John M. McPartland

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

Background The “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the “eCB deficiency syndrome” as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system—ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation. Methodology/Principal Findings We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances—alcohol, tobacco, coffee, cannabis) also modulate the eCB system. Conclusions/Significance Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

Cannabimimetic effects modulated by cholinergic compounds.

This report is based upon a clinical case series describing five patients who volitionally adultered cannabis with a variety of compounds that shared a common trait—cholinergic modulation. They included a nicotinic agonist, muscarinic antagonist and antiacetylcholinesterase compounds. Some of these compounds (e.g. tobacco) are known to exert pharmacokinetic effects upon cannabinoids (e.g. improved drug absorption). Contrarily, our patients claimed that the compounds altered pharmacodynamic ‘cannabimimetic’ effects. The case series was supported by forensic identification of adulterants and by use of a symptom causality algorithm. A survey of the gray literature and drug culture web sites indicated that the case series portended a larger social phenomenon. Furthermore, many clinical reports, animal behaviour studies and in vitro mechanistic studies substantiated our observations. In conclusion, we provide empirical data regarding a new trend in the drug culture—cholinergic modulation of cannabinoid effects—that presents new research directions.

Cannabis utilization and diffusion patterns in prehistoric Europe: a critical analysis of archaeological evidence

Archaeological evidence of Cannabis sativa is comprised of textiles, cordage, fibre and seeds, or pottery impressions of those materials, as well as pseudoliths and phytoliths (pollen is not addressed here). Previous summaries of this evidence connect hemp with Bronze and Iron Age cultures in Europe. This study improves upon earlier summaries by: (1) accessing a larger database; (2) relying on original studies instead of secondary sources; (3) stratifying evidence by its relative robustness or validity. We coupled digital text-searching engines with internet archives of machine-readable texts, augmented by citation tracking of retrieved articles. The database was large, so we limited retrieval to studies that predated 27 bce for west-central Europe, and pre-ce 400 for eastern Europe. Validity of evidence was scaled, from less robust (e.g., pottery impressions of fibre) to more robust (e.g. microscopic analysis of seeds). Archaeological sites were mapped using ArcGIS 10.3. The search retrieved 136 studies, a yield four-fold greater than previous summaries when parsed to our geographic/time constraints. Only 12.5% of studies came from secondary literature. No robust evidence supports claims of Neolithic hemp usage. One Copper Age site in southeastern Europe shows robust evidence (from the Gumelniţa-Varna culture). More robust evidence appears during the Bronze Age in southeastern Europe (Yamnaya and Catacomb cultures). An Iron Age steppe culture, the Scythians, likely introduced hemp cultivation to Celtic, Slavic and Finno-Ugric cultures. The results correlate with a recent palynology study of fossil pollen in Europe. We discuss possible autochthonous domestication of Cannabis in Europe.

Models of Cannabis Taxonomy, Cultural Bias, and Conflicts between Scientific and Vernacular Names

Debates over Cannabis sativa L. and C. indica Lam. center on their taxonomic circumscription and rank. This perennial puzzle has been compounded by the viral spread of a vernacular nomenclature, “Sativa” and “Indica,” which does not correlate with C. sativa and C. indica. Ambiguities also envelop the epithets of wild-type Cannabis: the spontanea versus ruderalis debate (i.e., vernacular “Ruderalis”), as well as another pair of Cannabis epithets, afghanica and kafirstanica. To trace the rise of vernacular nomenclature, we begin with the protologues (original descriptions, synonymies, type specimens) of C. sativa and C. indica. Biogeographical evidence (obtained from the literature and herbarium specimens) suggests 18th–19th century botanists were biased in their assignment of these taxa to field specimens. This skewed the perception of Cannabis biodiversity and distribution. The development of vernacular “Sativa,” “Indica,” and “Ruderalis” was abetted by twentieth century botanists, who ignored original protologues and harbored their own cultural biases. Predominant taxonomic models by Vavilov, Small, Schultes, de Meijer, and Hillig are compared and critiqued. Small’s model adheres closest to protologue data (with C. indica treated as a subspecies). “Sativa” and “Indica” are subpopulations of C. sativa subsp. indica; “Ruderalis” represents a protean assortment of plants, including C. sativa subsp. sativa and recent hybrids.

Cannabis is indigenous to Europe and cultivation began during the Copper or Bronze age: a probabilistic synthesis of fossil pollen studies

Conventional wisdom states Cannabis sativa originated in Asia and its dispersal to Europe depended upon human transport. Various Neolithic or Bronze age groups have been named as pioneer cultivators. These theses were tested by examining fossil pollen studies (FPSs), obtained from the European Pollen Database. Many FPSs report Cannabis or Humulus (C/H) with collective names (e.g. Cannabis/Humulus or Cannabaceae). To dissect these aggregate data, we used ecological proxies to differentiate C/H pollen, as follows: unknown C/H pollen that appeared in a pollen assemblage suggestive of steppe (Poaceae, Artemisia, Chenopodiaceae) we interpreted as wild-type Cannabis. C/H pollen in a mesophytic forest assemblage (Alnus, Salix, Populus) we interpreted as Humulus. C/H pollen curves that upsurged and appeared de novo alongside crop pollen grains we interpreted as cultivated hemp. FPSs were mapped and compared to the territories of archaeological cultures. We analysed 479 FPSs from the Holocene/Late Glacial, plus 36 FPSs from older strata. The results showed C/H pollen consistent with wild-type C. sativa in steppe and dry tundra landscapes throughout Europe during the early Holocene, Late Glacial, and previous glaciations. During the warm and wet Holocene Climactic Optimum, forests replaced steppe, and Humulus dominated. Cannabis retreated to steppe refugia. C/H pollen consistent with cultivated hemp first appeared in the Pontic-Caspian steppe refugium. GIS mapping linked cultivation with the Copper age Varna/Gumelniţa culture, and the Bronze age Yamnaya and Terramara cultures. An Iron age steppe culture, the Scythians, likely introduced hemp cultivation to Celtic and Proto-Slavic cultures.

Cannabis Systematics at the Levels of Family, Genus, and Species

Abstract New concepts are reviewed in Cannabis systematics, including phylogenetics and nomenclature. The family Cannabaceae now includes Cannabis, Humulus, and eight genera formerly in the Celtidaceae. Grouping Cannabis, Humulus, and Celtis actually goes back 250 years. Print fossil of the extinct genus Dorofeevia (=Humularia) reveals that Cannabis lost a sibling perhaps 20 million years ago (mya). Cannabis print fossils are rare (n=3 worldwide), making it difficult to determine when and where she evolved. A molecular clock analysis with chloroplast DNA (cpDNA) suggests Cannabis and Humulus diverged 27.8 mya. Microfossil (fossil pollen) data point to a center of origin in the northeastern Tibetan Plateau. Fossil pollen indicates that Cannabis dispersed to Europe by 1.8–1.2 mya. Mapping pollen distribution over time suggests that European Cannabis went through repeated genetic bottlenecks, when the population shrank during range contractions. Genetic drift in this population likely initiated allopatric differences between European Cannabis sativa (cannabidiol [CBD]>Δ9-tetrahydrocannabinol [THC]) and Asian Cannabis indica (THC>CBD). DNA barcode analysis supports the separation of these taxa at a subspecies level, and recognizing the formal nomenclature of C. sativa subsp. sativa and C. sativa subsp. indica. Herbarium specimens reveal that field botanists during the 18th–20th centuries applied these names to their collections rather capriciously. This may have skewed taxonomic determinations by Vavilov and Schultes, ultimately giving rise to todays vernacular taxonomy of “Sativa” and “Indica,” which totally misaligns with formal C. sativa and C. indica. Ubiquitous interbreeding and hybridization of “Sativa” and “Indica” has rendered their distinctions almost meaningless.