<i>Cannabis</i> and cannabinoids as an alternative remedy in metabolic syndrome

Montoya-Alatriste, Claudia Ali; Alarcon-Aguilar, Francisco Javier

doi:10.1590/s2175-97902022e20161

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e20161 copy

Cannabis and cannabinoids as an alternative remedy in metabolic syndrome

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Metabolic syndrome (MetS), an epidemic defined as a group of interconnected physiological, biochemistry, clinical, and metabolic factors, directly increases the risk of cardiovascular disease, atherosclerosis, type 2 diabetes, and death. MetS therapy includes diet, physical exercise, and a poly-pharmacological intervention. Cannabis is mainly recognized for its recreational uses and has several medical applications for neurological diseases, due to its hypnotic, anxiolytic, antinociceptive, anti-inflammatory, and anticonvulsant activities. Although several clinical observations in Cannabis smokers suggest metabolic effects, its utility in metabolic disorders is unclear. This review aims to determine under what conditions Cannabis might be useful in the treatment of MetS. Cannabis contains 120 phytocannabinoids, of which Δ⁹-THC mediates its psychoactive effects. Cannabinoids exert biological effects through interactions with the endocannabinoid system, which modulates several physiologic and metabolic pathways through cannabinoid receptors (CB1/CB2). Signaling through both receptors inhibits neurotransmitter release. In general, endocannabinoid system stimulation in Cannabis smokers and Δ⁹-THC signaling through CB1 have been implicated in MetS development, obesity, and type 2 diabetes. In contrast, CB1 antagonists and non-psychotropic phytocannabinoids like cannabidiol reduce these effects through interactions with both cannabinoid and non-cannabinoid receptors. These pharmacological approaches represent a source of new therapeutic agents for MetS. However, more studies are necessary to support the therapeutic potential of Cannabis and cannabinoids in metabolic abnormalities.

Keywords:
Cannabis; Cannabinoids; Metabolic syndrome; CB1 antagonists; Cannabidiol; Diabetes mellitus

Author (año)	Proposal	Risk factors
Kylin (1920)	Association	Hypertension/hyperglycemia/goat
Vague (1947)	Association	Obesity visceral/ metabolic abnormalities in ECD and DT2
Avogaro and Crepaldi (1965)	Metabolic syndrome	Hypertension/hyperglycemia/obesity
Reaven (1988)	Syndrome “X”	Introduce the concept of IR in ECV and DT2 (obesity was omitted)
Kaplan (1989)	"The quartet of death"	Obesity/IG, hypertriglyceridemia/hypertension
Haffner et al. (1992)	Insulin resistance syndrome	Obesity/IG, hypertriglyceridemia/hypertension

Organism/Clinical parameter	Insulin resistance	Bodyweight	Lipids	Blood pressure	Glucose	Other
World Health Organization (WHO)	IGT, IFG, T2DM, Sensibility to the insulin + another 2	Waist/hip >0.9 (M), <0.85 (W) or IMC >30 kg/m²	TG >150 mg/dl and/or HDL-C <35 mg/dL (M) and/or <39 mg/dl (W)	≥140/90 mm Hg	IGT, IFG, or DT2	MCA or ALB/CREA
European Group for the study of Insulin Resistance (EGIR)	Plasmatic insulin >75 percentile + another 2	WC ≥94 cm (M), >80 cm (W)	TG >150 mg/dl and/or HDL-C <35 mg/dL (M or W)	≥140/90 mm Hg or Rx hypertension	IGT, IFG (without DT2)	-
National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP III)	None; with at least 3 of the 5 next parameters	WC ≥102 cm (M); ≥88 cm (W)	TG >150 mg/dl HDL-C <40 mg/dL (M) <50 mg/dl (W)	≥130/85 mm Hg	≥110 mg/dl (include diabetes)	-
American Association of Clinical Endocrinologist (AACE)	IGT or IFG + or anyone of the next factors with base in clinical trials	BMI ≥ 25 kg/m²	TG >150 mg/dl HDL-C <40 mg/dL (M) <50 mg/dl (W )	≥130/85 mm Hg	IGT, IFG (without DT2)	Other of IR
International Diabetes Federation (IDF)	None	WC incremented (specific population) + 2 of the next	TG >150 mg/dl or Rx TG HDL-C <40 mg/dL (M) <50 mg/dl (W) or Rx HDL-C	≥130 systolic 85 mm Hg diastolic or Rx of hypertension	≥100 mg/dl (include diabetes)	-

No.	Type	No. de compounds
1	Δ⁹-tetrahydrocannabinol (Δ⁹-THC)	23
2	Δ⁸-tetrahydrocannabinol (Δ⁸-THC)	5
3	Cannabigerol (CBG)	16
4	Cannabicromene (CBC)	9
5	Cannabidiol (CBD)	7
6	Cannabinodiol (CBND)	2
7	Cannabielsoine (CBE)	5
8	Cannabicyclol (CBL)	3
9	Cannabinol (CBN)	11
10	Cannabitriol (CBT)	9
11	Miscellaneous	30

	Used in clinic	Experimental
Dronabinol (Marinol®)	Synthetic THC in sesame oil. Anorexia-cachexia in AIDS patients. Nausea and vomit due to antineoplastic therapy	CP55,940	Bicyclic cannabinoid. Like THC, it was used to demonstrate the existence of specific cannabinoid receptors in rat
Nabilone®	THC analog. Nausea and vomit due to antineoplastic therapy	HU-210	Analog of the THC 100-800 times more potent
Levonantradol	Tetracyclic cannabinoid (intramuscular)	HU-308, AM1241, JWH015	CB2 agonists
HU-211 (Dexanabinol)	No-psychotropic Cannabinoid. TNF inhibitor and NMDA antagonist. Clinical assay: Phase III (neuroprotector)	Win-55,212-2	CB1 cannabimimetic, structurally no associated to cannabinoids
		PRS-211,092	No-selective agonist
		ACEA	CB1 agonist
		AM630	CB2 antagonist

Central	Peripherical
Appetite and ingest	Inflammation
Nociception	Hormonal release
Frame of mind	Insulin sensibilization
Synaptic transmission	Cardiovascular function
Neuroprotection	Respiratory function
Motor function	Reproductive function
Memory	Immunomodulator
Learning	Bone formation
Fear	Energetic metabolism
Neural development	Architecture, proliferation, motility, adhesion and cellular apoptosis
Thermogenesis
Sleep/wake cycle
Synaptic plasticity
Stress response

	Central	Peripherical
CB1	Cortex	Spleen
	Nucleus accumbens	Tonsils
	Basal ganglia	Heart
	Hypothalamus	Prostate
	Cerebellum	Uterus
	Hippocampus	Ovary
	Amygdala	Sympathetic nerve endings
	Spinal cord	Adipose tissue
	Brainstem	Muscle
		Liver
		Gastrointestinal apparatus
		Pancreas
CB2	Glial cells	Spleen
	Spinal cord	Tonsils
		Heart
		Immune system: B and T cells, and macrophages
		Endothelium
		Bones
		Liver
		Pancreas

Central	Peripherical
Relaxation
Euphoria
Increased sensorial experiences (sounds, taste, color)
Time distortion	Pulse acceleration
Disinhibition	Increased blood pressure
Impaired concentration capacity	tachycardia
Reverie of the mind	Mydriasis
Tremor
Vertigo
Depression
Motor incoordination
Memory affectation

Trial identifier	Type of study	Trial objective	Kind of patients	Sample size	Results	Reference
National Institute on Drug Abuse (NIDA) Intramural Research Program and the Johns Hopkins Bayview Clinical Research Unit	Randomized, crossover, double-blind, placebo-controlled study	Investigate the effects of Cannabis by different routes on appetitive and metabolic hormones	Healthy adult Cannabis in several presentations	20	Cannabis use modulated blood concentrations of some appetitive and metabolic hormones, chiefly insulin	*Farokhnia et al., 2020*Farokhnia M, McDiamid GR, Newmeyer MN, Munjal V, Abulseoud OA, Huestis MA, et al. Effects of oral, smoked, and vaporized cannabis on endocrine pathways relates to appetite and metabolism: a randomized, double-blind, placebo-controlled, human laboratory study. Translational Psychiatry. 2020;10(1):71.
National Health and Nutrition Examination Survey (NHANES) 2009-2016	Prospective analysis (population survey)	Examine the association of marijuana use with insulin resistance	Adults with different body mass index (BMI) status.	129 509	Marijuana use reduces fasting insulin and HOMA-IR in obese but not non-obese adults, independent of the time of use.	Ngueta, Ndjaboue, 2020Ngueta G, Ndjabouse R. Lifetime marijuana use in relation to insulin resistance in lean, overweight, and obese US adults. J Diabetes. 2020;12(1):38-47.
National Health and Nutrition Examination Survey (NHANES) 2009-2016	Prospective analysis (population survey)	Explore the association of marijuana use with mean plasma fasting insulin levels and HOMA-IR	Obese adults with different HOMA-IR.	65 209	Marijuana use reduced fasting insulin levels and HOMA-IR score in US obese adults with HOMA-IR ≥ 2.13, but not in those with HOMA-IR < 2.13 or ≥ 5.72. The impact of Cannabis use is more significant after long-term exposure and is independent of BMI.	Ngueta, 2020Ngueta G. Impact of lifetime marijuana use on fasting plasma insulin levels and HOMA-IR score in obese adults with and without insulin resistance. Acta Diabetol. 2020;57(2):133-140.
Women’s Interagency HIV Study (WIHS) and Multicenter AIDS Cohort Study (MACS),	Prospective analysis (population survey)	Determine whether the self-reported frequency of marijuana use is associated with incident T2D	Women and men with and at risk for HIV	6260	Reduced risk of type 2 diabetes in marijuana users compared to none users, although all associations were not statistically significant. The results were similar for HIV-positive and HIV-negative participants.	*Okafor et al., 2020*Okafor CN, Plankey MW, Goodman-Meza D, Li M, Bautista KJ, Bolivar H, et al. Association between self-reported marijuana use and incident diabetes in women and men with at risk for HIV. Drug Alcohol Depend. 2020;209(4):107935.
Longitudinal study (R01 DA031176, PI: Gonzalez)	Prospective analysis from a longitudinal study	Examine the associations between Cannabis use and BMI	Adolescents ages 14-17 at risk for escalation in Cannabis use	401	Negative association between Cannabis use and BMI.	*Ross et al., 2020*Ross JM, Pacheco-Colón I, Haws SW, Gonzalez R. Bidirectional longitudinal associations between Cannabis use and body mass index among adolescents. Cannabis Cannabinoid Res . 2020;5(1):81-88..
Cannabis Eating Experience Questionnaire (CEEQ)	Online survey	Analyze appetite- and eating-related aspects of Cannabis self-administration	Adults from UK, Netherlands, and USA	798	Cannabis influences both the motivational factors that lead to the initiation of eating and the hedonic factors implicated in encouraging and maintaining eating.	*Roberts et al., 2019*Roberts CA, Jager G, Christiansen P, Kirkham TC. Exploring the munchies: An online survey of users’ experiences of cannabis effects on appetite and the development of a Cannabinoid Eating Experience Questionnaire. J Psychopharmacol. 2019;33(7):1149-1159.
US-based Coronary Artery Risk Development in Young Adults (CARDIA) study	Prospective analysis (population survey)	Examine Cannabis-attributable immunomodulation	Young adults	5115	Cannabis use was not associated with any of the biomarkers studied. Former Cannabis use was inversely associated with fibrinogen levels, whereas the associations were weaker for serum CRP and IL-6.	*Alshaarawy et al., 2019*Alshaarawy O, Sidney S, Auer R, Green D, Soliman EZ, Goff, DC, et al. Cannabis use and markers of systemic inflammation: The coronary artery risk development in young adults study. Am J Med. 2019;132(11):1327-1334.e1.
National Inpatient Sample 2009-2010 database using the Ninth Revision of International Classification of Disease code 304.3.	Prospective analysis (population survey)	Examine the prevalence of cardiovascular risk factors and events amongst patients with Cannabis use	Patients aged 18-55 years	316 397	Cannabis users increased the prevalence of most risk factors, including hypertension, obesity, tobacco use, and alcohol use, although diabetes mellitus was more frequently observed in non-cannabis users. Hyperlipidemia rates were similar between both groups.	*Kalla et al., 2018*Kalla A, Krishnamoorthy PM, Gopalakrishnan A, Figueredo VM. Cannabis use predicts risks of heart failure and cerebrovascular accidents: results from the National Inpatient Sample. J Cardiovasc Med (Hagerstown). 2018;19(9):480-484.
US-based Coronary Artery Risk Development in Young Adults (CARDIA) study	Prospective analysis (population survey)	Determine the association between lifetime exposure to Cannabis and subclinical atherosclerosis in mid-life.	Young adults	3498	Cumulative marijuana use was not associated with measures of atherosclerosis among middle-aged adults never exposed to tobacco. Still, a trend to increase the risk of atherosclerosis with very high exposure to Cannabis was observed.	*Auer et al., 2017*Auer R, Sidney S, Goff D, Vittinghoff E, Pletcher MJ, Allen NB, et al. Lifetime marijuana use and subclinical atherosclerosis: The Coronary Artery Risk Development in Young Adults (CARDIA) study. Addiction. 2017;113(5):845-856.
Baltimore Longitudinal Study of Aging (BLSA)	Randomized, double-blind, crossover study	Determine that the stimulation of the endocannabinoid system due to Nabilone regulates incretin secretion.	Healthy men of 21- to 55-year-olds Nabilone (THC analog)	20 lean, 20 obese	Nabilone induced a highly significant elevation (80%) in post-dose fasting GIP levels. Post-dose fasting insulin levels were elevated. Elevated GIP levels in obesity were observed as a consequence of increased endocannabinoid levels by Nabilone.	*Chia et al., 2017*Chia ChW, Carlson OD, Liu D, González-Mariscal I, Calvo SSC, Egan JM. Incretin secretion in humans is under influence of cannabinoid receptors. Am J Physiol Endocrinol Metab. 2017;313(3):E359-E366.
National Health and Nutrition Examination Survey (NHANES) 2005-2010	Prospective analysis (population survey)	Explore the relationship of Cannabis use with MetS	Users of 20- to 59-year-olds	8478	A specific association with the minor probability of suffer MetS in Cannabis users of 20-30 and 45-59 years old was observed.	*Vidot et al., 2016*Vidot DC, Prado G, Hlaing WWM, Florez HJ, Arheart KL, Messiah S. Metabolic syndrome among marijuana users in the United States: An analysis of National Health and Nutrition Examination Survey data. Am J Med . 2016;129(2):173-179.

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[1] *Correspondence: F. J. Alarcon-Aguilar. Laboratorio de Farmacología. Dpto. Ciencias de la Salud. División de Ciencias Biológicas de la Salud. Unidad Iztapalapa. Av. San Rafael Atlixco 186, México. CDMX, 09340. Ap. Postal 55-535. Mexico. Phone: 52-55-58046483. FAX 52-55-58044727. E-mail address: aaasj2@prodigy.net.mx.