HighlightsEschscholzia californicais a perennial plant tradi-tionally used by Native Americans for alleviatingpain and inducing sleep.California Poppy contains alkaloids, some of whichare unique to the plant[2, 4].Modern research has shown limited evidence in ani-mal models that the California Poppy has analgesic,sedative, and anxiolytic properties when taken as anethanolic extract or hot tea preparation[1, 7].BackgroundEschscholzia californica, otherwise known as the Cali-fornia Poppy, is a perennial traditional medicinal plantused by Native Americans and is present throughoutthe Western United States for its analgesic and sedativeeffects.California Poppy contains a complex mix of tertiaryand quaternary isoquinoline alkaloids with higher con-tent in flowering plants. It contains certain alka-loids such as escholtzine, californidine, and N-methyllau-rotetanine which have been shown to inhibit binding of[3H]8-OH-DPAT to the 5-HT1Areceptor, which is a re-ceptor subtype commonly found in anxiety and otherpsychiatric disorders. Metabolic studies in rats haveshown that californine and protopine are two alkaloidswhich are extensively metabolized.Figure 1: An image of a field of California Poppy plants.This type of binding activity is also known to havepotential drug interactions by modulating cytochromeP450 (CYP) activity, in particular through CYP3A4, forwhich many other drugs are also metabolized[2, 4]. In-deed, ethanolic extracts of California Poppy do affectCYP, however, tea extracts utilizing hot water do not.Other studies have seen extracts of California Poppy tar-geting the GABAAreceptor as well as serotonin recep-torsin-vitro.California Poppy extracts have been shown in ani-mal models to validate its traditional therapeutic use,demonstrating sedative, analgesic, and anxiolytic ef-fects which are likely linked to benzodiazepine receptoractivation.Unlike benzodiazepines, the poppy extracts did notshow anti-convulsant and muscle relaxant activity.California Poppy has been shown to improve sleep la-tency and durationin-vitro.Mode of ActionGiven insufficient literature in human and animal stud-ies on the exact mechanism which the California Poppyfunctions, there are only a few potential modes of actionwhich are known today.Gamma-aminobutyric acid (GABA) is recognized asone of the main neurotransmitters responsible for sleepregulation, and is thought that changes in centralGABAergic neurotransmission could be responsible forthe effects on insomnia from herbal remedies, given thatGABAAreceptor modulation is one of four key mecha-nisms of action for approved pharmacological therapeu-tics for insomnia. One of the earlier papers examin-ing the California Poppy’s effects on sleep proposed ben-zodiazepine receptor activation as one potential modesof action. Today it is known that over 20% of neu-rons in the brain are GABAergic and that the mostcommonly used hypnotics exert their effects on GABAsystems through allosteric modulation of the benzodi-azepine site. There are three GABA receptors in-volved in the regulation of sleep, and California Poppyis thought to act on the GABAAreceptor – however it isunknown if this is through direct binding similar to bar-biturates or if through binding to only selective subunitswithin the receptor similar to newer sleep medications.Although a hot tea preparation has been found notto inhibit CYP activity (and thus poses less of a riskof herbal-drug interactions), it has also been foundto have a sedative effect on rat models. The lack ofCYP activity is attributed to a lack of escholtzine, al-locryptopine, and protopine in the aqueous extract com-pared to an ethanolic extract which contains those 3 alka-loids and inhibits CYP activity. As is discussed[6, 7],the pharmacological effects and thus the mode of actionthrough which the California Poppy works is not onlydose-dependent, but also dependent on the method ofpreparation and alkaloids present in the final mixture.Additionally, it was seen that the alkaloids in anethanolic extract of California Poppy also bind to sero-tonin receptors, more specifically the 5-HT1Areceptor,preventing the binding of serotonin. This is thought tocontribute to the strong activity of the ethanolic extract,and also warrants further research into various potentialdrug interactions.The toxicology and metabolism of California Poppyis also not widely studied in literature. It is thoughtthat the alkaloids californine and protopine undergodemethylation and methylation procedures and areexcreted as the phenolic metabolites demethylene,demethylenemethyl californine, and demethylenemethylprotopine.Pharmacological EffectsA study on the effects of an aqueous extract of CaliforniaPoppy on mice showed sedative effects in the two com-partments and staircase tests, as well as a high-dosageeffect of sleep induction. It was also found that lowdoses yielded anxiolytic properties as determined by thestaircase and light/dark choice situation tests compara-ble to the effects of benzodiazepene. A follow-on papershowed that ethanolic extracts of California Poppy, al-though similar to benzodiazepenes, lacked their anticon-vulsant, muscle relaxant, and antipsychotic properties.It was also found that the California Poppy extracthad no antidepressant properties, no antihistaminic ef-fects, and no central analgesic effects (although dose-dependent peripheral analgesic effects were observed).A double-blind, randomized, placebo-controlled studyof patients with generalized anxiety examined the effectsof a combination of Hawthorn, California Poppy, andmagnesium; It was determined that total and somaticHamilton scale scores and subjective patient-related anx-iety fell in a fashion greater than the placebo. Thisgives insight into potential future formulations contain-ing California Poppy as one tool with clinical relevancein decreasing mild to moderate anxiety.Potential UsesAs described above, California Poppy has mechanismsof action similar to benzodiazepenes but with slightly differing properties[6, 7].These analgesic, and sedative effects[1, 4] as well astheir mechanisms of action largely support traditionalusage of the plant in alleviating pain and for sedativeeffects.Preliminary research also suggests that CaliforniaPoppy could be clinically relevant in applications as ananxiolytic, especially as part of a cocktail formulation.However, more research is needed and care needs to betaken to consult with medical professionals and furtherstudy the potential drug interactions[2, 4].References O. Bruni, L. Ferini-Strambi, E. Giacomoni, andP. Pellegrino. Herbal remedies and their possible ef-fect on the gabaergic system and sleep.Nutrients,13(2), 2021. S. Gafner, B. Dietz, K. McPhail, I. Scott, J. Glin-ski, F. Russell, M. McCollom, J. Budzinski, B. Fos-ter, C. Bergeron, M. Rhyu, and J. Bolton. Al-kaloids from eschscholzia californica and their ca-pacity to inhibit binding of [3h]8-hydroxy-2-(di-n-propylamino)tetralin to 5-ht1a receptors in vitro.Journal of Natural Products, 69(3):432–435, 2006. M. Hanus, J. Lafon, and M. Mathieu. Double-blind, randomised, placebo-controlled study to eval-uate the efficacy and safety of a fixed combinationcontaining two plant extracts (crataegus oxyacan-tha and eschscholtzia californica) and magnesium inmild-to-moderate anxiety disorders.Current Medi-cal Research and Opinion, 20(1):63–71, 2004. PMID:14741074. V. Manda, M. Ibrahim, O. Dale, M. Kumarihamy,S. Cutler, I. Khan, L. Walker, I. Muhammad, andS. Khan. Modulation of cyps, p-gp, and pxr by es-chscholzia californica (california poppy) and its alka-loids.Planta Med, 82(6):551–558, 2016. L. D. Paul and H. H. Maurer. Studies on themetabolism and toxicological detection of the es-chscholtzia californica alkaloids californine and pro-topine in urine using gas chromatography–mass spec-trometry.Journal of Chromatography B, 789(1):43–57, 2003. 40th Annual International Meeting of TheInternational Association of Forensic Toxicologists. A. Rolland, J. Fleurentin, M. Lanhers, C. Younos,R. Misslin, and J. Mortier, F.a nd Pelt. Be-havioural effects of the american traditional plant es-chscholzia californica: Sedative and anxiolytic prop-erties.Planta Med, 57(3):212–216, 1991. A. Rolland, J. Fleurentin, M. C. Lanhers, R. Misslin,and F. Mortier. Neurophysiological effects of an ex-tract of eschscholzia californica cham.(papaveraceae).Phytotherapy Research, 15(5):377–381, 2001.This document was created on September 7, 2021 and last up-dated on September 10, 2021.