Current Therapeutic Cannabis Controversies and Clinical Trial Design Issues

Abstract

This overview covers a wide range of cannabis topics, initially examining issues in dispensaries and self-administration, plus regulatory requirements for production of cannabis-based medicines, particularly the Food and Drug Administration “Botanical Guidance.” The remainder pertains to various cannabis controversies that certainly require closer examination if the scientific, consumer, and governmental stakeholders are ever to reach consensus on safety issues, specifically: whether botanical cannabis displays herbal synergy of its components, pharmacokinetics of cannabis and dose titration, whether cannabis medicines produce cyclo-oxygenase inhibition, cannabis-drug interactions, and cytochrome P450 issues, whether cannabis randomized clinical trials are properly blinded, combatting the placebo effect in those trials via new approaches, the drug abuse liability (DAL) of cannabis-based medicines and their regulatory scheduling, their effects on cognitive function and psychiatric sequelae, immunological effects, cannabis and driving safety, youth usage, issues related to cannabis smoking and vaporization, cannabis concentrates and vape-pens, and laboratory analysis for contamination with bacteria and heavy metals. Finally, the issue of pesticide usage on cannabis crops is addressed. New and disturbing data on pesticide residues in legal cannabis products in Washington State are presented with the observation of an 84.6% contamination rate including potentially neurotoxic and carcinogenic agents. With ongoing developments in legalization of cannabis in medical and recreational settings, numerous scientific, safety, and public health issues remain.

Pesticides in cannabis: A review of analytical and toxicological considerations

“…23 Furthermore, setting tolerance limits is complex and time-consuming. 26 has classed it as a possible human carcinogen after observing liver tumors in mice when exposed orally to high doses of this pesticide. 24 The Washington State Department of Agriculture (WSDA) has recently released a list of 271 pesticide products approved for use on cannabis.…”

Is cannabidiol a drug acting on unconventional targets to control drug‐resistant epilepsy?

“…Although artisanal cannabis is considered a “miracle therapy,” at present there are not regulations to maintain the quality and purity of the drug during the obtaining procedure. Artisanal cannabis oil may contain abiotic (dust, fertilizers) and biotic (ie, insect, fungi, bacteria) contaminants, heavy metals, pesticides, etc, a situation that represents a high risk to the health of patients. Unfortunately, the evaluation of the effects of artisanal cannabis is difficult, has yielded controversial results, and lacks controlled clinical studies …”

The Intricate Influence of the Placebo Effect on Medical Cannabis and Cannabinoids

“…Importantly, the term cannabis is unprecise as it refers to distinctly different phytopharmaceuticals (chemovars, extractions, etc.) derived from one plant species, thus causing controversies in the clinical development [44]. Given the association of CB1 receptor activation and the meaning response in non-opioid placebo analgesia, it is intriguing to speculate that psychoactive cannabis and cannabinoids enhance the meaning response biochemically, which could have clinical implications for placebo nonresponders (e.g., those carrying the FAAH C385A polymorphism), an aspect that has not been taken into account so far.…”