clear leftward shift of graph”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Reche 1996 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Antinociception from the combination appeared to be achieved without an increase in abuse liability”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Pugh 1996 source
Strength:hedged· not yet calibratedn = 3Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Tolerance to morphine alone rapidly established; no loss of effect with low-dose combinations of morphine + delta-9-THC”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Smith 2007 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Potency ratio: 8.5”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Smith 1998 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The rats trained for drug discrimination tasks had received repeated administration of opioids and cannabinoids over many months and may have been tolerant to drug effects at the doses administered”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Wakley 2011 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Potency ratio: 7.6”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Smith 1998 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
In the paper
“In opioid and delta-9-THC naïve rats, methadone 1.0 mg/kg significantly enhanced the antinociceptive effect of delta-9-THC, however this was not observed in rats that were previously trained for drug discrimination tasks.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Wakley 2011 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Combination of delta-9-THC and morphine did not have an effect on pain intensity.The combination resulted in lower ratings of unpleasantness of pain compared with either drug alone”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Roberts 2006 source
Strength:plain· not yet calibratedn = 13Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“No change in median amount of breakthrough opioid medication in any group Change in pain NRS (out of 10) from baseline was statistically significantly in favor of delta-9-THC:CBD compared with the placebo”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Johnson 2010 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In single-dose studies, 10 and 20 mg dronabinol significantly increased the amount of analgesic relief reported compared to placebo”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Narang 2008 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
In the paper
“Study 1: Pre-treatment with delta-9-THC did not enhance the fully efficacious dose of morphine but enhanced low-dose morphine and both doses of codeine, in addition to extending the time course.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Williams 2006 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Mean baseline NRS of 6.9 compared with 5.2 after four weeks of dronabinol.This represents a statistically significant reduction”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Narang 2008 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“No evidence of synergism.Morphine + HU-210 showed the greatest increase in hot plate latency (39.9 s ± 1.1 s), but was not significantly different from morphine alone”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Wilson 2008 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“5/12 patients (42%) achieved control of pain without opioid dose increase compared to the control group, where 2/14 (14%) achieved pain control The number that achieved pain control was not significantly different between groups”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Lissoni 2014
Strength:plain· not yet calibratedn = 5Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“No significant analgesic effect of dronabinol or morphine-dronabinol combination on heat, pressure or cold tests.Additive effect of morphine on transcutaneous electrical stimulation test Potentiation of analgesia not observed in this experimental pain study”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Naef 2003 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Mean baseline morphine dose of 195 mg (SD 147 mg) compared with 35 mg (SD 31 mg) after commencing smoked cannabis.Opioid dose reduction or cessation in each case Improved pain control described, with patients either reducing or ceasing morphine dose”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Lynch 2003 source
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Mean pain score reduction, from 34.8 (95% CI 29.4,40.1) at baseline to 24.1 (95% CI 18.8, 29.4) on day 5 with morphine, and from 43.8 (95% CI 38.6, 49.1) at baseline to 33.6 (95% CI 28.5, 38.6) on day 5 with oxycodone.Significant reduction overall.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Abrams 2011 source
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“No change in median amount of breakthrough opioid medication in any group.Note that patients were discouraged from reducing their opioid dose, so the opioid-sparing effect could not be observed”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Portenoy 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Treatment difference (change from baseline pain score): -0.75 points (95% CI -1.28, -0.22, p = 0.06 compared to placebo)”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Portenoy 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Studies included in qualitative synthesis (n = 28)”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
Strength:plain· not yet calibratedn = 28Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Studies included in quantitative synthesis (meta-analysis) of preclinical data for morphine (n = 6)”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
Strength:plain· not yet calibratedn = 6Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Median dose of piritramide alone was 74 mg (IQR 44-90) compared with 54 mg (IQR 46-88) when administered with dronabinol.”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
What the sources say
- Not checked yetcites Seeling 2006 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Studies included in quantitative synthesis (meta-analysis) of preclinical data for codeine (n = 2)”
§ Methylphenidate modifies the motion of the circadian clock Lamotrigine in mood disorders and cocaine dependence Cortical glutamate in postpartum depression Opioid-sparing Effect of Cannabinoids: A Systematic Review and Meta-analysis > Discussion
Strength:plain· not yet calibratedn = 2Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“studies have shown that cannabinoids produce clear opioid-sparing effects 73.”
From Psychosocial and pharmacological interventions for the treatment of cannabis use disorder (2018) · cites this paper as [73]
Experimental — accuracy not yet measuredIn the citing paper
“Indeed, a recent meta-analysis study reported strong evidence that cannabinoids produce opioid-sparing effects in preclinical studies, but only a single study of nine clinical studies provided evidence of opioid-sparing effects in humans (Nielsen et al, 2017).”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Nielsen et al, 2017
Statistics recomputed
Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.
- Consistentz = 5.59reported p < .001 · recomputed p < .001
“Z = 5.59, p < .001”
- Consistentz = 2.49reported p = .01 · recomputed p = .013
“Z = 2.49, p = .01”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Morphine meta-analysis Z statistic conflicts with its confidence interval
MinorThe reported mean difference of −0.56 and 95% CI of −0.83 to −0.29 imply a Z statistic of approximately 4.07, not 5.59.
“Z = 5.59, p < 0.001”
“MD in log 10 ED 50 -0.56[-0.83, -0.29]”
Wilson hot-plate latency differs between text and table
MinorThe text reports 38.9 seconds for morphine combined with HU-210, while Table 1 reports 39.9 seconds for that combination.
“morphine combined with HU-210 (38.9s ± 1.1 s)”
“Morphine + HU-210 showed the greatest increase in hot plate latency (39.9 s ± 1.1 s)”
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- Lissoni P, Porro G, Messina G, Porta E, Rovelli F, Roselli MG et al (2014). Morphine, melatonin, Marijuana, Magnolia and MYRRH as the "five m" schedule in the treatment of cancer pain and the possible dose-dependency of the antitumor and analgesic effects of the pineal hormone melatonin. Anticancer Res 34: 6033–6034.
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Metadata
- Authors
- Nielsen, S., Sabioni, P., Trigo, J. M., Ware, M. A., Betz-Stablein, B. D., Murnion, B., Lintzeris, N., Khor, K. E., Farrell, M., Smith, A., & Le Foll, B.
- Affiliations
- UNSW Sydney (AU)
- Centre for Addiction and Mental Health (CA)
- McGill University (CA)
- The University of Sydney (AU)
- Prince of Wales Hospital (AU)
- Corresponding author
- Nielsen, Suzanne
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2017-03-22
- Volume
- 42
- Issue
- 9
- Pages
- 1752-1765
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC5520783
- OpenAlex
- W2601973957
- Semantic Scholar
- 425a7d6d3175215eaa53fad85d7035e9be6e755c
- Cited by
- 265
- References
- 72
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 24 · 2023: 25 · 2022: 24 · 2021: 44 · 2020: 35 · 2019: 40 · 2018: 30 · 2017: 2
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Pain Management
- Keywords
- cannabinoids, opioid-sparing effect, opioid dose reduction, delta-9-tetrahydrocannabinol, morphine, codeine, analgesia, ED50, pain management
- MeSH terms
- Analgesics, Opioid, Animals, Cannabinoids, Drug Synergism, Humans, Pain
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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