Tinkering with THC-to-CBD ratios in Marijuana

The composition of marijuana remains largely unregulated, even though consumption is rising in parallel with rising evidence of harm [1]. The marijuana plant produces over 100 different cannabinoids, including the structurally distinct principals, ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Over two decades, THC concentrations in retail marijuana rose dramatically, while CBD levels declined, with THC:CBD ratios now 8 times greater than before [2]. U.S. federal guidelines have not been established for THC content or THC:CBD ratios in retail marijuana. The Food and Drug Administration has approved low-dose THC (initial oral dose 0.04 mg/kg b.i.d.) for treating nausea/vomiting associated with cancer chemotherapy for non-responders, for treating AIDS-associated anorexia/weight loss, and CBD (initial oral dose 2.5 mg/kg, b.i.d.) to treat rare, severe forms of epilepsy. Smokable marijuana (~20% THC; ~0.9 mg/kg) delivers THC at ~20 times the FDA-approved initial dose of oral THC and is now obtainable at THC:CBD ratios varying from 1:1 to 80:1. THC doses and ratios are germane to establishing safety standards, as THC and CBD engender markedly different or even antagonistic molecular, pharmacological and neuropsychiatric effects [3, 4]. Limiting its therapeutic potential, THC in marijuana acutely elicits psychosis, anxiolysis, intoxication, and cognitive impairment. With early initiation and prolonged use, marijuana is addictive and is “likely to increase the risk of developing schizophrenia and other psychoses; the higher the use the greater the risk” [5]. No comparable evidence implicates CBD in engendering euphoria, psychosis, cognitive impairment, anxiety, or addiction. High concentrations of THC and high ratios of THC:CBD in marijuana are associated with more robust euphoria, anxiety, and psychotic symptoms in otherwise normal people. Conversely, CBD mitigates the effects of THC by attenuating anxiety, cognitive deficits or psychosis: (a) in heavy marijuana users consuming a product with high CBD:THC ratios; (b) in marijuana users administered CBD or, (c) in research subjects given CBD combined with THC [4, 6, 7]. CBD diminishes the adverse effects of THC by poorly understood processes [3]. One of many possible targets is DCC, which guides formation of frontal cortical dopamine circuits during adolescence and is associated genetically with major psychiatric disorders. In rhesus monkeys treated repeatedly with THC, our pilot data showed upregulation of dcc mRNA in various brain regions, but if administered CBD combined with THC (CBD:THC ratio 3:1), dcc was not elevated [8]. If confirmed with a larger “n”, does THC in marijuana dysregulate dcc expression in human frontal cortex? Does dysregulation alter adolescent brain dopamine circuit formation, thereby contributing to psychosis in susceptible early onset, heavy marijuana users? Our preliminary research is one of many tantalizing leads that warrant comparisons of the pharmacological and pathological consequences of high/low THC doses, high/low THC:CBD ratios and whether CBD can attenuate the effects of a range of THC doses, especially after long-term use. Except for cannabidiol-specific products, most retail marijuana strains contain immoderately high concentrations of THC and scant CBD levels. Accumulating research documents the pitfalls of an unregulated industry producing psychoactive compounds, while operating without a foundation of informed science.

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Acknowledgements

The author thanks her indispensable collaborators Dr. Susan George, Dr. Jack Bergman, Dr. Stephen Kohut, Dr. Sarah Withey, Dr. Zhicheng Lin, Dr. Yasmin Hurd, Dr. A. Hasbi, and students Sophia Charles and Andrew Gumbert.

Funding

The research is funded by a grant from the NIH-National Institute on Drug Abuse NIDA: DA042178. The author receives funding for specific speaking engagements focused on the public health challenges of drugs of abuse and solutions.

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Correspondence to Bertha K. Madras.

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Madras, B.K. Tinkering with THC-to-CBD ratios in Marijuana. Neuropsychopharmacol 44, 215–216 (2019). https://doi.org/10.1038/s41386-018-0217-3

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