Kratom Botanical that at low doses produce stimulation and

at higher doses produce opioid effects

Potential for physical dependence and opioid-type effects/toxicities

Marketed in Western countries and increasing use/toxicities being reported

Jean J. Schensul, Ph.D. Institute for Community Research and WHPP Adapted from Elinore F. McCance-Katz, Presentation on urgent and emerging issues, SAMHSA, 2019

Why Kratom

• The personal story – death of a young man from West Hartford using Kratom

• The professional story – tracking new drugs, their appearance and their function at a given point in time.

• The commercial story – big business

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Kratom Story • Kratom is a tropical tree (Mitragyna speciose) native to Southeast Asia,

used traditionally to combat fatigue and improve work productivity among farm populations in Southeast Asia

• Has recently become popular as a novel psychoactive substance in Western countries (Cinosi et al, 2015).

• FDA is concerned that kratom, which affects the same opioid brain receptors as morphine, appears to have properties that expose users to the risks of addiction, abuse, and dependence

• Currently, there are no FDA-approved uses for kratom, and the agency has received concerning reports about its safety

• People use it to deal with pain, as a replacement for opiates, as a stimulant.

• For the first time, a researcher has isolated kratom's ingredients to see how they affect behavior in rats. The results are preliminary, but suggest the drug could hold promise for people dealing with addiction. (Business insider, 2018)

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• Kratom preparations contain varying amounts of several phytochemicals, making their pharmacological and toxicological evaluation unique and difficult.

• More than 20 alkaloids in kratom have been

identified in the laboratory.

• Mitragynine is classified as a kappa-opioid receptor agonist and is roughly 13 times more potent than morphine.

• Mitragynine/OH-mitragynine thought to be

responsible for the opioid-like effects.

Kratom Extract Composition

Source: Cinosi E.; Martinotti; et all. Following “the Roots” of Kratom (Mitragyna speciosa): The Evolution of an Enhancer from a Traditional Use to Increase Work and Productivity in Southeast Asia to a Recreational Psychoactive Drug in Western Countries; Biomed Res Int. 2015; 2015: 968786

• Capsules • Pills • Extract • Leaves

• Chewed • Brewed as tea • Smoked (from various internet sources

Ingesting Kratom

Red Thai

Red Bali- Native to Bali, Indonesia Red Vietnam- Native to Vietnam Red Maeng Da- Native to Thailand Red Borneo- Native to South Borneo Red Dampar- Native to Indonesia Red Indo- Native to Indonesia Red Sumatra- Native to Sumatra, Indonesia Red Malay- Native to Malaysia Red Gold- Native to Indonesia Red Bantuagie- Native to Indonesia Red Dragon- Native to Malaysia Red Horned Maeng Da- Native To Thailand Rain Forests Yellow Borneo- Native to North Borneo Yellow Kapuas- Native to Malaysia Yellow Gold- Native to Indonesia Chocolate Borneo- Native to South Borneo Dark Brown Bantuagie- Native to Indonesia

KRATOM “MENU” https://www.shopcbdkratom.com/pages/kratom-menu

Green Maeng Da- Native to Thailand Green Malay- Native to Malaysia Green Vietnam- Native to Vietnam Green Dampar- Native to Indonesia Green Cambodian- Native to Cambodia Green Borneo- Native to North Borneo Green Sumatra- Native to Thailand Green Indo- Native to Indonesia Green Dragon- Native to Malaysia Green Bali- Native to Bali, Indonesia Green Kapuas- Native to Malaysia Dark Green Borneo- Native to Borneo Green Bantuagie- Native to Indonesia Green Horned Maeng Da- Native To Thailand Rain Forests Super Indo- Native To Indonesia White Bali- Native to Bali, Indonesia White Borneo- Native to North Borneo White Maeng Da- Native to Thailand White Dampar- Native to Indonesia White Kapuas- Native to Malaysia White Sumatra- Native to Thailand White Bantuagie- Native to Indonesia

All Kratom strains effects vary. Kratom affects different people differently, and larger doses tend to be more sedative than energizing. To avoid getting a high tolerance to Kratom, it is highly recommended to change the Kratom strains and veins you take frequently

The effects of kratom in humans are dose-dependent: • Small doses produce stimulatory effects

resembling the stimulant effect of drugs such as cocaine or amphetamines.

• Larger dosages associated with sedative-narcotic, pain reducing effects that resemble drugs such as opiates.

• Regular kratom use is associated with addictive disorders, as evidenced by craving and compulsive use. Opioid withdrawal symptoms upon cessation.

Kratom: Effects

SOURCE: Prozialeck W. C., Jivan J. K., Andurkar S. V. Pharmacology of Kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. Journal of the American Osteopathic Association. 2012;112(12):792–799; Singh, 2014; Suwanlert, 1975; Ahmad and Aziz, 2012; Vicknasingam et al., 2010; Singh et al., 2014

• An anonymous online survey was conducted in October 2016 of 10,000 current kratom users through available social media and from the American Kratom Association (https://speciosa.org/home/ )

• 8,049 respondents completed the survey. • Findings:

• Kratom was primarily used by a middle-aged (31-50 years) males (56.91%) with income $35,000 or higher with private insurance (61.31%).

• Kratom was used to self-treat pain (68%) and emotional or mental conditions (66%) and for withdrawal symptoms associated with prescription opioid use.

• Subjects reported dose-dependent nausea and constipation with high doses (5g) and with and frequent dosing (Q22 doses/wk).

Use of Kratom in the US

SOURCE: Grundmann O.; Patterns of kratom use and health impact in the USVresults from an online survey. Drug Alcohol Depend. 2017; 175(5):63Y70.

National Poison Data System - United States and Puerto Rico January 2010–December 2015

Number of Kratom-related Reported Exposure Calls to Poison Centers in the US

SOURCE: Anwar M, Law R, Schier J. Notes from the Field. Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers — United States, 2010–2015. MMWR Morb Mortal Wkly Rep 2016;65:748–749. DOI: http://dx.doi.org/10.15585/mmwr.mm6529a4

Fatal Overdoses Involving Kratom

Source: CDC SUDORS Overdose Death Data

From July 2016 to June 2017, 25 fatal overdoses involving kratom across 8 CDC SUDORS states were identified

In 2017, the Food and Drug Administration (FDA) began issuing a series of warnings about kratom and has now identified at least 44 deaths related to its use. Most kratom associated deaths appeared to have resulted from adulterated products or taking kratom along with other potent substances.

• Kratom has gained popularity for its euphoric effects and is being popularized as a safe herbal product capable of giving a “legal” high (Swogger et al., 2015), and as an alternative to other sedative and stimulant type drugs (Warner et al., 2016).

• Reports of physical dependence on kratom in Western nations emerge from case reports from the UK (Boyer et al., 2008, McWhirter and

Morris, 2010), Germany (Kapp et al., 2011) and the US (Dorman et al., 2014, Nelsen et al., 2010, Forrester, 2013, Sheleg and Collins, 2011).

• It can be surmised that given the large and growing number of internet purchase sites for kratom (cited in Cinosi et al., 2015), addiction to kratom is also likely to be growing in the Western countries.

• No treatment specific to kratom addiction is available • One case of NAS in an infant whose mother was a kratom user

and who responded to opioid treatment.

Kratom Concerns

Kratom is restricted or illegal in: Australia Lithuania Romania Denmark Myanmar South Korea Finland Malaysia Sweden Israel Poland Thailand United Kingdom

International Status of Kratom

Scheduling is under consideration in U.S. On November 14, 2017, the FDA issued a public health advisory related to mounting concerns regarding the risks associated with kratom and reported deaths with use.

FDA Warning • FDA conducted laboratory testing of 30 different kratom products from a

variety of sources to determine if they contain heavy metals. The analysis found significant levels of lead and nickel at concentrations that exceed safe exposure for oral daily drug intake.

• Based on reported kratom usage patterns, heavy kratom users may be exposed to levels of lead and nickel many times greater than the safe daily exposure, as referenced in Appendix 2 of the Q3D Elemental Impurities Guidance for Industry.

• Based on these test results, the typical long-term kratom user could potentially develop heavy metal poisoning, which could include nervous system or kidney damage, anemia, high blood pressure, and/or increased risk of certain cancers.

• The FDA reminds consumers not to use these and other kratom products. On April 6, 2018, in response to FDA's mandatory recall order of April 2, 2018, Triangle Pharmanaturals, LLC of Las Vegas, Nevada initiated a recall for its products containing powdered kratom. ... This recall now includes at least 26 different products.

• https://search.usa.gov/search?utf8=%E2%9C%93&affiliate=fda&query=kratom&commit=Search (for multiple warnings and statements about Kraton

Field Studies on Ketum/Kratom

Use

Darshan Singh, PhD Centre for Drug Research Universiti Sains Malaysia

(USM)

From…..”Identifying Knowledge Gaps as Kratom Emerges on the Global Stage” – Summary Slides National Institute on Drug Abuse (NIDA) International Symposium at College on Problems of Drug Dependence (CPDD) San Diego, June 9 2018

Overview of Field Findings on Kratom Effects (D. Singh)

Chewing of fresh

leaves & consump

tion of kratom

decoction.

Kratom Dependence?

(Singh et al. Drug and Alcohol Dependence, 2014).

Self-report surveys in Malaysia found that regular

consumption was associated with kratom

dependence.

Kratom dependence was associated with higher frequency &

heavy kratom consumption.

Being dependent on kratom was not affiliated with impaired social functioning, though users had

difficulty abstaining from kratom use.

Regular users were more likely to increase their

kratom intake overtime.

Kratom Withdrawal Symptoms.

(Singh et al., Journal of Psychoactive Drugs, 2015 & )

Kratom withdrawal symptoms are claimed to

resemble opioid-like withdrawal symptoms.

Kratom produces dose-dependent withdrawal effects

during abrupt cessation.

Kratom users with long-term (>1 year) & chronic kratom use history (daily ingestion of >1

litter of brewed kratom tea) have difficulty ceasing from kratom

use.

However, users have their own ways to overcome (e.g. shower,

sleep, sweat profusely, etc.) kratom withdrawal symptoms.

Most users have never sought treatment for kratom withdrawal symptoms.

Safety.

(Kronstrand et al., Journal of Analytical Toxicology, 2011; Singh et al., Brain Research Bulletin, 2016; Lydeker et al., 2016; Anwar et al., CDC, 2016; Grundmann, Drug and Alcohol Dependence, 201 )

Long-term kratom effects are poorly

elucidated.

Long-term users appeared thin, have darker skin & hepatic face, experience constipation, dehydration, psychological problems &

experienced fatigue.

So far, there have been no kratom toxicity

incidents in Malaysia.

Perhaps, consumption of brewed kratom tea could be

less toxic than the ingestion of powdered kratom extracts.

In the West, kratom use (regardless of duration & quantity)

was associated with kratom exposure (poisoning & death).

Current toxicity cases stem from the co-used of kratom with other

substances & unresolved medical problems.

Users have elevated risk of experiencing

gastrointestinal (e.g. constipation, abdominal

pain, etc.) & cardiovascular (e.g.

tachycardia, hypertension,

drowsiness, etc.) related effects.

Despite the unpleasant

effects, majority have not sought

medical or mental health care treatment for kratom use.

Opioid Users Call Kratom a Godsend. The F.D.A. Says It’s a Menace

“The steep rise in the number of people suffering opioid addiction has helped spawn the widespread use of another substance: kratom, a green powdered herbal supplement that is widely available and virtually unregulated. It is also increasingly being used by those who swear by it as a curb for opioid addiction. Some veterans also say it helps control symptoms of post-traumatic stress. Several million Americans are now believedto use kratom.” (NY Times, April 18, 2019) .

• Kratom is a recognized emerging public health threat (MMWR. July 29, 2016;65(29):748Y749)

• People need to understand that ‘‘legal’’ and ‘‘available’’ are not the same as ‘‘safe.’’

• In the West, kratom has been valued for its analgesic effects and to aid in managing opioid withdrawal. However, some of these individual attempts have resulted in cases of toxicity and fatalities.

• Physicians should be aware of these herbal supplements and potential toxicity or withdrawal effects in patients including in newborns which cannot be picked up by the standard toxicology screen (Davidson et al, 2018).

• Preventionists should be aware of this drug and work with their communities raising awareness, providing education about effects and risks.

Conclusions Alerts

Great Debates: Should Kratom be Scheduled; should Kratom be studied; should Kratom be

used and if so for what and in what forms • WASHINGTON, July 30, 2018 /PRNewswire/ -- In a recent update of its

official position on the botanical kratom, the National Institute of Drug Abuse (NIDA) affirmed that, "Kratom by itself is not associated with fatal overdose," explaining that only when the natural ingredient is contaminated or "laced with other compounds" has it been associated with death

• "The American Kratom Association joins the three to five million American consumers who safely use kratom, as well as the healthcare professionals and government leaders who support kratom in its natural form, in calling upon the FDA to follow the science, to allow consumer access to the natural botanical, and to use its efforts and energy to go after those who lace it illegally," (The American Kratom Association (AKA)).

• “The AKA gives a voice to those who are suffering by protecting their rights to possess and consume safe and natural kratom. AKA represents millions of Americans, each of whom has a unique story to tell about the virtues of kratom and its positive effects on their lives. www.americankratom.org”

• UF College of Pharmacy receives $3.5 million NIDA grant to bolster kratom research (December 2018)