Acute effects of cannabigerol on anxiety, stress, and mood: a double-blind, placebo-controlled, crossover, field trial.

Cannabigerol (CBG) is a phytocannabinoid increasing in popularity, with preclinical research indicating it has anxiolytic and antidepressant effects. However, there are no published clinical trials to corroborate these findings in humans. The primary objective of this study was to examine acute effects of CBG on anxiety, stress, and mood. Secondary objectives were to examine whether CBG produces subjective drug effects or motor and cognitive impairments. A double-blind, placebo-controlled cross-over field trial was conducted with 34 healthy adult participants. Participants completed two sessions (with a one-week washout period) via Zoom. In each, they provided ratings of anxiety, stress, mood, and subjective drug effects prior to double-blind administration of 20 mg hemp-derived CBG or placebo tincture (T0). These ratings were collected again after participants ingested the product and completed an online survey (T1), the Trier Social Stress Test (T2), a verbal memory test and the DRUID impairment app (T3). Relative to placebo, there was a significant main effect of CBG on overall reductions in anxiety as well as reductions in stress at T1. CBG also enhanced verbal memory relative to placebo. There was no evidence of subjective drug effects or impairment. CBG may represent a novel option to reduce stress and anxiety in healthy adults.

Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis.

BACKGROUND: Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC. METHODS: Twenty healthy adults completed nine, double-blind outpatient sessions in which they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo; a subset of participants (n=12) completed a tenth session in which 30mg THC+15mg d-limonene was administered. Outcomes included subjective drug effects, cognitive/psychomotor performance, vital signs, and plasma THC and d-limonene concentrations. RESULTS: When d-limonene was administered alone, pharmacodynamic outcomes did not differ from placebo. Administration of 15mg and 30mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30mg THC+15mg d-limonene significantly reduced ratings of "anxious/nervous" and "paranoid" compared with 30mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics. CONCLUSIONS: D-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC. Future research should determine whether this effect extends to oral dose formulations and evaluate the interactions between other cannabis terpenoids or cannabinoids and THC.

The Naturalistic Cannabis Administration Protocol (NCAP): A Proof-of-Concept Study.

Lab-based studies examining the effects of cannabis administration on human behavior compromise ecological validity due to the influence of set and setting. Contextual factors of clinical settings have long been recognized as producing measurable changes in physiology, emotionality, and cognition. Among people who use drugs, these settings may be associated with higher levels of perceived stigma and stereotype threat which may meaningfully confound the effects of cannabis on outcomes of interest. Recent liberalization of cannabis regulation may allow novel and more ecologically valid approaches to assessing the acute effects of cannabis. The Naturalistic Cannabis Administration Protocol (NCAP) is a novel paradigm for the study of acute cannabis effects in an ecologically valid manner. Two independent studies demonstrated the safety and feasibility of the NCAP. Participants (N= 79; Mage = 25.44, SD = 5.67) self-administered the cannabis of their choice in their home and then (Study 1; n= 47) engaged in a leisure activity or (Study 2; n= 32) underwent cognitive assessment remotely via videoconference following cannabis administration. The NCAP was well tolerated across samples with no reported adverse events. These findings provide a rationale for the adoption of the NCAP to reduce research barriers and develop our research capabilities to fit the landscape of cannabis use today.

Survey of Patients Employing Cannabigerol-Predominant Cannabis Preparations: Perceived Medical Effects, Adverse Events, and Withdrawal Symptoms.

Introduction: Cannabigerol (CBG), and its precursor before decarboxylation, cannabigerolic acid is sometimes labeled the "mother of all cannabinoids." The purpose of the present study was to investigate reasons for use and self-reported therapeutic effects in CBG-predominant cannabis users. Usage patterns and adverse effects, including withdrawal symptoms were also explored. Methods: Cannabidiol-predominant cannabis users were recruited online to complete an online survey assessing CBG use patterns, conditions treated with CBG-predominant cannabis (containing >50% CBG), perceived efficacy, associated adverse events, and withdrawal symptoms. One hundred twenty-seven eligible participants (U.S. residents ages 21+ who reported using CBG-predominant cannabis in the past 6 months) completed the survey. Results: Most of the samples (n=65; 51.2%) reported use of CBG-predominant products solely for medical purposes (n=46; 36.2% reported use for medical and recreational purposes; n=8; 6.3% reported recreational use only, and n=8 were missing). The most common conditions the complete sample reported using CBG to treat were anxiety (51.2%), chronic pain (40.9%), depression (33.1%), and insomnia/disturbed sleep (30.7%). Efficacy was highly rated, with the majority reporting their conditions were "very much improved" or "much improved" by CBG. Furthermore, 73.9% claimed superiority of CBG-predominant cannabis over conventional medicines for chronic pain, 80% for depression, 73% for insomnia, and 78.3% for anxiety. Forty-four percent of CBG-predominant cannabis users reported no adverse events, with 16.5% noting dry mouth, 15% sleepiness, 11.8% increased appetite, and 8.7% dry eyes. Around 84.3% reported no withdrawal symptoms, with sleep difficulties representing the most frequently endorsed withdrawal symptom (endorsed by two respondents). Conclusions: This is the first patient survey of CBG-predominant cannabis use to date, and the first to document self-reported efficacy of CBG-predominant products, particularly for anxiety, chronic pain, depression, and insomnia. Most respondents reported greater efficacy of CBG-predominant cannabis over conventional pharmacotherapy, with a benign adverse event profile and negligible withdrawal symptoms. This study establishes that humans are employing CBG and suggests that CBG-predominant cannabis-based medicines should be studied in randomized controlled trials.

Cannabinoid Hyperemesis Syndrome Survey and Genomic Investigation.

Background: Cannabinoid hyperemesis syndrome (CHS) is a diagnosis of exclusion with intractable nausea, cyclic vomiting, abdominal pain, and hot bathing behavior associated with ongoing tetrahydrocannabinol (THC) exposure. Increasing cannabis use may elevate CHS prevalence, exacerbating a public health issue with attendant costs and morbidity. Objective, Design, and Data Source: This study, the largest contemporaneous database, investigated genetic mutations underlying CHS. Patients with CHS diagnosis and ongoing symptoms were compared with current cannabis users lacking symptoms. Target Population: A screening questionnaire was posted online. Of 585 respondents, 205 qualified as the CHS pool and 54 as controls; a reduced pool of 28 patients and 12 controls ultimately completed genomic testing. Results: Patients and controls were high-frequency users of cannabis flower or concentrates (93%), using multiple grams/day of THC-predominant material. Among patients, 15.6% carried diagnoses of cannabis dependency or addiction, and 56.6% experienced withdrawal symptoms. About 87.7% of patients improved after cannabis cessation, most suffering recurrence rapidly after resumption. Findings in patients included mutations in genes COMT {odds ratio, 12 (95% confidence limit [CL], 1.3-88.1) p=0.012}, transient receptor potential vanilloid receptor 1 (TRPV1) (odds ratio, 5.8 [95% CL, 1.2-28.4] p=0.015), CYP2C9 (odds ratio, 7.8 [95% CL, 1.1-70.1] p=0.043), gene coding dopamine-2 receptor (DRD2) (odds ratio, 6.2 [95% CL, 1.1-34.7] p=0.031), and ATP-binding cassette transporter gene (ABCA1) (odds ratio, 8.4 [95% CL, 1.5-48.1] p=0.012). Limitations: Some participants were reluctant to undergo genetic testing; only 28 of 99 CHS patients who agreed to testing ultimately returned a kit. Conclusion: This is the largest patient cohort of CHS examined to date, and first to note associated mutations in genes affecting neurotransmitters, the endocannabinoid system, and the cytochrome P450 complex associated with cannabinoid metabolism. Although the sample size was smaller than desired, these preliminary findings may contribute to the growing body of knowledge, stimulate additional investigation, help elucidate the pathophysiology of CHS, and, ultimately, direct future treatment.

Novel Solventless Extraction Technique to Preserve Cannabinoid and Terpenoid Profiles of Fresh Cannabis Inflorescence.

Despite its use by humans for thousands of years, the technology of cannabis usage and extraction is still evolving. Given that the primary pharmacological compounds of interest are cannabinoid and terpenoids found in greatest abundance in capitate glandular trichomes of unfertilized female inflorescences, it is surprising that older techniques of hashish making have received less technological advancement. The purpose of this study was to employ organically grown cannabis and to isolate pure trichomes from freshly picked flowers via exposure to vapor from solid CO2, commonly known as "dry ice", followed by their isolation via sifting through a 150 µ screens while maintaining the cold chain. Biochemical analysis was undertaken on fresh flower, frozen-sifted flower by-products, treated trichomes (Kryo-Kief™), dried flower, dried sifted flower by-product and dried kief. The dry ice process successfully concentrated cannabinoid content as high as 60.7%, with corresponding concentration and preservation of monoterpenoids encountered in fresh flower that are usually lost during the conventional cannabis drying and curing process. The resulting dried sifted flower by-product after dry ice processing remains a usable commodity. This approach may be of interest to pharmaceutical companies and supplement producers pursuing cannabis-based medicine development with an eye toward full synergy of ingredients harnessing the entourage effect.

No Evidence of Altered Reactivity to Experimentally Induced Pain Among Regular Cannabis Users.

OBJECTIVES: Recent years have seen an increase in the adoption of cannabinoid medicines, which have demonstrated effectiveness for the treatment of chronic pain. However, the extent to which frequent cannabis use (CU) influences sensitivity to acute pain has not been systematically examined. Such a determination is clinically relevant in light of hypersensitivity to pain associated with prolonged use of other analgesics such as opioids, and reports of increased pain sensitivity to experimentally induced pain during acute cannabis intoxication. This study explored differences in measures of pain intensity and tolerance. The authors hypothesized that individuals who report frequent CU would demonstrate greater experimental pain sensitivity. MATERIALS AND METHODS: Frequent cannabis users (≥3× per week; n=40) and nonusers (n=40) were compared on pain sensitivity, pain tolerance, and pain intensity in response to a cold-pressor task. Group differences were examined. RESULTS: Frequent CU was not associated with hyperalgesia as cannabis users and nonusers did not exhibit differences on measures of pain tolerance (t (78)=-0.05; P=0.96), sensitivity (t (78)=-0.83; P=0.41), or intensity (t (78)=0.36; P=0.72). DISCUSSION: Frequent cannabis users did not demonstrate hyperalgesia. This finding should help to inform evaluations of the relative harms and benefits of cannabis analgesic therapies.

Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes.

There is an active and growing interest in cannabis female inflorescence (Cannabis sativa) for medical purposes. Therefore, a definition of its quality attributes can help mitigate public health risks associated with contaminated, substandard, or adulterated products and support sound and reproducible basic and clinical research. As cannabis is a heterogeneous matrix that can contain a complex secondary metabolome with an uneven distribution of constituents, ensuring its quality requires appropriate sampling procedures and a suite of tests, analytical procedures, and acceptance criteria to define the identity, content of constituents (e.g., cannabinoids), and limits on contaminants. As an independent science-based public health organization, United States Pharmacopeia (USP) has formed a Cannabis Expert Panel, which has evaluated specifications necessary to define key cannabis quality attributes. The consensus within the expert panel was that these specifications should differentiate between cannabis chemotypes. Based on the secondary metabolite profiles, the expert panel has suggested adoption of three broad categories of cannabis. These three main chemotypes have been identified as useful for labeling based on the following cannabinoid constituents: (1) tetrahydrocannabinol (THC)-dominant chemotype; (2) intermediate chemotype with both THC and cannabidiol (CBD); and (3) CBD-dominant chemotype. Cannabis plants in each of these chemotypes may be further subcategorized based on the content of other cannabinoids and/or mono- and sesquiterpene profiles. Morphological and chromatographic tests are presented for the identification and quantitative determination of critical constituents. Limits for contaminants including pesticide residues, microbial levels, mycotoxins, and elemental contaminants are presented based on toxicological considerations and aligned with the existing USP procedures for general tests and assays. The principles outlined in this review should be able to be used as the basis of public quality specifications for cannabis inflorescence, which are needed for public health protection and to facilitate scientific research on cannabis safety and therapeutic potential.

Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no known cure and with an average life expectancy of 3-5 years post diagnosis. The use of complementary medicine such as medicinal cannabis in search for a potential treatment or cure is common in ALS. Preclinical studies have demonstrated the efficacy of cannabinoids in extending the survival and slowing of disease progression in animal models with ALS. There are anecdotal reports of cannabis slowing disease progression in persons with ALS (pALS) and that cannabis alleviated the symptoms of spasticity and pain. However, a clinical trial in pALS with these objectives has not been conducted. METHODS AND ANALYSIS: The Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease trial is a randomised, double-blind, placebo-controlled cannabis trial in pALS conducted at the Gold Coast University Hospital, Australia. The investigational product will be a cannabis-based medicine extract (CBME) supplied by CannTrust Inc., Canada, with a high-cannabidiol-low-tetrahydrocannabinol concentration. A total of 30 pALS with probable or definite ALS diagnosis based on the El Escorial criteria, with a symptom duration of <2 years, age between 25 and 75years and with at least 70% forced vital capacity (FVC) will be treated for 6 months. The primary objective of the study is to evaluate the efficacy of CBME compared with placebo in slowing the disease progression measured by differences in mean ALS Functional Rating Scale-Revised and FVC score between the groups at the end of treatment. The secondary objectives are to evaluate the safety and tolerability of CBME by summarising adverse events, the effects of CBME on spasticity, pain, weight loss and quality of life assessed by the differences in mean Numeric Rating Scale for spasticity and Numeric Rating Scale for pain, percentage of total weight loss and ALS specific quality of life-Revised questionnaire. ETHICS AND DISSEMINATION: The study has been approved by the local Institutional Review Board. The results of this study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT03690791.

Cannabis Therapeutics and the Future of Neurology.

Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.

Practical considerations in medical cannabis administration and dosing.

Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment. With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable. In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.

The Case for the Entourage Effect and Conventional Breeding of Clinical Cannabis: No "Strain," No Gain.

The topic of Cannabis curries controversy in every sphere of influence, whether politics, pharmacology, applied therapeutics or even botanical taxonomy. Debate as to the speciation of Cannabis, or a lack thereof, has swirled for more than 250 years. Because all Cannabis types are eminently capable of cross-breeding to produce fertile progeny, it is unlikely that any clear winner will emerge between the "lumpers" vs. "splitters" in this taxonomical debate. This is compounded by the profusion of Cannabis varieties available through the black market and even the developing legal market. While labeled "strains" in common parlance, this term is acceptable with respect to bacteria and viruses, but not among Plantae. Given that such factors as plant height and leaflet width do not distinguish one Cannabis plant from another and similar difficulties in defining terms in Cannabis, the only reasonable solution is to characterize them by their biochemical/pharmacological characteristics. Thus, it is best to refer to Cannabis types as chemical varieties, or "chemovars." The current wave of excitement in Cannabis commerce has translated into a flurry of research on alternative sources, particularly yeasts, and complex systems for laboratory production have emerged, but these presuppose that single compounds are a desirable goal. Rather, the case for Cannabis synergy via the "entourage effect" is currently sufficiently strong as to suggest that one molecule is unlikely to match the therapeutic and even industrial potential of Cannabis itself as a phytochemical factory. The astounding plasticity of the Cannabis genome additionally obviates the need for genetic modification techniques.

Pharmacological Foundations of Cannabis Chemovars.

An advanced Mendelian Cannabis breeding program has been developed utilizing chemical markers to maximize the yield of phytocannabinoids and terpenoids with the aim to improve therapeutic efficacy and safety. Cannabis is often divided into several categories based on cannabinoid content. Type I, Δ9-tetrahydrocannabinol-predominant, is the prevalent offering in both medical and recreational marketplaces. In recent years, the therapeutic benefits of cannabidiol have been better recognized, leading to the promotion of additional chemovars: Type II, Cannabis that contains both Δ9-tetrahydrocannabinol and cannabidiol, and cannabidiol-predominant Type III Cannabis. While high-Δ9-tetrahydrocannabinol and high-myrcene chemovars dominate markets, these may not be optimal for patients who require distinct chemical profiles to achieve symptomatic relief. Type II Cannabis chemovars that display cannabidiol- and terpenoid-rich profiles have the potential to improve both efficacy and minimize adverse events associated with Δ9-tetrahydrocannabinol exposure. Cannabis samples were analyzed for cannabinoid and terpenoid content, and analytical results are presented via PhytoFacts, a patent-pending method of graphically displaying phytocannabinoid and terpenoid content, as well as scent, taste, and subjective therapeutic effect data. Examples from the breeding program are highlighted and include Type I, II, and III Cannabis chemovars, those highly potent in terpenoids in general, or single components, for example, limonene, pinene, terpinolene, and linalool. Additionally, it is demonstrated how Type I - III chemovars have been developed with conserved terpenoid proportions. Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment.

Cannabis Roots: A Traditional Therapy with Future Potential for Treating Inflammation and Pain.

Introduction: The roots of the cannabis plant have a long history of medical use stretching back millennia. However, the therapeutic potential of cannabis roots has been largely ignored in modern times. Discussion: In the first century, Pliny the Elder described in Natural Histories that a decoction of the root in water could be used to relieve stiffness in the joints, gout, and related conditions. By the 17th century, various herbalists were recommending cannabis root to treat inflammation, joint pain, gout, and other conditions. There has been a subsequent paucity of research in this area, with only a few studies examining the composition of cannabis root and its medical potential. Active compounds identified and measured in cannabis roots include triterpenoids, friedelin (12.8 mg/kg) and epifriedelanol (21.3 mg/kg); alkaloids, cannabisativine (2.5 mg/kg) and anhydrocannabisativine (0.3 mg/kg); carvone and dihydrocarvone; N-(p-hydroxy-ß-phenylethyl)-p-hydroxy-trans-cinnamamide (1.6 mg/kg); various sterols such as sitosterol (1.5%), campesterol (0.78%), and stigmasterol (0.56%); and other minor compounds, including choline. Of note, cannabis roots are not a significant source of Δ9-tetrahydrocannabinol (THC), cannabidiol, or other known phytocannabinoids. Conclusion: The current available data on the pharmacology of cannabis root components provide significant support to the historical and ethnobotanical claims of clinical efficacy. Certainly, this suggests the need for reexamination of whole root preparations on inflammatory and malignant conditions employing modern scientific techniques.

Even High Doses of Oral Cannabidol Do Not Cause THC-Like Effects in Humans: Comment on Merrick et al. Cannabis and Cannabinoid Research 2016;1(1):102-112; DOI: 10.1089/can.2015.0004.

This short communication examines the question whether the experimental data presented in a study by Merrick et al. are of clinical relevance. These authors found that cannabidiol (CBD), a major cannabinoid of the cannabis plant devoid of psychotropic effects and of great interest for therapeutic use in several medical conditions, may be converted in gastric fluid into the psychoactive cannabinoids delta-8-THC and delta-9-THC to a relevant degree. They concluded that "the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a positive physiological response." They issued a warning concerning oral use of CBD and recommend the development of other delivery methods. However, the available clinical data do not support this conclusion and recommendation, since even high doses of oral CBD do not cause psychological, psychomotor, cognitive, or physical effects that are characteristic for THC or cannabis rich in THC. On the contrary, in the past decades and by several groups, high doses of oral CBD were consistently shown to cause opposite effects to those of THC in clinical studies. In addition, administration of CBD did not result in detectable THC blood concentrations. Thus, there is no reason to avoid oral use of CBD, which has been demonstrated to be a safe means of administration of CBD, even at very high doses.

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed "pharmacological treasure trove."