On 2015 Mar 08, David Keller commented:

Arguments against the use of cannabidiol or other cannabis derivatives to treat Parkinson's disease

Arguments against the use of cannabidiol to treat Parkinson's disease patients:

1) Persistent cannabis users show neuropsychological decline from childhood to midlife [1], which is abnormal and worrisome.

2) Cannabidiol (CBD) is a "major constituent of cannabis" [2]

3) We do not know which one, or which combination of cannabis constituents, contributes to the neuropsychological decline observed in persistent users. The possible culprits include CBD, THC, and other compounds present in cannabis.

4) The study by Chagas and colleagues [3] did not prove that long-term chronic CBD use does not contribute to neuropsychological decline.

5) The alleged benefit demonstrated by CBD was a minor improvement in PDQ-39 score of borderline statistical significance. CBD use did not affect the 3 other reported outcomes significantly.

6) The borderline improvement in PDQ-39 score observed with CBD use [3] does not justify the risk of neuropsychological decline which CBD, as a major constituent of cannabis, may cause [1].

7) Researchers who work with cannabis, CBD, THC or any combination of cannabis derivatives, should declare whether they currently use any such substances, as should those who comment, review or editorialize about these substances, because such use constitutes a source of potential bias, which I shall designate as "Cannabis Derivatives User Bias".

8) I do not use cannabis or any of its derivatives. I request that Dr. Kevin McKernan and all other commenters make similar disclosures.

References

1: Meier MH, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657-64. PubMed PMID: 22927402

2: Gallily R, Yekhtin Z, Hanuš LO. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy,2015,6,75-85

3: Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, dos Santos AC, Teixeira AL, Hallak JE, Crippa JA. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J Psychopharmacol. 2014 Nov;28(11):1088-98. doi: 10.1177/0269881114550355. Epub 2014 Sep 18. PubMed PMID: 25237116.

On 2015 Mar 05, David Keller commented:

The first reference given by Kevin McKernan contradicts him, and also contradicts itself

The first sentence of Dr. McKernan's first reference is: "Cannabidiol (CBD), a major constituent of Cannabis, has been shown to be a powerful anti-inflammatory and anti-anxiety drug, without exerting a psychotropic effect."[1] This sentence starts out by contradicting McKernan's assertion that "marijuana and Cannabidiol (CBD) are very rarely related", given that cannabis and marijuana are synonymous, and CBD is "a major constituent of Cannabis". Moreover, this sentence goes on to contradict itself by stating that CBD has been shown to be an "anti-anxiety drug" but "without exerting a psychotropic effect". It is clearly contradictory to state that an anti-anxiety drug has no psychotropic effect.

My main point is that it is perfectly acceptable for a basic scientist, like Dr. McKernan, to explore the properties of "cocktails of cannabinoids" in his laboratory. However, before exposing human subjects suffering from Parkinson's disease to cannabidiol, or any other "major constituent of cannabis", the neurological safety of these cannabinoids must be established. I see nothing "controversial" about the study conducted by Meier and colleagues (2); rather, it confirms the widely-held perception that chronic users of cannibis (marijuana) suffer neuropsychological degeneration. Until this worrisome safety signal is addressed, I do not consider it ethical to test CBD, THC or any other major constituent of cannabis on patients with Parkinson's disease, Alzheimer's disease, or any other neurodegenerative condition. The borderline-insignificant gain in the PDQ-39 score observed in this study is simply not worth the risk, even if the benefit had been statistically significant.

The amount of research into the beneficial effects of cannabidiol and other chemicals found in marijuana seems excessive, given the scant benefits demonstrated in this study, and others like it. How much of this zeal to promote the benefits of marijuana-derived compounds is driven by the wish for full legalization of this drug? I propose the following experiment: legalize marijuana in all 50 states and also by the Federal government. Once its advocates are free to grow, smoke, and consume this plant in any form or fashion without restrictions of any kind, I predict that the amount of research into the benefits of marijuana-derived chemicals will drop significantly.

Lastly, it is reasonable to expect that a regular user of cannabis or any of its derivatives might exhibit bias when reporting results of a trial, or when commenting on them ("user bias"). For this reason, use of cannabis or any of its derivatives should be disclosed in the same fashion as a financial bias. Full disclosure: I do not use any of these substances, and I call on Dr. McKernan to make a similar disclosure.

References

1: Gallily R, Yekhtin Z, Hanuš LO. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy,2015,6,75-85

2: Meier MH, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657-64. PubMed PMID: 22927402

On 2015 Feb 26, Kevin McKernan commented:

Marijuana must not be conflated with Cannabidiol

David Keller highlights a few controversial studies pointing out the adverse effects of "marijuana". This is known as a straw man argument as marijuana and Cannabidiol (CBD) are very rarely related. Most Marijuana is THC enriched and lacking CBD as a direct result. Pathways in the plant that synthesize THCA are in competition for GPP required to make CBDA (CBD's carboxylated precursor). Most "Marijuana" is devoid of CBD as a result. Likewise, most recreational "Marijuana" is consumed with a route of administration via smoking and cannot deliver 300mg/day via the hepatic portal system which is known to metabolize many cannabinoids into other active molecules not experienced with smoking "marijuana". Likewise, THC is pharmaceutically very different than CBD such that any reference to studies investigating the non descriptive 'Marijuana' are obsolete and irrelevant. The investigator bias on display here is clearly in the camp of Dr. Keller not understanding some of the basics of Cannabidiol research. For reference I would point to the following references highlighting the very distinct nature of CBD compared to THC. Any attempt to conflate these two molecules has already been thoroughly established as foolhardy in the endocannabinoid sciences. For instance, CBD does not get patients 'stoned' and its mechanism of action is not related to the CB1 receptor. Some of the most exciting work in this field is exploring cocktails of cannabinoids found in more raw forms of the plant as these cocktails appear to widen the dose response curve. The above studies p-value will likely improve utilizing the methods recently published by Gallily et al.

In summary, the Parkinsons genetic pathways continue to highlight the relevance of Parkin, LRRK2 and mitochondrial dysfunction. These genes are involved in the ROS pathway and lipid soluble antioxidants with very tolerant therapeutic indexes are a perfectly rational approach for Parkinsons disease. Future studies stratifying the genetics of the disease and widening the dose response curve with work like Gallily et al are likely to be very productive for the field.

References

Gallily- http://www.scirp.org/journal/PaperDownload.aspx?paperID=53912 http://www.sciencedirect.com/science/article/pii/S0006899306034718 https://www.google.com/patents/US6630507 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942876/ http://onlinelibrary.wiley.com/doi/10.1002/jat.2828/abstract;jsessionid=33248CFFF91EA20AE26A6C2EFE120DEE.f04t03?deniedAccessCustomisedMessage=&userIsAuthenticated=false http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/ http://www.pnas.org/content/95/14/8268.short http://jop.sagepub.com/content/early/2008/11/21/0269881108096519.short

On 2014 Sep 26, David Keller commented:

The cognitive adverse effects of cannabidiol must be discussed

Chronic cannabis use causes irreversible cognitive impairment, and is considered neurotoxic for that reason (1). Many marijuana addicts cite acute cognitive dysfunction as their intended goal; in street terms, this is known as being "stoned". Any proposal to treat Parkinson disease with cannabidiol, cannabis or marijuana itself which fails to assess and report cognitive impairment raises the question of investigator bias.

Lastly, the results of a clinical trial are commonly deemed statistically significant when the probability that the findings are the result of chance is less than 5% (2). A p-value equal to 0.05 is usually described as being of borderline or marginal statistical significance.

References

1: Meier MH, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657-64. PubMed PMID: 22927402;

2: Higgins JPT and Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0, revised March, 2011

On 2014 Sep 26, David Keller commented:

The cognitive adverse effects of cannabidiol must be discussed

Chronic cannabis use causes irreversible cognitive impairment, and is considered neurotoxic for that reason (1). Many marijuana addicts cite acute cognitive dysfunction as their intended goal; in street terms, this is known as being "stoned". Any proposal to treat Parkinson disease with cannabidiol, cannabis or marijuana itself which fails to assess and report cognitive impairment raises the question of investigator bias.

Lastly, the results of a clinical trial are commonly deemed statistically significant when the probability that the findings are the result of chance is less than 5% (2). A p-value equal to 0.05 is usually described as being of borderline or marginal statistical significance.

References

1: Meier MH, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657-64. PubMed PMID: 22927402;

2: Higgins JPT and Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0, revised March, 2011

On 2015 Feb 26, Kevin McKernan commented:

Marijuana must not be conflated with Cannabidiol

David Keller highlights a few controversial studies pointing out the adverse effects of "marijuana". This is known as a straw man argument as marijuana and Cannabidiol (CBD) are very rarely related. Most Marijuana is THC enriched and lacking CBD as a direct result. Pathways in the plant that synthesize THCA are in competition for GPP required to make CBDA (CBD's carboxylated precursor). Most "Marijuana" is devoid of CBD as a result. Likewise, most recreational "Marijuana" is consumed with a route of administration via smoking and cannot deliver 300mg/day via the hepatic portal system which is known to metabolize many cannabinoids into other active molecules not experienced with smoking "marijuana". Likewise, THC is pharmaceutically very different than CBD such that any reference to studies investigating the non descriptive 'Marijuana' are obsolete and irrelevant. The investigator bias on display here is clearly in the camp of Dr. Keller not understanding some of the basics of Cannabidiol research. For reference I would point to the following references highlighting the very distinct nature of CBD compared to THC. Any attempt to conflate these two molecules has already been thoroughly established as foolhardy in the endocannabinoid sciences. For instance, CBD does not get patients 'stoned' and its mechanism of action is not related to the CB1 receptor. Some of the most exciting work in this field is exploring cocktails of cannabinoids found in more raw forms of the plant as these cocktails appear to widen the dose response curve. The above studies p-value will likely improve utilizing the methods recently published by Gallily et al.

In summary, the Parkinsons genetic pathways continue to highlight the relevance of Parkin, LRRK2 and mitochondrial dysfunction. These genes are involved in the ROS pathway and lipid soluble antioxidants with very tolerant therapeutic indexes are a perfectly rational approach for Parkinsons disease. Future studies stratifying the genetics of the disease and widening the dose response curve with work like Gallily et al are likely to be very productive for the field.

References

Gallily- http://www.scirp.org/journal/PaperDownload.aspx?paperID=53912 http://www.sciencedirect.com/science/article/pii/S0006899306034718 https://www.google.com/patents/US6630507 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942876/ http://onlinelibrary.wiley.com/doi/10.1002/jat.2828/abstract;jsessionid=33248CFFF91EA20AE26A6C2EFE120DEE.f04t03?deniedAccessCustomisedMessage=&userIsAuthenticated=false http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/ http://www.pnas.org/content/95/14/8268.short http://jop.sagepub.com/content/early/2008/11/21/0269881108096519.short

On 2015 Mar 08, David Keller commented:

Arguments against the use of cannabidiol or other cannabis derivatives to treat Parkinson's disease

Arguments against the use of cannabidiol to treat Parkinson's disease patients:

1) Persistent cannabis users show neuropsychological decline from childhood to midlife [1], which is abnormal and worrisome.

2) Cannabidiol (CBD) is a "major constituent of cannabis" [2]

3) We do not know which one, or which combination of cannabis constituents, contributes to the neuropsychological decline observed in persistent users. The possible culprits include CBD, THC, and other compounds present in cannabis.

4) The study by Chagas and colleagues [3] did not prove that long-term chronic CBD use does not contribute to neuropsychological decline.

5) The alleged benefit demonstrated by CBD was a minor improvement in PDQ-39 score of borderline statistical significance. CBD use did not affect the 3 other reported outcomes significantly.

6) The borderline improvement in PDQ-39 score observed with CBD use [3] does not justify the risk of neuropsychological decline which CBD, as a major constituent of cannabis, may cause [1].

7) Researchers who work with cannabis, CBD, THC or any combination of cannabis derivatives, should declare whether they currently use any such substances, as should those who comment, review or editorialize about these substances, because such use constitutes a source of potential bias, which I shall designate as "Cannabis Derivatives User Bias".

8) I do not use cannabis or any of its derivatives. I request that Dr. Kevin McKernan and all other commenters make similar disclosures.

References

1: Meier MH, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657-64. PubMed PMID: 22927402

2: Gallily R, Yekhtin Z, Hanuš LO. Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy,2015,6,75-85

3: Chagas MH, Zuardi AW, Tumas V, Pena-Pereira MA, Sobreira ET, Bergamaschi MM, dos Santos AC, Teixeira AL, Hallak JE, Crippa JA. Effects of cannabidiol in the treatment of patients with Parkinson's disease: an exploratory double-blind trial. J Psychopharmacol. 2014 Nov;28(11):1088-98. doi: 10.1177/0269881114550355. Epub 2014 Sep 18. PubMed PMID: 25237116.