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Transcript of SQ3R
Preread. Scan the material. Look for titles, subtitles, pictures, diagrams, bold and italic type. Process Task *Found on Teachers Pay Teachers and created by the blogger of The Teaching Reef is a poster, strategy outline chart, and fold-able brochure activity for both fiction and non-fiction. Save this one to your favorites, it's free! Resources Conclusion Students can be evaluated by using a SQ3R handout that students are able to utilize as a guide while reading. Students should be able to ask themselves questions and actively think about the text. Students should be able to answer their questions as well as find other important information in the text.
Observation of this strategy in use would be another type of assessment to use. Evaluation Get more out of
what you read. SQ3R is a useful technique for fully absorbing written information. It helps you create a good mental framework of subjects, into which you can fit facts correctly. It helps you set study goals. It also prompts you to use the review techniques that will help to fix information in your mind. (http://www.mindtools.com/pages/article/newISS_02.htm)
Did you catch all of that? Ok, if you are like me, you probably read this but couldn't recite or summarize a word of it.
That's where SQ3R comes in to play! Let's check it out! The SQ3R Reading Method Q-Question
Ask yourself questions about what you have just read and write them down. Who, what, where, when, why. R-Read
Read each section to answer your questions. R-Recite
Cover the answers to your questions and recite them by saying them out loud or writing them down. R-Review
Go back over the material. Reread your notes and go over the main points. http://blackboard.boisestate.edu/@@/AD3A87F63462DDB951B9A38D0C609564/courses/1/1133-SC-12100ED-LTCY440003/content/_1665172_1/Pirates%20book.pdf Alright! Let's test it out! Step 1 & 2 (Survey & Question)Click the link below and look over this book about Pirates. Read the title, subtitles, picture captions, etc. As you survey the book, ask yourself what questions you may have. Write them down on the left side of note paper.
Step 3,4,5 (Read, Recite, Review)Read the story and answer your questions as you go. Write them down on the right side of your note paper. Highlight anything else that seems important to you. Recite the answers to your questions out loud and lastly, review again and again all of the important information. http://www.teacherspayteachers.com/Product/SQ3R-A-Strategy-For-Text *Quick and simple information on SQ3R:
http://www.pbchistoryonline.org/middle-school-lessons/Strategies/strategy--SQ3R.htm The SQ3R Reading Strategy is a great tool to get students (and adults) thinking about what they are reading while they are reading. Students who can effectively use SQ3R will be able to "get it" the first time they read a text. And as a bonus, you can use the strategy while reading your college textbooks!


E-cigarettes use poses a threat to adolescents and pregnant mothers, says WHOListen /
Electronic-cigarettes known as e-cigarettes pose a threat to people's health and efforts made to discourage adolescents from smoking.
That's according to the World Health Organization (WHO).
WHO on Tuesday issued a report on regulating e-cigarettes which are marketed by manufacturers as aids to quit smoking, or as healthier alternatives to tobacco.
The agency said that since 2005, the product has created a global industry with 466 brands worth an estimated $3 billion a year.
Douglas Bettcher is Director of Prevention of Non-communicable Diseases at WHO.
"Evidence shows that while they are likely to be less toxic than conventional cigarettes, e-cigarettes use poses threats to adolescents and fetuses of pregnant mothers using these devices. E-cigarettes also increase the exposure of non-smokers and bystanders to nicotine and a number of other toxicants, the report indicates, and existing evidence also shows that e-cigarettes aerosol is not merely, as is often quoted, water vapour." (29")
The report on "Electronic nicotine delivery systems" (ENDS) will be discussed at a tobacco control conference scheduled to be held in Moscow in October.
Daniel Dickinson, United Nations


Some people start a business to improve the quality of their life. Others seek to work for themselves. And some see an opportunity in the market they can't resist.
But sometimes the desire to use business as a means of creating positive change ignites the entrepreneurial spirit in you.
This is called “social entrepreneurship,” and it’s an approach to business that’s gaining popularity as globalization brings conversations about sustainability and international development to a world stage. It’s also leading more people to ask themselves, “What can I do for the world today?”
Social entrepreneurship involves starting mission-based enterprises that dedicate some or even all of their profits toward furthering a cause—giving their customers a purpose behind every purchase.
- What is social entrepreneurship?
- Finding a product to sell and a mission to lead
- Funding your social enterprise
- Marketing your mission
- The rise of social entrepreneurship
What is social entrepreneurship?
Social entrepreneurship is when you start a business for a philanthropic cause. Also called “altruistic entrepreneurship”, it’s broad and can include both non-profit organizations like Doctors Without Borders, which rely almost exclusively on donations and grants, and for-profit companies like Tesla, which turns a profit by putting its clean energy products front and center.
Social entrepreneurs are innovators who start companies and organizations that are committed to giving back.
What’s a social enterprise?
A social enterprise is a type of business where the bottom line and success metrics are measured in more than just profits. Instead, social enterprises typically measure success based on a triple bottom line:
- People. The human impact of your business, and your ability to affect social change, improve lives, and develops a community in a sustainable way.
- Planet. Your environmental impact—how you contribute to a sustainable planet or reduce the carbon footprint (CO2 emissions) of your business and customers.
- Profit. Like traditional businesses, social enterprises need to make money in order to sustain themselves, pay workers, and grow as an enterprise.
Social entrepreneurship is about harnessing commerce for a good cause.
What are the types of social entrepreneurship?
Social entrepreneurship takes many other forms too:
- Nonprofit. A tax-exempt, non-business entity that invests excess funds back into the mission.
- Co-operative. A business organized by and for its members. Credit unions and community grocery stores are some examples of co-ops. REI is also an example of a co-op.
- Social purpose business. These businesses start on the foundation of addressing a social mission.
- Social firm. Social firms employ those in the community who need jobs. FareStart is a great example—it employs at-risk youth and serves healthful meals.
- Socially responsible business. These companies support social missions as a part of their day-to-day business operations.
- For-profit. Perhaps the vaguest category, these businesses are profit-first but donate funds, raise awareness, or otherwise support causes. Warby Parker’s Buy a Pair, Give a Pair program is a prime example.
Do social entrepreneurs make money?
The short answer is that it depends. In many cases, social entrepreneurs do make money. They’re living proof that you can be successful as a business owner and do good at the same time. However, in some cases, the entrepreneurs elect not to take a profit for themselves.
One of the challenges to succeeding in social entrepreneurship is that it’s easy to measure profit (did you make money or did you not make money?), but it’s not as easy to measure your impact on people or the planet and communicate that to others.
Social entrepreneurs adopt a business model that puts their mission at the center of their business and are held accountable to their customers and stakeholders based on their proposed impact.
The benefits of building a social enterprise
For today’s consumers and businesses, social responsibility is a growing priority as concerns about climate change, international development, and supply chain ethics become a more prominent topic of international discussion.
In a CSR survey by Cone Communications, 87% said they will purchase a product because a company supports an issue they care about. This reflects a shift in consumer awareness about the impact of their purchase decisions. Not only are businesses held to a higher standard, but many consumers are holding themselves to a higher standard as well.
So while social enterprises, by definition, must dedicate a portion of their profits to the impact they want to make, they do enjoy the following benefits that help them succeed:
- Mission-based branding. A company story with a cause at its core makes consumers feel good about every purchase they make from you.
- Partnership opportunities. A social enterprise, because of its mission-based motivations, can partner with other non-profit organizations and for-profit companies to leverage existing audiences and established reputations to create a presence in their market. “In kind” resources and discounts are not uncommon for social enterprises.
- Press coverage. Publications and blogs love to cover social innovation and changemakers and their impact, helping social enterprises evangelize their efforts and share their impact.
- Certifications and support systems. Social enterprises can be eligible for grants, “impact investing” opportunities that focus on job creation and sustainability, and special certifications such as a Benefit Corporation status that make it easier to establish credibility, commit to transparency, and attract customers, employees, volunteers, and investors.
For the sake of this piece, we’ll look at what it takes to create a sustainable for-profit social enterprise. And that starts, as most businesses do, with figuring out which of your business ideas you want to pursue and what that business will sell.
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Finding a product to sell and a mission to lead
The mission might come first for social entrepreneurs, but that doesn’t eclipse the importance of choosing the right things to make and sell. When all is said and done, a for-profit social enterprise needs to make money to survive just like any other business idea.
But there’s a pattern amongst successful social enterprises of establishing a good “product-cause fit” that aligns their mission with what they sell.
Social entrepreneurship examples
Taaluma Totes, which produces socially responsible bags made with fabrics sourced from across the globe, was founded to cultivate more connection between cultures around the world. Plus, it uses 20% of its profits as micro loans for farmers and small business owners in the countries from which its fabrics are sourced—enabling the farmers and small business owners to continue to fund and run their fabric operations.
Chocolate company Askinosie also focuses on sourcing from international markets. Its cocoa beans come from the Amazon, the Philippines, Tanzania, and Ecuador. Its transparency report publicly shows exactly how much is paid out to small farmers. Fellow chocolate brand Taza Chocolate also publishes its own transparency report to show how it supports farmers.
Cotopaxi makes and sells outdoor gear for adventurers and travelers, dedicating 2% of total revenue to provide grants to specific non-profits that seek to alleviate poverty in different parts of the world.
Social entrepreneur David Merritt founded two ventures with a more local focus that address social problems facing Detroit youths:
- Merit: a for-profit apparel brand that donates 20% of all purchases to fund college scholarships for underserved youth.
- Give Merit: a non-profit organization that raises money for and hosts youth programs.
Learn More: Find out how to start a t-shirt business of your own.
LSTN Sound Co. sells premium headphones and donates a portion of its profits to the Starkey Hearing Foundation to help restore hearing. It’s helped more than 30,000 people around the world.
Love Your Melon sells beanies and hats and, on top of donating 50% of profits to pediatric cancer research and supporting patients, has a Campus Crew Program that mobilizes students across the United States to help with its mission.
These are only a handful of the many examples of ecommerce-based social enterprises that do a great job of not only tying a sense of purpose to their products, but using traditional business strategies, such as event marketing and giveaways, to promote their mission.
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Defining your mission and illustrating your impact
A social enterprise’s mission is a competitive advantage that can help them stand out in a crowded market—if they can communicate their motivation and the impact they can make.
Many social enterprises adopt a model where they donate a portion of profits to a cause, but that's not the only way to position your company as a social enterprise.
"It’s not just saying, ‘Hey, we have a social mission as an organization, and X percent of our sales goes to nonprofit X, Y, and Z.’ I think it needs to be deeper and more authentic than that."
There are also social enterprises that focus on:
- Creating jobs within the communities they care about, such as hiring local ex-convicts or ethically outsourcing production to communities in need of fair work and career development opportunities.
- Reducing their carbon footprint by planting trees or going out of their way to reduce carbon emissions throughout their entire supply chain and educating customers about the topic.
- Hosting workshops and people-development initiatives to teach skills and empower others to build better lives for themselves and their communities.
- Advocating for diversity and inclusion on behalf of underrepresented groups and becoming an engine of inspiration, such as GoldieBlox does by making toys to expose young girls to the joys of engineering.
Transparency and sustainable impact are essential for a successful social enterprise. And these things are easier to achieve if your cause is close to your heart and measurable.
“Integrity is doing the right thing, even when no one is watching,” in the words of C.S Lewis.
Transparency is about visibly demonstrating your integrity and holding yourself accountable to your mission and the people who support it.
Depending on your mission, you can directly implement your plans for change as a social entrepreneur and expand your contributions as you grow. But if you choose to partner with non-profit organizations (NPOs) to help execute the “social” part of your social enterprise (as many do), be sure to do your homework before you reach out. Ask questions like:
- What am I ultimately giving back to?
- How will my contributions actually be used and what are the organization’s operating costs?
- How does the organization measure its success?
- Is their impact sustainable or will it only end up doing more harm in the long run?
- Does this organization have an ethical history as a non-profit?
This is all part of your founding story—the tale of why you started your business—and will likely come up again and again in your elevator pitch, About page, PR efforts, and more. So refine your story with your mission in mind and your action plan for creating change.
Funding your social enterprise
Social enterprises are accountable to the cause they support, which means automatically setting aside a portion of future revenue to invest in increasing impact.
Social entrepreneurs have to be creative with how they raise money, and crowdfunding is a popular option.
Crowdfunding websites such as Kickstarter not only help you raise money to get your idea off the ground but also expose your mission to a community that exists on the very premise of supporting projects and causes they believe in.
GoldieBlox's Kickstarter campaign exceeded its funding goal by a landslide and helped launch the successful business it is today.
There are also a growing number of grants you can apply to for social enterprises that meet specific requirements, and the trend of “impact investing,” where the return on investment expected isn’t just financial but includes social and environmental impact as well.
How to market your social enterprise
What works when it comes to marketing can vary from business to business, but the need for transparency and the “for-benefit” position that social enterprises adopt make certain marketing strategies especially effective at generating awareness.
After all, you’re marketing your mission, not just your business.
1. Content marketing
Digital media and the internet enable storytelling at a scale that wasn’t possible before.
From shooting videos to sharing photos on social media, social enterprises can leverage content to share real stories of the impact they’re making and provide proof that every customer’s purchase helped do some good in the world.
Visit the affected community and film a documentary-style video. Or create an infographic for a data-based illustration of your impact or why your vision of change is needed.
There are ample opportunities for a social enterprise to spread its mission and tell its stories with content.
Learn more with these resources:
- 7 Free Content Creation Tools to Help You Earn More Engagement Online
- 8 Brilliant Blogs Run by Ecommerce Stores (And What You Can Learn From Them)
- 4 Ecommerce Blog Post Templates To Build Traffic For Your Store
Since NPOs often host events for fundraising and other initiatives, social enterprises can partner with or sponsor the causes that relate to their mission.
Whereas this would be deemed a marketing expense for traditional businesses, for a social enterprise it can double as an investment in their cause.
3. Public relations
With a feel-good story and a carefully crafted pitch, a social enterprise can win media mentions from bloggers and publications that are constantly on the lookout for something interesting to cover.
Since there’s a purpose behind your company, there’s usually a lot more meat to the story by default than there might be for a traditional business.
Learn more about getting media coverage for your brand:
- 7 Free Outreach Tools That Will Level Up Your Business Development Game
- How to Create a Press Kit That Gets Publicity for Your Business
- How to Write a Press Release That Journalists Won't Ignore
4. Social media
Purchasing isn’t the only way for people to support your mission. They can donate their voices online too.
According to an analysis by CoSchedule on why people share things online, 84% used social sharing as a way to support causes or issues they care about.
As long as you integrate your mission into your marketing, you can expect your audience to help you spread the word.
Learn more in these articles:
- How to Create a Social Media Content Calendar in 4 Simple Steps
- How to Create a Social Media Marketing Strategy: A Beginner's Guide
- 17 Social Media Marketing Strategies to Grow Your Online Sales
The rise of social entrepreneurship
Social entrepreneurship isn’t the only way a business can be for-benefit and not just for-profit.
Many companies are owning their social responsibility based on a growing belief that those with the power to do so can and should try to make the world a better place.
Our connected world has brought about a new era of awareness, where we can find problems to solve and lives to improve across the street or across the world if we choose.
People from all over are making the decision to make change in whatever way they can, whether it’s by being more conscious of what they buy as consumers or building an engine for social and environmental good by becoming entrepreneurs.
With a single website, you can reach a world of consumers who want to help you make a difference. Shopify is a flexible platform to build your site, share your mission, and generate sales to fund that mission. It’s all about figuring out your cause and what to sell on Shopify to support that cause.


In typical dorid nudibranchs, the mantle is thick and extends over the foot. The surface
of the mantle may bear tubercles which vary in size, shape and number and are often a character
used to identify nudibranchs. In many dorids acid glands and/or spicules are incorporated in the mantle tissue and it is thought that these are mainly defensive in function. However in Goniodorids, Polycerids and some other dorid families the mantle is progressively reduced to a ridge around the side of the body, from which pallial tentacles or processes arise. These processes usually have coloured tips and contain defensive glands and have been shown to produce chemicals distateful to fish. These chemicals are often manufactured from similar chemical compounds in the bryozoan or ascidian prey, or may be the same molecules selectively re-secreted by the nudibranch.
In aeolid nudibranchs the mantle is extended into long finger-like projections called
cerata (singular; ceras). The cerata contain branches of digestive gland and often this is
visible through the ceratal epidermis. In aeolids the tips of the cerata contain cnidosacs
which usually store nematocysts (stinging cells) that are obtained from ingested cnidarian
prey, such as hydroids, sea-anemones and soft corals. If disturbed, the nudibranch is capable
of discharging these stinging cells through a terminal pore in the ceras; this is an effective
deterrent to predatory fish.
The gills. In nudibranchs the gills are probably the most important respiratory organ, however gaseous exchange also occurs over the entire body surface. In dorids the gills consist of several feather-like structures that encircle the anus. This structure is termed the branchial plume and is situated in the posterior part of the animals' back. In true dorids (ie. Dorididae, Rostangidae, Chromodorididae, etc. ) the gills can be retracted into a gill-pocket. These dorids are known as cryptobranch dorids as opposed to phanerobranch dorids in which the gills are contractile but not retractile into a pocket. Goniodorids, Onchidorids and Polycerids are phanerobranch dorids. In aeolids the cerata function as gills. The ceratal epidermis is thin enough to enable oxygen from the surrounding water to diffuse in and carbon dioxide (a waste product of respiration) to diffuse out. In the dendronotaceans the cerata are branched or tuberculate, this increases the surface area available for gas exchange. The arminaceans are a mixed bag, with cerata in most species, occasionally branched, but in the Arminidae leaf-like gills are hidden in a ridge between the mantle and foot.
The oral veil. In some nudibranchs the front region of the head is extended to form an oral veil. This structure varies from one species to another e.g. in Dendronotus frondosus it has branched processes; in Polycera quadrilineata it forms up to six finger-like processes and in Doto species it is smooth edged with two lateral flaps.
The oral tentacles. Many nudibranch species have a pair of processes, one on either side of the mouth, which are probably involved in identifying food by taste or touch.


Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188–197, 2020).
Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride.
Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related.
Consistent with mitragynine’s pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating β-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.
Kratom products are used globally for health and well-being, improved mood, sleep, attention, and coffee-caffeine-like alerting effects (Grundmann, 2017; Henningfield et al. 2018, 2022; Swogger et al. 2022). There is recreational use; however, many people who use opioids recreationally report kratom as a poor substitute for producing opioid-like euphoria but do find it useful to self-manage withdrawal and discontinue opioid use (Coe et al. 2019; Garcia-Romeu et al. 2020; Prozialeck et al. 2019; Swogger et al. 2022). Estimates of incidence and prevalence of intake vary from 2 to 16 million in the United States (US) (American Kratom Association 2019; Covvey et al. 2020; Henningfield et al. 2021; Palamar 2021; Schimmel et al. 2021) and many millions more globally, with the highest prevalence in Southeast Asia and Indonesia where kratom grows in abundance and has been widely consumed for centuries (Brown et al. 2017; Cinosi et al. 2015; Prozialeck et al. 2021; WHO ECDD 2021; Vicknasingam et al. 2010).
People also read: Kratom effects; Can You Overdose On Kratom?
Deaths attributed directly to kratom use in the US and globally are rare and were not documented in Southeast Asia (Prozialeck et al. 2019; Ramanathan and McCurdy 2020). Analyses of kratom-associated deaths found that most of such deaths are more likely attributed to the use of other substances and causes not related to kratom (Gershman et al. 2019; Henningfield et al. 2019; National Institute on Drug Abuse 2020; Olsen et al. 2019).
Provisional estimates from the US Centers for Disease Control and Prevention (CDC) indicated that nearly 76,000 of more than 100,000 drug overdose deaths in 2021 were attributable to opioids (CDC 2021). In October 2021, the US Department of Health and Human Services (US DHHS) announced that drug overdose prevention efforts would include a substantial increase in harm reduction efforts to reduce opioid and other drug overdose deaths (US DHHS 2021). Kratom was not mentioned in the 2021 US DHHS announcement; however, US national surveys indicated that kratom is increasingly taken as a harm reduction strategy by thousands of opioid users to reduce and/or eliminate their opioid use related to pain and/or opioid use disorder (Grundmann 2017; Grundmann et al. 2018; Coe et al. 2019; Garcia-Romeu et al. 2020; Prozialeck et al. 2019, 2020, 2021; Swogger et al. 2022).
Oral mitragynine was investigated because mitragynine is the only alkaloid present at potentially biologically active levels in many widely marketed and consumed kratom products that also include mitragynine isolates. Many products have low or nondetectable concentrations of other alkaloids that may contribute to respiratory and other effects (Chakraborty et al. 2021; Sharma et al. 2019; Sharma and McCurdy 2021). Furthermore, unlike opioids and other substances widely used recreationally that are taken intravenously, insufflated, or inhaled (e.g., O'Brien 2015), kratom is taken almost exclusively by the oral route as dried kratom leaf powder teas, foods, or beverages to mask its bitter unpleasant taste, or leaf powder-filled capsules (Cinosi et al. 2015; Henningfield et al. 2018, 2022; Ramanathan and McCurdy 2020; Singh et al. 2016).
Earlier studies concluded that mitragynine has low respiratory depressant potential as compared to morphine or other µ-opioid agonists but did not include blood oxygen and related blood gas measures. Macko et al. (1972) measured respiratory rate in cats and dogs following morphine and/or codeine or mitragynine administration and found fewer effects from mitragynine. In another recently published study (Hill et al. 2022), 3 to 90 mg/kg mitragynine doses were compared to 3, 10, and 30 mg/kg morphine doses administered by oral gavage to mice tested in plethysmography chambers enabling measurement of minute respiratory volumes. Morphine produced dose-dependent decreases in minute volumes. The maximal effect of 90 mg/kg mitragynine was between that obtained with 10 to 30 mg/kg morphine.
The present study was designed to further evaluate mitragynine’s respiratory effects including effects on blood gases. The same basic approach as FDA utilized in its own studies comparing a broad range of substances to a prototypic respiratory depressing opioid, oxycodone (Xu et al. 2020, 2021) was employed. Oxycodone was selected by the FDA as the prototypic opioid for comparison and the dosing strategy was typical of what FDA often recommends to drug developers, namely inclusion of the therapeutic dose equivalent, and two or more supratherapeutic doses of oxycodone (6.75, 60, and 150 mg/kg).
The rational for selection of the mitragynine doses was to begin with a low dose utilized by other investigators (20 mg/kg), then systematically increase the dose until the highest tolerable dose or the highest chemically feasible dose due to ethical limitations followed by the laboratory on oral gavage (10.0 mL/kg or about 3.5 mL maximum) and limited mitragynine solubility. The laboratory determined that 400 mg/kg was the maximum dose based on solubility in Tween 20 solvent in a volume of approximately 3.5 mL (adjusted individually per animal based on actual body weight). The 400 mg/kg dose is substantially larger than the highest dose employed in most animal studies and is equivalent to 64.5 mg/kg in humans (dividing by 6.2 for allometric scaling). This is many times higher than is consumed by humans, whose typical per serving intake ranges from approximately 0.35 to 2.0 mg/kg per serving (Prozialeck et al. 2020; Singh et al. 2016; Swogger et al. 2022).
Respiratory effect measures were partial pressure carbon dioxide (pCO2), oxygen saturation (sO2), partial pressure oxygen (pO2), bicarbonate (HCO3), pH, and lactate in rat blood after oral mitragynine and oxycodone. Observable signs of drug effects for 12 h after dosing by veterinary-trained technicians with extensive experience in rat safety and pharmacokinetics studies are also reported (see details in the “Methods” section). The full pharmacokinetics of oxycodone and mitragynine will be reported elsewhere, whereas the present article reports maximum concentrations (Cmax) and time of Cmax (Tmax), confirming dose-dependent increases in oxycodone and mitragynine.
Adult male Sprague Dawley rats (n = 48) approximately 80 days old weighed between 350 and 375 g at the time of surgical placement of carotid artery catheters at Charles River Laboratories. Actual body weights on dosing days ranged from 323.0 to 372.8 g. Animals were acclimated for 1 day at the CARE research facility due to concerns about the patency of the arterial catheters for collecting the primary blood gas and pharmacokinetic parameters. To ensure catheter patency, the catheters were flushed with heparinized saline every other day. A small amount of heparinized saline was left in the catheter as a “locking solution” to prevent clots from forming.
Rats were single-housed in a temperature-controlled room (20–26 °C) under a 12:12 h light/dark cycle, with 15–70% humidity and corn cob bedding. Animals had ad libitum access to Teklad Rodent Chow 2018 and filtered tap water, and no other medications were administered.
Animal care procedures were approved by the CARE Research Institutional Animal Care and Use Committee and animal welfare complied with the US Department of Agriculture’s (USDA) Animal Welfare Act (9 CFR Parts 1, 2, and 3), the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences 2011), and laboratory standard operating procedures. Animals were euthanized and disposed of without necropsy in accordance with accepted American Veterinary Medical Association guidelines (Underwood and Anthony 2020).
Drug preparation and administration
All drug doses were administered by oral gavage in maximum volumes of 10 mL/kg based on pre-session body weights for each animal following the ethical limitations of the laboratory. Table 1 includes doses and the number of days from delivery of the animals to Care Research from Charles River Labs that each dose was administered. Oxycodone hydrochloride from Sigma-Aldrich (Product Number O1378-500 mg) was dissolved in sterile water the morning of each test day. Doses were based on the weight of 100% pure oxycodone hydrochloride (6.75, 60.0, and 150.0 mg/kg). Mitragynine, 99.9% pure, extracted from Mitragyna Speciosa from Coryn Pharmaceuticals (Product Number 5057), was dissolved, or suspended in 20% Tween 20, because it is not water soluble. Mitragynine dissolved poorly in 20% Tween 20 above concentrations of roughly 10 to 15 mg/mL, requiring mitragynine doses to be prepared individually for each animal immediately before testing using vortex and sonication. To achieve the 240 and 400 mg/kg doses, the solution was in the form of a suspension, mixed well by vortex, and administered within 1 min of each preparation. Mitragynine was stored at room temperature in the dark and used within 62 days of receipt, with study completion within seven days from the first to the last dose.
Table 1 Administered doses, sequence of drug dosing, and the day following rat receipt the session was conducted. Test sessions were initiated between 7:30 and 8:30 AM during the light cycle.
| Group # drug dose mg/kg*|| Sequence|| Days after rats delivered for session|
| 1. Oxycodone 6.75|| 5|| 8**|
| 2. Oxycodone 60|| 4|| 4|
| 3. Oxycodone 150|| 3|| 2|
| 4. Mitragynine 20|| 1|| 1|
| 5. Mitragynine 40|| 1|| 1|
| 6. Mitragynine 80|| 2|| 2|
| 7. Mitragynine 240|| 5|| 8**|
| 8. Mitragynine 400|| 4|| 4|
*Doses were calculated for each animal based on its pre-session body weight
**Blood gas analyzer failure required testing after a 4-day washout
The three initial mitragynine doses (20, 40, and 80 mg/kg) were the same as in earlier rat studies (Avery et al. 2019; de Moraes et al. 2009; Jagabalan et al. 2019), where data suggested maximum tolerable doses might be several times higher than 80 mg/kg. Drs. Henningfield and Huestis were briefed by the study director (Dr. Magnuson) 12 h after dosing each test day to determine if the next provisionally planned dose was likely tolerable and/or if it should be adjusted to document the dose–response curve as fully as possible. Because there were no observed behavioral effects, adverse events, or changes in blood gases at 80 mg/kg, the next dose was adjusted to 240 mg/kg, and the highest dose set to the maximum chemically feasible dose of 400 mg/kg.
Test session sequence
Two groups were tested each day. Table 1 shows the dosing sequence and the days after the animals were delivered to the laboratory. Mitragynine doses increased from the lowest to highest doses, while oxycodone doses descended from the highest to lowest doses. Due to a malfunction of the blood gas analyzer, animals dosed with oxycodone 60 mg/kg and mitragynine 240 mg/kg had blood gases measured for only 2 h. No data from these doses were utilized, and the animals underwent a 4-day washout period. The oxycodone 60 mg/kg dose was administered the next day to naïve rats. Animals originally dosed with 60 mg/kg oxycodone were re-dosed with 6.75 mg/kg oxycodone after the 4-day washout, and animals originally dosed with 240 mg/kg mitragynine were re-dosed with 240 mg/kg mitragynine after the 96 h washout. Protocol changes were approved by the ethical committee and permitted rats adequate recovery from the few blood collections performed.
Test session protocol
Animals were removed from their home cages for weighing at approximately 6 am each day and at 24 h post-dose, for drug administration and blood collections, and immediately returned to their home cages. Blood collections occurred pre-dose between 7:30 and 8:30 am and 1, 2, 4, 6, 8, and 12 h post-dose. A total of 300 µL whole blood (EDTA anticoagulant) was drawn at each time point (2.1 mL total). Approximately 100 µL was for blood gas analysis with a portable blood gas testing device (VetScan i-STAT Alinity V Handheld Analyzer with CG4 + cartridges (Zoetis/Abaxis/Abbott)) at 7 time points following procedures described by Xu et al. (2020). Blood gases were measured within 10 min after each blood collection.
A single blood gas measurement obtained data for all blood gas parameters at each time point for each animal and at each dose. A two-way ANOVA with multiple comparisons was performed, with the Dunnett test accounting for multiple comparisons, and significance set to p <
0.05. The remaining 200 µL blood was processed immediately for subsequent plasma oxycodone or mitragynine analyses, with storage at − 60 °C or below. Arterial ports were flushed with saline-heparin after each blood draw and every other day.
Observable signs were collected by the two veterinary-trained session monitors who identified and recorded adverse events and deviations from normal behavior. Observable signs included general activity (lethargy, impaired motor function, and righting response), response to stimulus (finger snap or clap near the animal), abnormal behaviors such as bracing (defined as a rigid posture with limbs slightly splayed), and apparent increases or decreases in respiration from normal/control. These items were given special attention as effects commonly observed in mu-agonist opioid studies, and our interest in comparing mitragynine’s effects to those of oxycodone, a prototypical mu-agonist opioid. Observations were conducted at each blood collection and monitored closely following dosing, and anytime an abnormality was observed by one of the two veterinary-trained session monitors. Observations were detailed in writing by the technician who made them. The technician observers were not blinded to treatments.
Six animals received each dose; 200 μL (K2EDTA) blood was processed to obtain plasma (~ 100 μL) for pharmacokinetic analysis. A total of 336 samples were analyzed for oxycodone and mitragynine in two separate validated LC–MS/MS assays. Pharmacokinetic analyses were performed with a non-compartment model (WinNonlin Phoenix professional, Version 8.3, Certara, Princeton, NJ) to determine pharmacokinetic parameters. The maximum plasma concentration (Cmax) and time of maximum plasma concentration (Tmax) following 6.75, 60, and 150 mg/kg oxycodone and 20, 40, 80, 240, and 400 mg/kg/d mitragynine group are presented. Due to space limitations and the many pharmacodynamic findings in this manuscript, a separate report will describe complete oxycodone and mitragynine pharmacokinetics.
Oxycodone and mitragynine pharmacokinetics
Table 2 shows the maximum observed plasma concentrations (Cmax) for oxycodone and mitragynine. Cmax increased by dose from 20 to 400 mg/kg, but each dose increase did not produce a significant increase based on a one-way ANOVA with Tukey’s post hoc analysis and a significance value of p < 0.05. Mitragynine Cmax results were significantly different between the 20 and 40 mg/kg doses and the 240 and 400 mg/kg mitragynine doses, and the 80 mg/kg dose and the 400 mg/kg dose. Although the 240 mg/kg mean Cmax was 5601 and the 400 mg/kg mean Cmax was 7982 ng/mL, this increase was not statistically significant.
Table 2 Median maximum plasma concentrations (Cmax), with the minimum and maximum plasma concentration observed by drug and dose
| n|| Median Cmax|
| Oxycodone|| || || |
| 6.75|| 6|| 33.5|| 10.7–51.5|
| 60|| 6|| 39.9|| 34.5–1179|
| 150|| 5*|| 131|| 93.2–5532|
| Mitragynine|| || || |
| 20|| 6|| 723|| 317–1010|
| 40|| 6|| 1720|| 1043–2032|
| 80|| 6|| 2497|| 1538–3125|
| 240|| 4**|| 5182|| 3783–7444|
| 400|| 6|| 7513|| 4404–10,096|
*One animal’s data were not included in the analysis due to incomplete washout prior to redosing
**Another animal’s data were not included in the analysis due to incomplete washout prior to redosing and one eliminated due to extreme outlier for Cmax
The maximum plasma concentration generally occurred within 1–2 h (Tmax) but varied across animals, occurring as late as 12 h in some animals. Three animals were not included in the pharmacokinetic or pharmacodynamic analyses due to two animals not achieving concentrations below the limit of quantification (one in 150 mg/kg oxycodone group and one in the 240 mg/kg mitragynine group) after a 4-day washout period prior to redosing. One animal in the 240 mg/kg mitragynine group had a catheter blockage and tail blood was collected at time points 6, 8, and 12 h; however, for unexplained reasons, the blood analytic result was an extreme outlier for Cmax at 23,425 ng/mL—a concentration threefold higher than any obtained with the 400 mg/kg dose. This result failed the outlier test and was not included in any analyses.
Respiratory blood gas results
Figure 1 presents the change from pre-dose baseline levels over time of oxycodone and mitragynine on the partial pressure of carbon dioxide (pCO2), which Xu et al. (2021) suggested is more sensitive than partial pressure of oxygen (pO2). None of the three blood gas parameters significantly deviated from baseline at the therapeutic 6.75 mg/kg oxycodone dose. The pCO2 was significantly increased relative to baseline at 1, 4, and 6 h for the 60 mg/kg oxycodone dose and at 1, 2, and 4 h for the 150 mg/kg oxycodone dose. There was a rapid decrease in sO2 and pO2 following the 60 and 150 mg/kg oxycodone doses, with the sO2 significantly depressed at 1, 4, and 6 h for the 60 mg/kg oxycodone dose and 1, 2, 4, and 6 h for the 150 mg/kg oxycodone dose, while no statistically significant decreases in pO2 were observed for either 60 or 150 mg/kg oxycodone. By 8 h post-drug administration, pCO2, sO2, and pO2 were no longer significantly different from baseline for higher oxycodone doses. There were no significant differences in pCO2, sO2, and pO2 following 20, 40, 80, 240, or 400 mg/kg mitragynine from baseline to 12 h.
Changes from baseline over time following oxycodone in a partial pressure of carbon dioxide (pCO2), c oxygen saturation (sO2), and e partial pressure of oxygen (pO2); and changes from baseline over time following mitragynine b partial pressure of carbon dioxide (pCO2), d oxygen saturation (sO2), and f partial pressure of oxygen (pO2). Asterisks indicate significant differences from baseline (p≤0.05, one asterisks (*) 60 and two asterisks (**) 150 mg/kg oxycodone). Oxycodone is shown in purple. 6.75 mg/kg, dotted lines and circles; 60 mg/kg, dashed lines and squares; 150 mg/kg, solid lines and triangles. Mitragynine is shown in green; 20 mg/kg, dotted lines and circles; 40 mg/kg, short dashes and squares; 80 mg/kg, dashed and dotted lines and triangles; 240 mg/kg, long dashed lines and Xs; 400 mg/kg, solid lines and diamonds. Figure1 Source
Figure 2 presents oxycodone and mitragynine effects on blood lactate, bicarbonate (HCO3), and pH. No mitragynine or oxycodone dose produced any statistically significant changes in HCO3 concentrations for 12 h after drug administration with the exception of the 400 mg/kg at 12 h post-drug administration. There were no significant changes from baseline in blood lactate following any oxycodone or mitragynine dose. Following 150 mg/kg oxycodone, the pH dropped significantly compared to baseline from 1–4 h and at 1 h after the 60 mg/kg oxycodone dose. There were no significant changes from baseline in pH after any mitragynine dose.
Changes from baseline over time and by dose (see key) following oxycodone on the left side panels (blue) and mitragynine on the right side panels (green) for lactate (top panels), bicarbonate (HCO3) (middle panels), and pH (bottom panels). Asterisks indicate significant differences from baseline (p≤0.05, one asterisk (*) 60 and two asterisks (**) 150 mg/kg oxycodone). Figure2 Source
Observable signs including potential drug-related adverse effects
There was no evidence of opioid or other drug effects or any behavioral observation in any of the animals receiving 6.75 mg/kg oxycodone or 20, 40, 80, and 240 mg/kg mitragynine that was visibly apparent to staff monitoring the animals.
Following 60 and 150 mg/kg oxycodone, the trained observers recorded numerous reports of behavioral effects including decreased activity, lethargy, apparently decreased respiration, and impairments to motor function. Four of the six animals at 60 mg/kg oxycodone showed overt signs of opioid exposure including pronounced behavioral effects and lethargy typical of opioids. One animal receiving 60 mg/kg oxycodone died between the 2 and 4 h time points, apparently as a result of the animal pulling its catheter and causing internal bleeding. These data were not used in the results. Four of the five remaining animals in the 60 mg/kg group appeared normal at 24 h, while one animal was found dead at 7:53 AM the next morning, almost 24 h following drug exposure.
The 150 mg/kg oxycodone dose produced notably stronger behavioral effects and lethargy typical of opioids with observable signs occurring in all 6 animals at 1–2 h. At 4 h post-dose, 3 of the 6 animals appeared normal. However, one of those animals was subsequently found dead approximately 5 h post-drug exposure. Two of the remaining 5 animals continued to exhibit behavioral signs at 6, 8, and 12 h, while all others returned to normal by 6 h. All 5 remaining animals appeared normal at 24 h.
The 400 mg/kg mitragynine dose produced milder observable signs than 60 and 150 mg/kg oxycodone. These observations included alteration of motor behavior, lethargy, and/or incoordination in 5 of 6 animals, with no observed abnormal behavior in the sixth animal. The slowed behavior suggested potentially decreased respiratory rate at 2 and 4 h in five animals.
Approximately 40 min after the 400 mg/kg mitragynine dose, one animal displayed “full body spasms” when picked up to be removed from the home cage for blood collection. Under observation (away from home cage) at approximately 1 h post-mitragynine dose, the animal exhibited what was described as a seizure-like activity for approximately 30 s that was described as moderate. No further seizure-like behavior was observed.
The purpose of this study was to evaluate the respiratory effects of kratom’s primary alkaloid, mitragynine, in comparison to oxycodone, a prototypic opioid that reliably produces dose-related respiratory depression and death in humans, rats, and other species. As far as we are aware, this is the first study of mitragynine’s respiratory effects that followed the approach published previously by Xu et al. (2020, 2021) that utilized blood gas assessment of respiratory function. The respiratory effects of a 20-fold range of mitragynine doses were compared to those of therapeutic and supratherapeutic doses of oxycodone for comparative assessments of the respiratory effects of drugs. The main finding was that mitragynine produced no evidence of respiratory depression at doses many times higher than typical human doses, whereas oxycodone produced the expected dose-related respiratory depressant effects consistent with its strong morphine-opioid (i.e., µ-opioid) receptor-mediated effects. These findings are consistent with mitragynine’s pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating β-arrestin pathway (Kruegel et al. 2016, 2019; Váradi et al. 2016).
Observable signs and blood pharmacokinetics confirmed that the administered doses produced the dose-related pharmacodynamic and pharmacokinetic results expected, namely, higher plasma concentrations and stronger behavioral effects.
The blood gas assessments revealed striking dose and drug-related effects. We found that oxycodone, in the same oral doses used by Xu et al. (2020), did not produce significant respiratory depressant effects at the therapeutic equivalent dose of 6.75 mg/kg, and had strongly depressant effects at 60 mg/kg and more severe and longer lasting effects at 150 mg/kg. In contrast, mitragynine did not produce dose-related respiratory depression or life-threatening effects at any dose, and there were no dose-related trends in blood oxygen or carbon dioxide. Consistent with the conclusion of Xu et al. (2021), pCO2 appeared to be a more sensitive measure of the respiratory depressant effects of oxycodone than blood oxygen measures; however, none of the blood gas measures showed dose-related changes associated with mitragynine administration.
This is not the first study to conclude that mitragynine does not produce opioid-like dose-dependent respiratory depressant effects. This was also demonstrated by Macko et al. (1972), and Hill et al. (2022) found no respiratory depressant effect at 3 mg/kg but did find some respiratory depression at 10 mg/kg, which they reported did not change at higher doses. Whether this difference from the present finding is unique to mice, measurement techniques or another factor is not known. In addition, Váradi et al. (2016, p. 7) reported that, in contrast to the dose-dependent respiratory depressant effects of morphine, a mitragynine analog “shows a lower propensity to cause respiratory depression and constipation compared with the canonical opioid, morphine.”
The human equivalent doses (HEDs) of those tested in this rat study are based on estimated body surface area dividing the rat doses by 6.2 (Nair and Jacob 2016). Based on this conversion, the HEDs of 20, 40, 80, 240, and 400 mg/kg are 3.2, 6.6, 12.9, 38.7, and 64.5 mg/kg respectively. Manufacturers of mitragynine-containing kratom extracts state that about 25 mg per serving or about 0.35 mg/kg in a 70 kg human is the minimal amount that provides sufficient self-reported benefits by consumers to support repeat sales. Some marketed products are labeled with this amount and commonly marketed products in Southeast Asia in the form of tea-like decoctions typically contain 22.5 to 75 mg but with wide variation across marketed products (Brown et al. 2017; Cinosi et al. 2015; Prozialeck et al. 2020; WHO ECDD 2021). Thus, it appears that the mitragynine doses administered in the present study range from the high end of consumer use (e.g., at the 20 mg/kg dose) to levels many times higher than would be voluntarily consumed or considered desirable or tolerable, regardless of their apparent limited effects on respiratory function. Some people who are self-treating chronic pain and/or using to maintain opioid abstinence may consume larger doses of 2–5 mg/kg 2–4 times per day (Cinosi et al. 2015; Figura et al. 2020; European Monitoring Centre 2015; McCurdy et al. 2020; Ramanathan and McCurdy 2020; Sharma and McCurdy 2021; Swogger et al. 2022; WHO ECDD 2021).
Self-report data posted on internet websites were summarized in several kratom use reviews (e.g., Cinosi et al 2015; Henningfield et al. 2018, 2022; Swogger and Walsh 2018; Veltri and Grundmann 2019). These data suggest that kratom intake is typically limited by non-life-threatening but discomfort-producing gastrointestinal symptoms and/or undesirable lethargy. Furthermore, for most kratom consumers, higher doses do not produce the powerful euphoria-like highs sought by people who recreationally use opioids, cocaine, and amphetamine and that is an incentive for the frequent dose escalation that contributes to the high risk of overdose deaths associated with such drugs (Swogger et al. 2022; Swogger and Walsh 2018; Henningfield et al. 2018, 2022).
An important caveat to the foregoing observations is that it should not be concluded that kratom is without life-threatening risks under some conditions and in some people, any more than such assumption should be made for any dietary or consumer product. It is possible, if not plausible, that in some yet-to-be documented combination with other drugs or underlying health conditions, high-dose kratom consumption could pose a serious risk. Therefore, it is prudent, as discussed elsewhere (e.g., Swogger et al. 2022) to not consume kratom with other drugs or in high dosages. For example, buprenorphine is a partial agonist that is approved for the treatment of pain and opioid use disorder and also produces little evidence of life-threatening depression over a broad range of doses. Buprenorphine did not produce life-threatening respiratory depression in humans even after a 16 mg intravenous dose (Umbricht et al. 2004; Huestis et al. 2013). However, buprenorphine is associated with overdose deaths when combined with benzodiazepines and other sedative-hypnotic drugs (Pergolizzi et al. 2015; Pergolizzi and Raffa 2019; Schuman-Olivier et al. 2013).
The absence of evidence for respiratory depressant effects in rats documented here does not rule out the possibility of respiratory depressant effects in some human conditions and in combination with other substances. Mitragynine in isolation and kratom produce diverse opioid and nonopioid mediated effects that warrant further study (Ahmad et al. 2022; Harun et al. 2022; Behnood-Rod et al. 2020; Hemby et al. 2019; Henningfield et al. 2018, 2022; Reeve et al. 2020; Sharma and McCurdy 2021; Wilson et al. 2020; Yue et al. 2018). However, as compared to opioids and other substances that contributed to the 2021 annualized rate of 108,000 drug overdose deaths, the relative risk of kratom appears to be far lower than that of opioids, methamphetamine and cocaine, alcohol, and many other substances of abuse (CDC 2021; Giroir 2018; Henningfield et al. 2019; United Nations Commission on Narcotic Drugs 2021).
The risk of kratom producing seizures is real but low and extensive surveillance to determine the conditions under which kratom may increase the risk may be necessary. For example, Boyer et al. (2008) reported a seizure in a person with no history of seizures following the ingestion of 100 mg modafinil combined with an unknown amount of kratom. Follow-up evaluation including computerized tomography and magnetic resonance brain imaging was normal. Modafinil itself can lower the seizure threshold and possibly cause seizures (Artsy et al. 2012; Bahramnjead et al. 2018). Thus, it is not known if kratom contributed but an interaction cannot be ruled out.
Current findings in the context of recent advances in understanding the pharmacology of mitragynine
The finding that a broad range of mitragynine doses did not produce respiratory depression is not novel in itself because there are earlier studies of mitragynine across diverse doses and conditions, albeit at generally lower doses of 20–56 mg/kg in rats. These studies did not as intensively evaluate respiratory effects, and most did not include a pharmacokinetic assessment of mitragynine in comparison to a prototypic opioid. Several studies administered mitragynine to mice and dogs in experimental models with behaviorally functioning animals in conditioned place preference, self-administration, and intracranial self-stimulation models, reviewed recently by Henningfield et al. (2022), Ramanathan and McCurdy (2020), Sharma and McCurdy (2021), and WHO ECDD (2021). None of these studies reported life-threatening effects of mitragynine of 20–56 mg/kg and higher (e.g., Avery et al. 2019; Behnood-Rod et al. 2020; Maxwell et al. 2020; Obeng et al. 2021; Gutridge et al. 2020; Hassan et al. 2021; Kamble et al. 2021; Suhaimi et al. 2021; Todd et al. 2020). For example, a pharmacokinetics and safety study in beagle dogs reported a “mild transient sedation” lasting about 2–4 h after 5 mg/kg oral mitragynine but without clinically significant effects on vital signs (Maxwell et al. 2020). Váradi et al. (2016) found that morphine, but not a mitragynine analog, dose-dependently decreased respiratory rate in rats.
The main strengths of the present study include its dose-related comparison of oxycodone to substantially higher doses of mitragynine than were tested in most other studies and by close adherence to the protocol used in two published studies for evaluating respiratory effects (Xu et al. 2020, 2021). Its main limitation with respect to its goals was that the limit of tolerability, as defined by life-threatening effects, was not discovered and was limited by dosing restrictions. Future studies will consider alternative oral dosing approaches to enable the administration of higher doses. It is also possible that the two groups of animals that were not mitragynine naïve due to the blood gas analyzer failure were affected by their prior mitragynine exposure despite the 4-day washout period. Nor does this single ascending dose (SAD) approach address the effects of chronic dosing as can be informed by multiple ascending dose (MAD) studies. Future studies will help better understand the generalizability of the present findings, although the overall findings that the respiratory effects of mitragynine are weak albeit at lower doses as compared to morphine-like opioids are not novel. It also is important to evaluate the effects of mitragynine in combinations with drugs commonly taken with kratom including opioids, sedatives, alcohol, and stimulants. Further studies of mitragynine and other kratom constituents and analytes are clearly warranted to continue to advance science and public health.
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- Jagabalan Y, Zainal H, Al Ganaby A, Murugaiyah V, Ramanathan S (2019) Pharmacokinetic modeling of single dose Kratom (mitragynine) in rats. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018, Putrajaya, Malaysia. Front Pharmacol. https://doi.org/10.3389/conf.fphar.2018.63.00087
- Kamble SH, Berthold EC, King TI, Raju Kanumuri SR, Popa R, Herting JR, León F, Sharma A, McMahon LR, Avery BA, McCurdy CR (2021) Pharmacokinetics of eleven kratom alkaloids following an oral dose of either traditional or commercial kratom products in rats. J Nat Prod 84(4):1104–1112. https://doi.org/10.1021/acs.jnatprod.0c01163
- Kruegel AC, Gassaway MM, Kapoor A, Váradi A, Majumdar S, Filizola M, Javitch JA, Sames D (2016) Synthetic and receptor signaling explorations of the Mitragyna alkaloids: mitragynine as an atypical molecular framework for opioid receptor modulators. J Am Chem Soc 138(21):6754–6764. https://doi.org/10.1021/jacs.6b00360
- Kruegel AC, Uprety R, Grinnell SG, Langreck C, Pekarskaya EA, Le Rouzic V, Ansonoff M, Gassaway MM, Pintar JE, Pasternak GW, Javitch JA, Majumdar S, Sames D (2019) 7-Hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects. ACS Cent Sci 5(6):992–1001. https://doi.org/10.1021/acscentsci.9b00141
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- Maxwell EA, King TI, Kamble SH, Raju KS, Berthold EC, León F, Avery BA, McMahon LR, McCurdy CR, Sharma A (2020) Pharmacokinetics and safety of mitragynine in beagle dogs. Planta Med 86(17):1278–1285. https://doi.org/10.1055/a-1212-5475
- McCurdy C, Grundmann O, McLaughlin J (2020) Kratom Resources. Department of Pharmacodynamics, College of Pharmacy, University of Florida. https://pd.pharmacy.ufl.edu/research/kratom/. Accessed 8 March 2022
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- National Institute on Drug Abuse (2020). Kratom Drug Facts. National Institutes of Health, Bethesda, MD. https://www.drugabuse.gov/publications/drugfacts/kratom. Accessed 8 March 2022
- Obeng S, Wilkerson JL, León F, Reeves ME, Restrepo LF, Gamez-Jimenez LR, Patel A, Pennington AE, Taylor VA, Ho NP, Braun T, Fortner JD, Crowley ML, Williamson MR, Pallares VLC, Mottinelli M, Lopera-Londoño C, McCurdy CR, McMahon LR, Hiranita T (2021) Pharmacological comparison of mitragynine and 7-hydroxymitragynine: in vitro affinity and efficacy for μ-opioid receptor and opioid-like behavioral effects in rats. J Pharmacol Exp Ther 376(3):410–427. https://doi.org/10.1124/jpet.120.000189
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- Olsen EO, O’Donnell J, Mattson CL, Schier JG, Wilson N (2019) Notes from the field: unintentional drug overdose deaths with kratom detected—27 states, July 2016–December 2017. MMWR Morb Mortal Wkly Rep 68(14):326–327 https://doi.org/10.15585/mmwr.mm6814a2
- Palamar JJ (2021) Past-Year kratom use in the U.S.: Estimates from a nationally representative sample. Am J Prev Med 61(2):240-245. https://doi.org/10.1016/j.amepre.2021.02.004
- Pergolizzi JV Jr, Raffa RB (2019) Safety and efficacy of the unique opioid buprenorphine for the treatment of chronic pain. J Pain Res 12:3299–3317. https://doi.org/10.2147/JPR.S231948
- Pergolizzi JV Jr, Scholten W, Smith KJ, Leighton-Scott J, Willis JC, Henningfield JE (2015) The unique role of transdermal buprenorphine in the global chronic pain epidemic. Acta Anaesthesiol Taiwan 53(2):71–76. https://doi.org/10.1016/j.aat.2015.06.001
- Prozialeck WC, Avery BA, Boyer EW, Grundmann O, Henningfield JE, Kruegel AC, McMahon LR, McCurdy CR, Swogger MT, Veltri CA, Singh D (2019) Kratom policy: the challenge of balancing therapeutic potential with public safety. Int J Drug Policy 70:70–77. https://doi.org/10.1016/j.drugpo.2019.05.003
- Prozialeck WC, Edwards JR, Lamar PC, Plotkin BJ, Sigar IM, Grundmann O, Veltri CA (2020) Evaluation of the mitragynine content, levels of toxic metals and the presence of microbes in kratom products purchased in the western suburbs of Chicago. Int J Environ Res Public Health 17(15):5512. https://doi.org/10.3390/ijerph17155512
- Prozialeck WC, Lamar PC, Krupp M 2nd, Moon M, Phelps LE, Grundmann O (2021) Kratom use within the context of the evolving opioid crisis and the COVID-19 pandemic in the United States. Front Pharmacol 12:729220. https://doi.org/10.3389/fphar.2021.729220
- Ramanathan S, McCurdy CR (2020) Kratom (Mitragyna speciosa): worldwide issues. Curr Opin Psychiatry 33(4):312–318. https://doi.org/10.1097/YCO.0000000000000621
- Reeve ME, Obeng S, Oyola FL, Behnke M, Restrepo LF, Patel A, Ho NP, Williamson MR, Jimenez LR, McCurdy CR, McMahon LR (2020) The adrenergic a2 receptor-mediated discriminative-stimulus effects of mitragynine, the primary alkaloid in Kratom (Mitragyna speciosa) in rats. FASEB J 34(S1):1. https://doi.org/10.1096/fasebj.2020.34.s1.05233
- Schimmel J, Amioka E, Rockhill K, Haynes CM, Black JC, Dart RC, Iwanicki JL (2021) Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross-sectional study. Addiction 116(1):176–181. https://doi.org/10.1111/add.15082
- Schuman-Olivier Z, Hoeppner BB, Weiss RD, Borodovsky J, Shaffer HJ, Albanese MJ (2013) Benzodiazepine use during buprenorphine treatment for opioid dependence: clinical and safety outcomes. Drug Alcohol Depend 132(3):580–586. https://doi.org/10.1016/j.drugalcdep.2013.04.006
- Sharma A, Kamble SH, León F, Chear NJ, King TI, Berthold EC, Ramanathan S, McCurdy CR, Avery BA (2019) Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandemmass spectrometry. Drug Test Anal 11(8):1162–1171. https://doi.org/10.1002/dta.2604
- Sharma A, McCurdy CR (2021) Assessing the therapeutic potential and toxicity of Mitragyna speciosa in opioid use disorder. Expert Opin Drug Metab Toxicol 17(3):255–257. https://doi.org/10.1080/17425255.2021.1853706
- Singh D, Narayanan S, Vicknasingam B (2016) Traditional and non-traditional uses of Mitragynine (Kratom): a survey of the literature. Brain Res Bull 126(Pt 1):41–46. https://doi.org/10.1016/j.brainresbull.2016.05.004
- Suhaimi FW, Hassan Z, Mansor SM, Müller CP (2021) The effects of chronic mitragynine (Kratom) exposure on the EEG in rats. Neurosci Lett 745:135632. https://doi.org/10.1016/j.neulet.2021.135632
- Swogger MT, Walsh Z (2018) Kratom use and mental health: a systematic review. Drug Alcohol Depend 183:134–140. https://doi.org/10.1016/j.drugalcdep.2017.10.012
- Swogger MT, Smith KE, Garcia-Romeu A, Grundmann O, Veltri CA, Henningfield J, Busch LY (2022) Understanding kratom use: a guide for healthcare providers. Front Pharmacol 13:801855. https://doi.org/10.3389/fphar.2022.801855
- Todd DA, Kellogg JJ, Wallace ED, Khin M, Flores-Bocanegra L, Tanna RS, McIntosh S, Raja HA, Graf TN, Hemby SE, Paine MF (2020) Chemical composition and biological effects of kratom (Mitragyna speciosa): in vitro studies with implications for efficacy and drug interactions. Sci Rep 10(1):19158. https://doi.org/10.1038/s41598-020-76119-w
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- U.S. Drug Enforcement Administration (DEA) (2016) DEA Rulemaking Docket, Comment on FR Doc # 2016–24659, Schedules of Controlled Substances: Temporary Placement of Mitragynine and 7-Hydroxymitragynine into Schedule I. Public comments on FR Doc # 2016–24659 (23,220 public comments). https://www.regulations.gov/docket/DEA-2016-0015/comments. Accessed 8 March 2022
- Umbricht A, Huestis MA, Cone EJ, Preston KL (2004) Effects of high-dose intravenous buprenorphine in experienced opioid abusers. J Clin Psychopharmacol 24(5):479–487. https://doi.org/10.1097/01.jcp.0000138766.15858.c6
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- Váradi A, Marrone GF, Palmer TC, Narayan A, Szabó MR, Le Rouzic V, Grinnell SG, Subrath JJ, Warner E, Kalra S, Hunkele A, Pagirsky J, Eans SO, Medina JM, Xu J, Pan YX, Borics A, Pasternak GW, McLaughlin JP, Majumdar S (2016) Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit β-arrestin-2. J Med Chem 59(18):8381–8397. https://doi.org/10.1021/acs.jmedchem.6b00748
- Veltri C, Grundmann O (2019) Current perspectives on the impact of Kratom use. Subst Abuse Rehabil 10:23–31. https://doi.org/10.2147/SAR.S164261
- Vicknasingam B, Narayanan S, Beng GT, Mansor SM (2010) The informal use of ketum (Mitragyna speciosa) for opioid withdrawal in the northern states of peninsular Malaysia and implications for drug substitution therapy. Int J Drug Policy 21(4):283–288. https://doi.org/10.1016/j.drugpo.2009.12.003
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The authors express their appreciation to Daniel Wang and Yolanda Green for their editorial assistance with the manuscript and Gina Bittner for the development of the figures and tables.
This study was funded without restrictions by the American Kratom Foundation (AKF), a 501(c)3 nonprofit entity established by the American Kratom Association to promote science and policy research on plants and their potential health benefits. AKF had no input into the design of the study, evaluation of results, or publication of this article.


“I study weird water animals.”
“Human speaking and writing is all about using words and pictures to form ideas and share them with others so that everyone is made better.”
“I study how city people use water, often too much, and what that means for other living things who also live in cities.”
All of the sentences above were written using only words from the thousand most common ones found in written English fiction. The idea was inspired by an xkcd comic from a few years ago in which Randall Munroe explained the Saturn V rocket in this manner, titling it “Up Goer Five.” He has since expanded the concept to write and draw a whole book of blueprints, due to be published later this year.
Meanwhile, the comic also inspired Cambridge-based geneticist Theo Sanderson to create a basic online text editor that would only allow use of the same word list Munroe used in the Up Goer Five diagram.
Soon enough other researchers stumbled upon this editor and decided to try their hand at explaining their research using only this fairly basic vocabulary. I love the idea, and I think it’s more than just entertainment – these attempts are actually clever communication exercises. If you’ve spent any time in graduate school, you know what it’s like to try and explain your research project to people outside your specialty – and scientists continue to face this communication challenge throughout their professional lives. This applies to other professions as well, but not all are as laden with jargon as science can be.
In fact, it is a similar challenge that science writers face, too. When I write, I spend a lot of time translating technical terms and processes into everyday language that is accessible even to people who have never read a research paper. It is fun, and always a worthwhile exercise, so it’s nice to see a tool which encourages scientists to think about this problem as well, and to try to tackle it.1
On Twitter, you can find a slew of entries under #UpGoerFive, and that is also where those sentences in the first paragraph came from. Here’s just one example.
— Mark Scheuerell (@mark_scheuerell) May 14, 2015
Furthermore, there is also a lovely Tumblr with a bunch of entries. Make sure to check it out, as it features pearls such as “I study how tiny pieces of fire rocks get shot out of the ground into the sky.”
There is something to be said about simplicity, as Up Goer Five editor definitely helps break out of the jargon box so many scientists are stuck in. You can write comics and paragraphs in this way and have fun, but personally I think that any longform story would greatly suffer from a lack of Nice Big Words. I thought about writing this blog post in the editor, but gave up on the idea pretty quickly.
‘Science’ really should be in the top 1000 words.
- Although as a writer with a large vocabulary I found the exercise a little frustrating. Here’s what this paragraph came out to be after I had to change it in the editor to only use permitted words: “In fact, it is a problem that people who write about what I write about face, too. When I write, I spend a lot of time changing big words into words that other people who do not know the field can understand as well. It is fun, and always a nice thing to do. This is why I like seeing a thing which lets people who work in hard fields to think about this word problem as well, and to try to change it.” ↩


The fourth-quarter comeback to win the game. The tumor that appeared on a second scan. The guy in accounting who was secretly embezzling company funds. The situation may be different each time, but we hear ourselves say it over and over again: “I knew it all along.”
The problem is that too often we actually didn’t know it all along, we only feel as though we did. The phenomenon, which researchers refer to as “hindsight bias,” is one of the most widely studied decision traps and has been documented in various domains, including medical diagnoses, accounting and auditing decisions, athletic competition, and political strategy.
In a new article in the September 2012 issue of Perspectives on Psychological Science, a journal of the Association for Psychological Science, psychological scientists Neal Roese of the Kellogg School of Management at Northwestern University and Kathleen Vohs of the Carlson School of Management at the University of Minnesota review the existing research on hindsight bias, exploring the various factors that make us so susceptible to the phenomenon and identifying a few ways we might be able to combat it. This article is the first overview to draw insights together from across different disciplines.
Roese and Vohs propose that there are three levels of hindsight bias that stack on top of each other, from basic memory processes up to higher-level inference and belief. The first level of hindsight bias, memory distortion, involves misremembering an earlier opinion or judgment (“I said it would happen”). The second level, inevitability, centers on our belief that the event was inevitable (“It had to happen”). And the third level, foreseeability, involves the belief that we personally could have foreseen the event (“I knew it would happen”).
The researchers argue that certain factors fuel our tendency toward hindsight bias. Research shows that we selectively recall information that confirms what we know to be true and we try to create a narrative that makes sense out of the information we have. When this narrative is easy to generate, we interpret that to mean that the outcome must have been foreseeable. Furthermore, research suggests that we have a need for closure that motivates us to see the world as orderly and predictable and to do whatever we can to promote a positive view of ourselves.
Ultimately, hindsight bias matters because it gets in the way of learning from our experiences.
“If you feel like you knew it all along, it means you won’t stop to examine why something really happened,” observes Roese. “It’s often hard to convince seasoned decision makers that they might fall prey to hindsight bias.”
Hindsight bias can also make us overconfident in how certain we are about our own judgments. Research has shown, for example, that overconfident entrepreneurs are more likely to take on risky, ill-informed ventures that fail to produce a significant return on investment.
While our inclination to believe that we “knew it all along” is often harmless, it can have important consequences for the legal system, especially in cases of negligence, product liability, and medical malpractice. Studies have shown, for example, that hindsight bias routinely afflicts judgments about a defendant’s past conduct.
And technology may make matters worse. “Paradoxically, the technology that provides us with simplified ways of understanding complex patterns – from financial modeling of mortgage foreclosures to tracking the flow of communications among terrorist networks – may actually increase hindsight bias,” says Roese.
So what, if anything, can we do about it?
Roese and Vohs suggest that considering the opposite may be an effective way to get around our cognitive fault, at least in some cases. When we are encouraged to consider and explain how outcomes that didn’t happen could have happened, we counteract our usual inclination to throw out information that doesn’t fit with our narrative. As a result, we may be able to reach a more nuanced perspective of the causal chain of events.


Traditionally, Earl Grey is a black tea flavoured with the oil of a bergamot; a citrus fruit found in Italy. Although it is one of the most popular blends of tea in Britain, a survey in 2010 revealed that a significant minority of people (14%) associate drinking Earl Grey tea with being posh or upper class.
There are many stories about the origins of Earl Grey tea but it is widely understood that it was named after British Prime Minister, Charles Grey who lead Great Britain and Ireland through four years of political transformation between November 1830 and July 1834.
A member of the now redundant Whig Party, Charles Grey is perhaps most famous for authoring the Reform Bill of 1832. His Government also saw the abolishment of slavery.
Grey was respected but rarely loved. His achievements were few, but they were significant…. In character he was a man of contradictions, headstrong but easily discouraged by failure, imperious but indecisive, cautious and introspective.
E. A. Smith (2004), ‘Grey, Charles, second Earl Grey (1764–1845)’
According to one of the more popular legends surrounding Earl Grey tea, Lord Grey was presented with the exquisite tea blend in 1803 by a grateful Chinese mandarin after saving his son from drowning. Sadly, this story must be taken with a large pinch of salt because there are no records of Earl Grey having ever visited China. Likewise, Britain was also on the brink of war with China.
A London tea house, Jacksons of Piccadilly, now owned by Twinings, also lay claim to the original Earl Grey formula. They assert that Lord Grey gave the tea recipe to a partner of the company in 1830 and they have been producing it ever sense. Nonetheless, the first advertisements for Earl Grey tea did not appear for another fifty years.
The Grey family themselves maintain that the tea was blended by a Chinese mandarin-speaking individual at Howick Hall in Northumberland, the ancestral seat of Earl Grey. The water n the region had high levels of limescale and as such, had an unpleasant chalky effect on the taste of tea. Indeed, in their accounts, the bergamot was used to offset these effects.
So will we ever know the real story of Earl Grey tea? It seems not but the mystery and folklore that surrounds this delicate and distinctive tea, only adds to its appeal.
Thomas Phillips [Public domain], via Wikimedia Commons


MIT discovers a new state of matter, a new kind of magnetism
Researchers at MIT have discovered a new state of matter with a new kind of magnetism. This new state, called a quantum spin liquid (QSL), could lead to significant advances in data storage. QSLs also exhibit a quantum phenomenon called long-range entanglement, which could lead to new types of communications systems, and more.
Stanford's quantum entanglement device brings us one step closer to quantum cryptography
A new study makes quantum encryption much more practical, and brings us closer to the dream of a latency-free internet.
Quantum entangled batteries could be the perfect power source
Two European theoretical physicists have shown that it may be possible to build a near-perfect, entangled quantum battery. In the future, such quantum batteries might power the tiniest of devices -- or provide power storage that is much more efficient than state-of-the-art lithium-ion battery packs.
Chinese physicists achieve quantum teleportation over 60 miles
We're talking years in the future, but this would certainly be the first step towards building a global quantum network.
The first universal quantum network
German scientists at the Max Planck Institute of Quantum Optics have created the first quantum network that could be feasibly scaled up to become a "quantum internet."
Quantum PageRank faster than Google's classical physics version
This story has all the hallmarks of being utterly awesome: PageRank, one of the most significant discoveries in recent history, has been converted by some Spanish computer scientists into a quantum algorithm that outperforms its classical physics predecessor.
World's first programmable quantum photonic chip
A team of engineering geniuses from the University of Bristol, England has developed the world's first re-programmable, multi-purpose quantum photonic computer chip that relies on quantum entanglement to perform calculations.


Unmanned Aerial Vehicles
Today you can buy a Google phone and get GPS, Computer, Linux, Camera, and Internet in a very small package. This can also control servos through a USB port. Making a UAV is getting really easy.
UAVs are regulated over land and so not used much. But in the open ocean regulations are not such a show stopper. The lack of regulations is a competitive advantage for developers. Could then sell UAVs to ship owners for pirate patrol or other applications.
While probably not critical to the first seasteads, UAVs could eventually make life on seasteads better in a number of ways.
Trains used to hand off mail and pick up mail while going at full speed. We could make a system such that small packages (maybe 25 lbs to 200 lbs) could be delivered from a UAV to a seastead. This might be as simple as a rope with a hook from a pole leaning over the side of the seastead. The UAV would fly such that a loop caught on the hook and pulled the package out the back of the UAV. There is a UAV helicopter with 150 lbs payload, 100+ MPH, and 6 hour flight time.
This could be done just from seasteads out in the ocean with no help from land. UAVs could stay between 500 feet and 1000 feet so they were not going to hit ships or airplanes. Probably would not raise too much protest.
The ability to quickly get a medical supplies or a replacement part could make living on a seastead much easier.
A UAV flying high can relay communications over long distances. If the UAV is located between the seasteaders and land it could link them to land.
To do this we something on land wherever we want to link to. These might be cellular Internet or other existing commercial service, or it might be something dedicated to us. The higher the UAV flies the longer the potential link distance is. A UAV could hang out higher than normal airplane traffic. However, getting to/from there it would have to pass through regular airplane heights. There may be people who don't like this and they could block it by regulating the land bases. However, there are lots of different islands and some are small enough that they would not want to lose the money paid for the right to do this. So probably something could be worked out, but at a cost/year.
Multiple UAVs could be used to make links covering very long distances, like all the way across the Atlantic.
Rope between Seasteads
Could use a small quadcopter to bring an initial line between two seasteads that wanted to do a ship-to-ship transfer.
UAVs with cameras could patrol a wide area around the seasteads. Could also use infrared or radar. Would make a quick sneak attack by pirates very hard.
- dragonfly.com - commercial multicopter
- Camcopter S-100 - UAV helicopter - cruise 55 kts with endurance 6 hours with 55 lbs payload
- DIYdrones.com - Amateur UAVs
- list of UAV projects
- Paparazzi - open source flight computer project
- OpenUAV - open UAV project
A quadcopter with GPS and camera.
Collection of different unmanned vehicles.
Someone using a RC helicopter to catch a fish.


Volume 2 of the IFRAO-Brepols series:
OF ROCK ART RESEARCH:
a multilingual dictionary
Robert G. Bednarik, Mario Consens, Alfred Muzzolini, Jakov Sher,
Dario Seglie and Mila Simões de Abreu
is the first dictionary compiled specifically for rock art research.
It follows the publication of an English rock art glossary in the journal Rock Art Research in November 2000. To be adopted by the International Federation of Rock Art Organisations (IFRAO), it has been translated by some of the worlds foremost scholars in the field into French, German, Italian, Spanish, Portuguese and Russian. In a discipline that has hitherto been without an agreed terminology, even communication within a single language has been difficult. The proliferation of idiosyncratic terminologies of often academically isolated researchers, many of which have been used by only one scholar, has not only retarded progress and the transference of knowledge, it has led to countless misunderstandings and even personal feuds. The purpose of this dictionary is to create a single terminological standard as well as a cross-lingual uniformity of usage. It focuses particularly on scientific aspects, technical applications and epistemological rigour. It does not set out to create a terminological straitjacket for the discipline, but a common standard of reference, particularly in areas that have in the past been susceptible to greatly differing interpretations.
This dictionary comprises seven sections in seven languages, each listing the same terms alphabetically. It contains also a table interlinking all of these languages, listing all terms explained. This translation table is organised alphabetically according to the English terms. The volume is indispensable for scientific translators, rock art scholars, archaeologists and others concerned with aspects of pre-historic rock art, and is also intended for the guidance of students and authors working in this field.


To view an abstract, select an author from the vertical list on the left side.
2005 Grant - Das
Effect of Gamma-Secretase Inhibition on the Anti-Beta-Amyloid Immune Response
Pritam Das, Ph.D.
2005 New Investigator Research Grant
One of the hallmarks of Alzheimer's disease is accumulation in the brain of a small protein fragment called beta-amyloid. Research has shown that this fragment may play a primary role in Alzheimer pathology. For this reason, therapies aimed at reducing the amount of the protein are being pursued.
Pritam Das, Ph.D., and colleagues will investigate the potential benefits of combining two therapiesóa vaccine-like therapy and inhibition of a protein called gamma-secretase. Vaccination is designed to spur the body's own immune system to remove beta-amyloid. Inhibiting gamma-secretase, which is involved in production of the toxic protein fragment, is intended to prevent formation of beta-amyloid. Together the two therapies might prove more effective than either alone.
Gamma-secretase also has other roles, some of which make this combination therapy even more attractive. Recently, scientists discovered that the protein stimulates immune cells that cause inflammation. In the brain, inflammation can be particularly dangerous, and in fact, a recent clinical trial of a beta-amyloid vaccine had to be halted because of this side effect. Gamma-secretase inhibitors may, therefore, prevent unwanted inflammation.
Das and colleagues have also found that when gamma-secretase is inhibited in mice, the animals develop a stronger immune response to beta-amyloid vaccines. While the reasons for this are unclear, it suggests that the combination therapy of vaccine and gamma-secretase inhibition could yield a more robust immune defense against beta-amyloid in humans.
To further investigate the benefit of the dual therapy, Das and colleagues will use genetically altered mice that produce large amounts of beta-amyloid. The researchers will administer gamma-secretase inhibitors followed by vaccination therapy. They will monitor how rapidly beta-amyloid is cleared from the brain and investigate the reasons why the secretase inhibitor spurs the immune response. Findings could lead to new more effective treatments for Alzheimer's disease.


Localization is the process of adapting an internationalized application platform or application to a specific cultural environment. In localization, the same semantics are preserved while the syntax or presentation forms may be changed.
Localization is the act of tailoring an application for a different language or script or culture. Some internationalized applications can handle a wide variety of languages. Typical users understand only a small number of languages, so the program must be tailored to interact with users in just the languages they know.