Kratom
The natural product kratom (Mitragyna speciosa) has been used for hundreds of years in Southeast Asia, primarily brewed in teas. In Malaysia and Thailand, there is a long history of kratom use as a social custom, in laborers to invigorate work, and in individuals addicted to opioids as a self-remedy for their dependence and withdrawal in lieu of prescription or illicit opioid use. The use of kratom-related products around the world, including the US, is rapidly expanding, with users reporting the same benefits as those described in Southeast Asia. Kratom contains dozens of alkaloids, and the McCurdy group is actively isolating individual alkaloids while the McMahon group is engaged in exploring their pharmacology in whole animals. In addition to gaining a better understanding of the pharmacological mechanisms behind the biological activity of the alkaloids contained in this natural product, the team is actively developing synthetic analogs of kratom alkaloids as potential medicines for the treatment of pain, psychiatric conditions including depression, and drug dependence. Additionally, Grundmann’s group is conducting epidemiological research on the patterns of Kratom use, its potential health impact, and risk of dependence. Grundman’s scientific collaborations further explore the effects of Kratom in both traditional Kratom users in Southeast Asia and in Western countries. Given the diverse range of pharmacological effects of Kratom extracts, the observed health implications can provide important insights into its current and future applications as a dietary supplement and potential medicine.
Dr. Grundmann is also broadly interested in natural products and their clinical applications. Together with various national and international collaborators he conducts pre-clinical and clinical experiments to further our understanding of complex plant extracts and their potential benefits in a range of disorders.
- Prozialeck WC, Avery BA, Boyer EW, Grundmann O, Henningfield JE, Kruegel AC, McMahon LR, McCurdy CR, Swogger MT, Veltri CA, Singh D. Kratom policy: The challenge of balancing therapeutic potential with public safety. Int J Drug Policy. 2019, 70, 70-77.
- Hiranita T, Leon F, Felix JS, Restrepo LF, Reeves ME, Pennington AE, Obeng S, Avery BA, McCurdy CR, McMahon LR, Wilkerson JL. The effects of mitragynine and morphine on schedule-controlled responding and antinociception in rats. Psychopharmacology (Berl). 2019 [Epub ahead of print]
- Sharma A, Kamble SH, León F, Chear NJ, King TI, Berthold EC, Ramanathan S, McCurdy CR, Avery BA. Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometry. Drug Test Anal. 2019 [Epub ahead of print]
Kava
Kava is derived from Piper methysticum, a shrub that grows in the South Pacific islands. It is traditionally prepared as an aqueous suspension from the roots of this shrub and is consumed as a daily beverage to help people relax, socialize, and improve sleep quality. It has also been marketed as a dietary supplement on the US market for decades to support calm and relaxation. Kava was once used to treat mild and moderate anxiety in Europe in the 1990s. It was banned for clinical use in Europe from 2001 – 2014 because of concerns about potential hepatotoxicity. Limited epidemiological data suggest that kava consumption may reduce cancer risk. Various biological activities have also been reported for kava in vitro and in vivo.
Attracted by these interesting biological activities and potential risks, the Xing group have been investigating kava from multiple directions with the integrations of pharmacognosy, medicinal chemistry, molecular and cellular biology, various animal models, bioanalytical chemistry, and clinical trials. Over the years, the group have demonstrated its potential to reduce cancer risk in several animal models, particularly against tobacco carcinogen NNK-induced lung tumorigenesis with unprecedented efficacy. We have identified dihydromethysticin, a natural kavalactone, as the lung cancer chemopreventive agent with a unique mechanism of action. Surrogate biomarkers have been identified from the in vivo studies, which facilitate its clinical translation. At the same time, extensive structure-activity relationship is ongoing to potentially identify more potent lead candidates and to help identify the up-stream cellular target(s). The group have also identified some lipophilic ingredients that synergize with the hepatotoxicity of acetaminophen in vivo, which may account for kava’s hepatotoxic risk. Guided by some of these results, a number of clinical trials have been implemented or planned. The ultimate goal is to provide a better understanding of this interesting botanical product and guide its best use in humans, including its benefit(s), risk(s), the responsible ingredient(s), the mechanisms of action, and the quality control and quality assurance of proper product(s) for human use.
- Triolet J, Shaik AA, Gallaher DD, O’Sullivan MG, Xing C. Reduction in colon cancer risk by consumption of kava or kava fractions in carcinogen-treated rats. Nutrition and cancer. 2012, 64(6), 838-846.
- Narayanapillai SC, Leitzman P, O’Sullivan MG, Xing C. Flavokawains A and B in kava, not dihydromethysticin, potentiate acetaminophen-induced hepatotoxicity in C57BL/6 mice. Chemical research in toxicology. 2014, 27(10), 1871-1876.
Seaweed
Marine algae (seaweeds) have been used as a food source and medicine for centuries. This includes green algae (Chlorophyta), red algae (Rhodophyta), and brown algae (Ochrophyta). Seaweed is a major part of the diet in parts of Asia. Numerous beneficial properties of algal extracts and constituents have been reported, however, usually only in a descriptive manner, without pinpointing specific bioactive components or invoking specific molecular pathways. For example, green algae of the genus Ulva also known as sea lettuce are among the most commonly consumed seaweeds. They have been associated with multiple beneficial effects, such as anti-inflammatory, protective and detoxifying activity, that are helpful in many diseases and conditions. The majority of these effects are related to antioxidant activity. The Luesch group has embarked on a quest to back up the anecdotal evidence revolving around dietary seaweeds and found that the antioxidant activity of several seaweed extracts is associated not with direct radical scavenging, but with a more sustained mechanism involving activation of endogenous antioxidant enzymes through regulating the activation of the antioxidant response element (ARE) at the transcriptional level. The promise exhibited by the initial screening campaigns of seaweed extract libraries has prompted more in-depth chemical and biological evaluation of selected species. The work has led to the discovery of several small molecules with Nrf2-dependent antioxidant and anti-inflammatory activity. The ultimate goal is to characterize bioactive components of seaweeds on the molecular and cellular levels and to identify the relevance of these changes caused by the seaweed ingestion that may drive beneficial functional responses.
- Ratnayake R, Liu Y, Paul VJ, Luesch H. Cultivated sea lettuce is a multiorgan protector from oxidative and inflammatory stress by enhancing the endogenous antioxidant defense system. Cancer Prev Res. 2013, 6(9), 989-999.
- Wang R, Paul VJ, Luesch H. Seaweed extracts and unsaturated fatty acid constituents from the green alga Ulva lactuca as activators of the cytoprotective Nrf2-ARE pathway. Free Radic Biol Med. 2013, 57, 141-153.