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Mitragyna Speciosa: Taking the American Counterculture by Storm

Mitragyna Speciosa: Taking the American Counterculture by Storm

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August 15, 2017 By John Reed 1 Comment

Mitragyna Speciosa, A.K.A. Kratom, has almost become a staple in the American counterculture. Walk into any head shop, smoke shop, or locally owned convenience store and you are sure to find hidden behind the counter at least the Maeng Da strain, if you are lucky there will be a couple of others to choose from. Kratom was not widely known until the Food and Drug Administration decided to place kratom on the radar back in October 2016. The DEA blindsided consumers in August with a sudden announcement that it would make two compounds in kratom – mitragynine and 7-hydroxymitragynine – Schedule I substances, effectively banning the plant with as little as 30 days’ notice. By doing so, the FDA only hindered their hopes of banning the beneficial herb due to an overwhelming outcry by the kratom community. 1

Never before has the FDA seen a public campaign of this nature. “Based on the response we’ve gotten over the last month or so, we believe it’s the prudent and reasonable action to take,” DEA spokesman Russ Baer says. “We want to make sure this is a transparent process. We want to have an open dialog with the public.”2 During the public comment period, well over 2,000 kratom advocates, who were greatly opposed to the ban called the FDA to share their concerns and personal success stories in hopes of overturning their decision to ban the supplement.  “That was eye-opening for me personally,” DEA spokesperson Melvin Patterson said to the Washington Post. “I want the kratom community to know that the DEA does hear them. Our goal is to make sure this is available to all of them.”3 Another spokesman for the FDA, Russ Baer, went on to say “They have claimed individually that kratom has given them medical value,” Baer says, “that it has medical utility ranging from migraine headaches to chronic pain, to Crohn’s disease, to anxiety, depression, opioid withdrawal – these are all conditions that medicines usually try to alleviate.”2 Even the President took notice when upset advocates flooded the White House with petitions urging Donald Trump to second guess the FDA’s hasty actions.4 Lawmakers throughout the United States also began signing legislature in hopes of gaining both public popularity and also voicing their opinions as kratom advocates, and users as well.

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Since the initial threat of a ban, Kratom sales have boosted throughout America both online and in the storefront. In August, when the threat of a ban loomed heavily on the kratom community, online stores experienced an overnight boom in sales leaving most vendors out of stock until things smoothed over. Many advocates, out of fear of losing access to the herb, began seeking sources outside the United States. Vendors in Indonesia began flooding Facebook groups in attempts to gain access to the Kratom community. Many offer the best strains, kilograms for under $70, and guaranteed shipment through customs. Canadian farms also became another source for many Kratom connoisseurs to purchase through. This left many buyers in outrage as their product was confiscated in route by customs, or they sent money via PayPal only to never hear from the seller again and be out large sums of money.

When researching Kratom use, or rise thereof, in the United States, I found little information on the exact number of users. In fact, since studies in general have rarely been conducted a search through Google only turned up minimal information. One thread on Reddit had this to say on use of kratom in America today, Reason I ask is that over the last couple of weeks I’ve seen a variety of numbers from articles/posts stating hundreds to thousands. It’s hard to get a grasp on the size of the potential constituency unless we have an idea. From the DEA’s own intent letter, they mention 55,000kg being encountered by Law Enforcement in two years (2014-2016), or close to 12 million doses (their estimation). That number of just the encountered amount really seems high for hundreds or thousands of people. Makes me wonder if the Kratom community is much bigger than we even know.

I think it’s a point worth investigating. If anyone has any ideas, I’d love to hear them. This question could be helped by any vendors that have a raw count too. This information might be useful to the AKA.”5

Regardless of the number of users, it is safe to say that Mitragyna Speciosa has taken American counterculture by storm! Whether it is used to wean off narcotics, or to eliminate pain in chronic pain patients, or one of the other many beneficial reasons to take kratom, the fact cannot be denied that Americans love their kratom! And by the looks of it, it is luckily not leaving the scene anytime soon.

Filed Under: Kratom (Mitragyna speciosa) Tagged With: Kratom, Kratom sales, kratom use, Mitragyna speciosa

The Legal Status of Kratom

The Legal Status of Kratom

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July 14, 2017 By John Reed Leave a Comment

Kratom is an amazing nootropic that has been used the world over by countless people to treat pain, feel better and relieve anxiety. This plant-based product has been used by millions of individuals worldwide and is a fixture among traditional cultures in South East Asia. It is considered safe when used as directed and is seen as a useful tool in treating opiate withdrawal. Several countries have places restrictions on kratom use while others have outright outlawed it. It all started in Thailand where the government placed a ban on kratom use in the 1920s after they realized that the cheap price of kratom, a plant that grows in abundance and could sometimes be found for free, was cutting in on the government’s opium trade.

From 196 countries in the world, just 4 countries have made this plant completely illegal for human consumption under any circumstances. Only few countries have not banned it completely, but still have strict regulations on human consumption, and in most of the countries is legal available for human consumption, because of its importance.

United States: In United States, kratom is not banned. It is legal and allowed for  human consumption but only in the states of  Wisconsin, Vermont,  Indiana and Tennessee have laws  which forbid the use of kratom. You do not need a prescription to purchase it and it is not currently regulated by the FDA. Kratom has improved the quality of life for countless individuals living within the borders of these four states, and because of ignorant and uniformed state leadership, these American Citizens will no longer be able to legally benefit from this all-natural tree leaf. There are some states considered to be hotspots at least in terms of keeping this trade safe. Again, you should be proactive and ready to investigate or research of its current legal status before purchasing it from any sources. Some of these states, where kratom is watched include Vermont, Arizona, Iowa, Hawaii, and Louisiana.

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.United Kingdom: At the moment, kratom is completely legal for purchase and use within the country. You can purchase Kratom in the UK without a prescription and it is not currently scheduled or restricted. Throughout the region, which include England, Scotland, Northern Ireland, Scotland, and Wales — any user can purchase the herb over the internet, but this herb tend to be a lot more expensive than North American based retailers.

Canada: Kratom is completely legal in Canada and its expected to become the next big hub of Kratom use. With the statistics of Kratom showing optimistic figures, this herbal medicine is all set to become a global movement. Because this country has a progressive mentality regarding traditional medicine and healthcare and due to this fact it’s hardly surprising the herb is legal and safe to ingest.

Australia: Kratom is currently illegal in Australia at this time and is listed as a schedule 9 drug, because they believed it had the potential for abuse, despite the fact that the Committee recognized that no cases of Mitragynine abuse had occurred in Australia. Because this legal status is unreasonable and unjustified, followers of natural remedies have lost all hope.

Austria: Kratom is legal for consuming and purchasing in Austria.

Belgium: Kratom is not a controlled plant in Belgium and all of the alkaloids present in it remains unscheduled. It is categorized as completely legal drug and hence is available easily at the local vendors

Brazil: Kratom use is legal in Brazil where the leaves of the plant as well as Kratom extracts are sold by local vendors. Trade and consumption has no legal obligations here.

Denmark: Although the purchase and sale of kratom was legal until 2009, currently it is considered as a controlled substance in the country and is therefore a substance with a few restrictions on its use.

Finland: Kratom in not entirely banned, the country requires you to possess a valid prescription in order to be able to buy or import the drug for consumption. The herb is classified as a medicinal substance and its importation is prohibited by section 19 count 1 of the Medicines Act. Importing the plant to Finland is illegal, your shipment will be confiscated at the border.

Germany: Due to the fact that laws have recently changed, this country’s stand on this herb is a little vague. In the past, people could import and export the kratom with no legal repercussions. In these days, the plant is listed as an unlicensed drug due to the Section 73 of Medicines Act. The act says that entering the country with the drug on you, can get you problems at the border security check. The law also outlines potential penalties including fines and jail time for Germans who unlawfully order it online.

Greece: Kratom use is permitted in Greece. It is feely available to use without any prescription. Neither Kratom as plant or Mitragynine appear to be listed in Greece’s controlled substances law.

Hungary: While Mitragyna Speciosa leaves are illegal to human consumption, kratom leaves and extracts can be purchased at headshops sold as incense.

Indonesia: This country is a leading producer and exporter of Mitragyna products. It is legal to grow and sell in this country, and illegal to export it, but Indonesian strains continue to be sold and enjoyed around the world. It is reported that Indonesia has banned kratom for export, but we believe that it is not illegal inside Indonesia. In 2013, one visitor reports that a vendor in Indonesia shipped them kratom into the US without any problem.

Ireland: According to previous Irish Statute Law or in the Misuse of  Drugs Act you could buy Kratom locally in Ireland. However, recently, the government has declared this herb as an illegal substance and its use an offence with a penalty of fine or punishment. It is a controlled substance under the Misuse Of Drugs act since 2011.

Italy: There are not sufficient proof supporting the current legal status of kratom in the country. Despite that, some if the Italian users claim that the herb is completely legal in their country and has no legal issues associated with its consumption. But, it will be best to consult an official for legit legal status of this substance.

Malaysia: If you want to sell kratom in Malaysia, it’s necessary to get a license issued by the government for the same. If you don’t posses this license, it is illegal to either plant, grow, sell or perhaps consume this herb for any purpose..

Myanmar: In Myanmar or Burma, is completely forbidden to sell or consume kratom.

Netherlands:  Kratom is legal in the Netherlands, actually this country is a leading supplier of kratom and its supplements in the entire Europe. In the country it can be purchased from smartshops as well as from online Dutch vendors.

New Zealand: According to New Zealand new law if you want to consume kratom you will need prescription. According to the Medicines Amendment Regulations Act of 2009, Mitragyna Speciosa leaves and its products are categorized under Schedule 1 as a prescription drug. Thisact regulate that is illegal to buy or sell kratom in this country, unless you have this valid medical prescription.Who is found to be growing, selling or consuming this drug without a prescription is breaking the law and is accused of breaking the law and this actc results with a punishment.

Romania: Romania banned kratom (including Mitragynine and 7-Hydroxymitragynine) on February the 10th, 2010. So obviously, it is prohibited to sell, buy, grow or even consume this drug anywhere in the country, otherwise, this act will be punished.

Russia: There are rules in this country that are not clearly understoond and hence this is a controversial topic. Some sources say that it is still legal while others cite a change in the law some time in 2011. Therefore if you want to consume kratom in Russia the best thing you can do is to consult a government official about its current legal status before consuming the drug in this country.

Sweden: In this moment, Mitragyna Speciosa leaves are illegal to use in Sweden and it is not listed on any drug schedules. However, there are indications that this law may change in the future.

South Korea: According to some reports, South Korea is another country that has outlawed Kratom use. It is heavily regulated with severe criminal penalties imposed against people who attempt importing this plant.

Thailand: Kratom tree is originated from Thailand, and was used by the ancestors of this country in many ways. Actually Mitragyna Speciosa leaves are commonly prepared as a tea and consumed as a drink similar to coffee. However, it is shocking that the country has still categorized it as a level 5 Narcotic, making it illegal to buy or sell this herb. It is interesting to know that the “Thai Kratom” product available online actually comes from Indonesia or other nearby countries.

Illegal:

These are the countries that prohibited kratom use:

  • Australia
  • Malaysia
  • Myanmar
  • Thailand

Strict Guidelines:

In these countries kratom is categorized as a Schedule 1 drug and has powerful regulations.

  • Denmark
  • Finland
  • Germany
  • New Zealand
  • Romania

References:

-http://speciosa.org/

-http://kratomlegend.com/

-http://www.mitragyna.com/legality/

Filed Under: Kratom (Mitragyna speciosa) Tagged With: Kratom, kratom legal status

Mitragyna Speciosa: Could This Be the Answer to America’s Opioid Epidemic?

Mitragyna Speciosa: Could This Be the Answer to America’s Opioid Epidemic?

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June 27, 2017 By John Reed 1 Comment

As the pharmaceutical companies continue to push narcotics onto Americans, the rate for addiction and death has almost tripled over the last decade. According to the World Drug Report in 2012, “It is estimated that between 26.4 million and 36 million people abuse opioids worldwide,1 with an estimated 2.1 million people in the United States suffering from substance abuse disorders related to prescription opioid pain relievers in 2012 and an estimated 467,000 addicted to heroin.”2 According to the National Center for Health Statistics, the number of overdose deaths involving opioids rose from 28,647 in 2014 to 33,091 in 2015.3

  • Heroin overdose deaths rose from 10,574 in 2014 to 12,990 in 2015, an increase of 23 percent.
  • Overdose deaths involving synthetic opioids other than methadone rose from 5,544 in 2014 to 9,580 in 2015, an increase of 73 percent. This category of opioids is dominated by fentanyl-related overdoses, and recent research indicates the fentanyl involved in these deaths is illicitly manufactured, not from medications containing fentanyl.
  • Taken together, 19,885 Americans lost their lives in 2015 to deaths involving primarily illicit opioids: heroin, synthetic opioids other than methadone (e.g., fentanyl), or a mixture of the two.
  • Overdose deaths involving prescription opioids, excluding the category predominated by illicit fentanyl, rose only slightly from 16,941 in 2014 to 17,536 in 2015, a 4% increase.
  • NOTE: A portion of the overdose deaths involved both illicit opioids and prescription opioids.3 

   

       Fig.1

The total number of opioid pain relievers prescribed in the United States has skyrocketed in the past 25 years. The number of prescriptions for opioids (like hydrocodone and oxycodone products) have escalated from around 76 million in 1991 to nearly 207 million in 2013, with the United States their biggest consumer globally, accounting for almost 100 percent of the world total for hydrocodone (e.g., Vicodin) and 81 percent for oxycodone (e.g., Percocet).4

Recently, the DEA and FDA began working together to crack down on the amount of opiates distributed in America by physicians and pharmaceutical companies; such as hydrocodone, oxycontin and morphine. “Fourteen billion opioid pills are now dispensed annually in the United States – enough for every adult American to have a bottle of pills. Certainly, the pharmaceutical industry is at fault for decades of misleading information about their products and the medical community bears responsibility for its role in over-prescribing these dangerous and addictive drugs, but we remain deeply troubled by the sheer volume of opioids available – volumes that are approved by DEA.”5

Kratom Is a Surprising Answer to This Terrifying Dilemma

Kratom is neither a drug nor an opiate. It is a deciduous tree that grows natively in Southeast Asia and has been used for its healing properties for centuries. The leaves of the plant contain dozens of alkaloids that can produce both stimulation and sedation as well as euphoria in those that ingest it. 7-hydroxymitragynine and Mitragynine are the most active alkaloids contained within the herb and are believed to be responsible for most of the effects that it produces.  Mitragynine (the most plentiful alkaloid) is an opioid agonist, meaning that it is drawn toward the opioid receptors in the brain. In the brain of an addict, those opiate receptors begin to ‘cry out’, so to speak, for that drug. Kratom’s unique alkaloid 7-hydroxymitragynine bind to those needy receptors and ease the withdrawal symptoms by tricking the brain into thinking it has found its fix.

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Side effects of Maend Da

A dose of Kratom can help to relieve the unpleasant side effects of the withdrawal by attaching its alkaloids to the delta-opioid receptors in the brain.  Although opiate drugs bind to the mu-opioid receptors, the mitragynine’s unique ability to attach to the delta receptors can relieve withdrawal symptoms without the risk of further dependency, thus alleviating these common withdrawal symptoms:

  • Anxiety
  • Muscle aches
  • Increased tearing
  • Insomnia
  • Runny nose
  • Sweating
  • Yawning
  • Abdominal cramping
  • Diarrhea
  • Dilated pupils
  • Goose bumps
  • Nausea
  • Vomiting
  • Agitation

The effects can be felt in as little as ten minutes and can last six hours or more, depending on the type of Kratom and how much was taken.  Kratom will not produce extremely strong euphoric feelings like opiates do, but it can soothe an opiate addiction successfully, and is a much safer and healthier alternative to methadone or suboxone.

All Kratom types affect the opioid receptors in some way and can provide relief from withdrawal symptoms.  The most popular choice for addicts are the red vein strains due to their sedating and strong pain-relieving qualities. At high doses, almost any type of Kratom will provide sedation, however the red strains are generally better suited for withdrawal symptoms.  White vein Thai, Red vein Borneo, Red vein Thai and Red vein Malay are all popular strains for this purpose.7

When using Kratom for opiate withdrawals, it is important to remember to monitor your dosing closely. Using Kratom for this purpose will require a higher dose than someone who was just using it to enhance their mood or treat mild pain.  While Kratom is not addictive, it can be habit forming.  In larger quantities, kratom can cause ill effects; such as nausea, vomiting, headaches and dizziness. Do not use more than recommended. Below is the general Kratom dosing guide.  Most Kratom users reach their desired effects in the mild and moderate ranges, however a heavy opiate user may need to use doses in the strong and very strong range to ease their withdrawals.  This, of course, is determined by the quantity and type of narcotics the person is used to consuming, their body composition, the strain of Kratom and other unique variables.  It is always safest to use the smallest amount of Kratom to ease your symptoms.  As time passes, you can lower your dose and use Kratom more sporadically.7

Strength Dose Effect
     
Threshold
1-3 grams
subtle
Mild 2-4 grams stimulant-like
Moderate 3-6 grams stimulant or sedative-like
Strong 6-10 grams more sedative/euphoric
Very Strong 8-15 grams very sedative/euphoric

The above table represents an ‘average’ amongst Kratom users and should only be used as a guide. Results vary from person to person and from plant to plant based on many factors8

[1]https://www.drugabuse.gov/about-nida/legislative-activities/testimony-to-congress/2016/americas-addiction-to-opiods-heroin-prescription-drug-abuse.html

[2]UNODC, World Drug Report 2012. http://www.unodc.org/unodc/en/data-and-analysis/WdR-2012.htm[3] https://obamawhitehouse.archives.gov/the-press-office/2016/12/08/continued-rise-opioid-overdose-deaths-2015-shows-urgent-need-treatment

[4]International Narcotics Control Board Report 2008.United Nations Pubns. 2009. Pg.20

[5]https://www.painnewsnetwork.org/stories/2016/10/4/dea-cutting-opioid-supply-in-2017

[6] https://medlineplus.gov/ency/article/000949.htm

[7] http://kratomrevealed.com/kratom-for-opiate-withdrawal-definitive-guide/

Other articles that may interest you

  • A Beginner’s Guide to Kratom Usage
  • Kratom Maeng Da: An Extended research of user’s experiences

Filed Under: Kratom (Mitragyna speciosa) Tagged With: Kratom, kratom use, Mitragyna speciosa

Kratom Effects: the disputed ancient opioid plant with the debated effects

Kratom Effects: the disputed ancient opioid plant with the debated effects

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June 12, 2017 By John Reed Leave a Comment

Mitragyna speciosa is the scientific name of Kratom, a well-known tropical tree with a long history of traditional use in many parts of Africa, Southeast Asia, the Phillipines and New Guinea1,2. Kratom is a 4-16 meter high tree that belongs to the Rubiaceae or coffee family1,2 and is also known as Thom, Thang, Biak, Kakuam, Mambog, Ithang, and Ketum3,4 and there are different varieties of it with various stimulant, opioid or other effects5.  The most known varieties of Kratom that are sold on the internet are: Bali Kratom, Malaysian Kratom, red, green or white vein Thai kratom, Maeng Da Kratom, white-veined Borneo Kratom, New Guinea Kratom, Java Kratom, Sumatra red, the Rifat strain, the bumblebee strain, and red and green Riau6.

Historical uses of Kratom

Traditionally, in some Southeast Asian regions, the leaves of the tree were either chopped fresh or used dried and were used either for chewing or for tea preparation so as labor workers to combat fatigue and to become more productive7. Furthermore, it has long been used by people in Thailand or Malaya as a painkiller and opioid8. Nowadays, Kratom is actually consumed throughout the world for its stimulant effects and as an opioid substitute (in form of tea, chewed, smoked, in form of powder mixed with chocolate, milk or other ingredients or even ingested in the form of capsules).

Biochemical consistency of Kratom and registered effects

Several case studies have associated Kratom exposure with psychosis, seizures9, hepatotoxicity10, pulmonary and kidney injury11, cardiac12 or thyroid13 injury, other medical conditions, and deaths14. According to a recent study2 that analyzed one of the strongest varieties of Kratom, Maeng Da (Thai)15, different Kratom preparations may contain varying amounts of several phytochemicals, making their pharmacological and toxicological evaluation unique and difficult  (see Fig. 1).

Figure 1: An estimate of Thai kratom extract composition. The phytochemicals isolated from various parts of the tree include overall 40 structurally related alkaloids as well as several flavonoids, terpenoid saponins, polyphenols, and various glycosides2.

The debated effects of Kratom consumption

However, the clinical manifestations of Kratom effects are not well defined and the clinical studies are limited. Research data and many blogs and forums15-21 suggest that both positive and negative effects of Kratom exist.  The positive symptoms, according to some users include feeling relaxed, energetic, sociable, and euphoric. Other reports suggest that kratom increases sensory perception and users experience no pain22. On the other hand, the negative symptoms are mostly described as side effects or withdrawal symptoms that users mentioned. These effects are stomach ache, nausea and vomiting22, dry mouth, polyuria, anorexia, weight loss and frequent constipation7, tiredness and a loss of appetite23, and psychological symptoms such as hostility, aggression, anxiety, depressed mood, dysphoria, moodiness, annoyance, restlessness, visual alterations and unsteadiness24, low sexual drive, and irritability25, in addition to some other symptoms reported such as inability to work, muscle and bone pain, and jerky movements of the limbs7, and cold symptoms such as chills and sneeze. Some users also report symptoms like sweats, dizziness, vomiting, itching, mouth and throat numbness, and sedation24. One of the very characteristic cultural syndromes called the “rain panic,” which is of greatest concern for regular kratom users is the sense of frozen into the bone with muscle pain, joint aches, cough, sneezing, and trembling and was described by Saingam et al25.

More research on Kratom would reveal its benefits and its dangers

It is important to note that mortalities after Kratom consumption have been reported to occur in individuals with blood mitragynine concentrations between 0.45 and 1.0 μM26. Thus, it is difficult to draw conclusions about the safety of its consumption. For sure, more research about its’ pharmacokinetics and its’ side effects is needed and for the time being a careful intake would be wise.

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References

  1. Hassan Z, Muzaimi M, Navaratnam V, Yusoff NH, Suhaimi FW, Vadivelu R, Vicknasingam BK, Amato D, von Hörsten S, Ismail NI, Jayabalan N, Hazim AI, Mansor SM, Müller CP From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction Neurosci Biobehav Rev. 2013 Feb; 37(2):138-51.
  2. Cinosi E, Martinotti G, Simonato P, et al. 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 Research International. 2015
  3. Fluyau, Dimy, and Neelambika Revadigar. “Biochemical Benefits, Diagnosis, and Clinical Risks Evaluation of Kratom.”Frontiers in Psychiatry 8 (2017): 62. PMC. Web. 11 June 2017.
  4. Gruley B Is Kratom a Deadly Drug or a Life-Saving Medicine? BloomBerg December 2016 https://www.bloomberg.com/news/features/2017-06-08/no-one-has-ever-made-a-corruption-machine-like-this-one
  5. Warner ML, Kaufman NC, Grundmann O (2016). “The pharmacology and toxicology of kratom: from traditional herb to drug of abuse”. J. Legal Med. (Review). 130 (1): 127–38.
  6. Raffa R.B.Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium Source. CRC Press Taylor & FrancisGroup; Boca Raton, FL, USA: 2014.
  7. Suwanlert S A study of kratom eaters in Thailand. Bull Narc. 1975 Jul-Sep; 27(3):21-7.
  8. Ahmad K, Aziz Z Mitragyna speciosa use in the northern states of Malaysia: a cross-sectional study. J Ethnopharmacol. 2012 May 7; 141(1):446-50.
  9. Nelsen JL, Lapoint J, Hodgman MJ, Aldous KM Seizure and coma following Kratom (Mitragynina speciosa Korth) exposure. J Med Toxicol. 2010 Dec; 6(4):424-6.
  10. Pantano, F., Tittarelli, R., Mannocchi, G., Zaami, S., Ricci, S., Giorgetti, R., … Marinelli, E. (2016). Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat. International Journal of Molecular Sciences, 17(4)
  11. McIntyre IM, Trochta A, Stolberg S, Campman SC Mitragynine ‘Kratom’ related fatality: a case report with postmortem concentrations.J Anal Toxicol. 2015 Mar; 39(2):152-5.
  12. Lu J, Wei H, Wu J, Jamil MF, Tan ML, Adenan MI, Wong P, Shim W Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes. PLoS One. 2014; 9(12):e115648.
  13. Sheleg SV, Collins GB A coincidence of addiction to “Kratom” and severe primary hypothyroidism. J Addict Med. 2011 Dec; 5(4):300-1.
  14. Karinen R, Fosen JT, Rogde S, Vindenes V An accidental poisoning with mitragynine. Forensic Sci Int. 2014 Dec; 245():e29-32.
  15. https://www.salviaextract.com/blog/green-malaysian-the-most-popular-kratom-strain/
  16. http://www.sagewisdom.org/kratomguide.html
  17. https://azarius.net/encyclopedia/15/Kratom_Mitragyna_speciosa/
  18. http://ensobotanicals.com/truth-maeng-da-kratom/
  19. http://kratomguides.com/maeng-da-kratom-benefits-side-effects-dosage/
  20. http://discoverkratom.org/maeng-da-review/
  21. https://www.kratomscience.com/strains-effects-and-dosage/
  22. Swogger MT, Hart E, Erowid F, Erowid E, Trabold N, Yee K, Parkhurst KA, Priddy BM, Walsh Z Experiences of Kratom Users: A Qualitative Analysis. J Psychoactive Drugs. 2015 Nov-Dec; 47(5):360-7.
  23. Kapp FG, Maurer HH, Auwärter V, Winkelmann M, Hermanns-Clausen M Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J Med Toxicol. 2011 Sep; 7(3):227-31.
  24. Singh D, Narayanan S, Vicknasingam B Traditional and non-traditional uses of Mitragynine (Kratom): A survey of the literature. Brain Res Bull. 2016 Sep; 126(Pt 1):41-46.
  25. Saingam D, Assanangkornchai S, Geater AF, Balthip Q Pattern and consequences of krathom (Mitragyna speciosa Korth.) use among male villagers in southern Thailand: a qualitative study. Int J Drug Policy. 2013 Jul; 24(4):351-8.
  26. Saidin NA, Holmes E, Takayamab H, Gooderham NJ.The cellular toxicology of mitragynine, the dominant alkaloid of the narcotic-like herb, Mitragyna speciosa Korth. Toxicol Res (2015) 4:1173.

Filed Under: Kratom (Mitragyna speciosa) Tagged With: Kratom, kratom effects, Thai kratom

Green Malaysian Kratom – The Strongest Strain

Green Malaysian Kratom – The Strongest Strain

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May 26, 2017 By John Reed 2 Comments

Kratom, also known as Mitragyna Speciosa, Kratum or Keetum, is an evergreen tree, from the same family as the coffee tree (Rubiaceae), indigenous to Thailand, Indonesia, Malaysia, Myanmar and Papua New Guinea, where it has been used in traditional medicine since at least the nineteenth century, as a substitute for opioid painkillers, a sleep aid or as a recreational drug. The tree can grow to a height of 25 m (82 ft) tall, the trunk may grow to a 0.9 m (3 ft) diameter. The leaves are dark green and glossy, and can grow to over 14–20 cm (5.5–7.9 in) long and 7–12 cm (2.8–4.7 in) wide when fully open. Its leaves produce a psychoactive effect which can range from stimulation to sedation, sometimes even both. The use of kratom goes back several thousand years, it has a long history of human usage and is legal in many countries, being available mostly in online shops and some random stores or even gas stations. It was first formally documented by Dutch botanist Pieter Willem Korthals in the early 19th century. Given the fact that it grew in distinctly different areas, the plant has evolved to adapt to its environment, developing different types of strains, effects ranging between leafs of each strain.

CLASSIFICATION

If you are new to kratom and are just learning, there is a lot of information out there and the majority of it is confusing. For one, you have all these options in front of you and it is really hard to choose a strain if you have no idea what to expect or what each strain helps you with. The most common misconception about kratom is it being mistaken for a “legal high”. There are different varieties of Mitragyna Speciosa strains available for purchase. Reputable vendors use the standard names for strains. The names for kratom leaves cosist of the country the tree is from, the region the plant was picked and the color of the leaves veins. For example “Green Vein Indo” would tell the user that the product is from a green veined leaf from a tree in Indonesia. The difference between red, green or white veins leaves are as follows:

The Red veins leaf:

These are your sedating strains. After the initial rush of energy, the calming effects take over. Red vein is often used for pain relief and as a substitute for opiate detoxing.  Some users report that it gives them a euphoric feeling.

The Green and White veins leaves:

These are the energetic strains, the white ones being slightly higher in energy. These leaves produce more stimulating effects than red vein varieties. Green vein leaves are known for providing clearer thinking as well as extra endurance, and is preferred by active people, such as athletes and labor workers. Some users have reported that green vein leaves have been useful for anxiety and depression symptoms.

The most popular of kratom strains are:

Green Malaysian – This is a very popular strain. Green Malaysian is a long lasting energizing strain. It is easier than some other strains to take due to its pleasant taste. It is considered on the more euphoric side of the effect scale. When taken, the kratom effects can last up to 8 hours for a beginner and around 3-4 hours for an experienced user.

Bali – Bali kratom effects are both relaxing and energizing. Higher doses of bali kratom tend to be more relaxing, while lower doses produce stimulating effects. For a new user, the kratom effects can last around 5-6 hours. Experienced users may feel the effects for around 3 hours.

Red Vein Bali – This strain is also known for its balanced alkaloid content. It has a unique taste and is a bit more sedating. Red Veined Bali is often used for pain relief due to its sedating effects. It is also effective for opiate detoxing.

Green Vein Bali – Green-Veined Bali is found in Borneo and Sumatra. It has a high alkaloid level that resembles Maeng Da. This Mitragyna Speciosa strain is becoming popular because of its balanced level of alkaloids. The kratom effects are said to be both relaxing and slightly stimulating with waves of euphoria. A perfect balance of energy and sedation.

Thai – Thai kratom is known for energizing effects and as a sexual stimulant. It lasts for about 4-6 hours. Because Mitragyna Speciosa trees were banned in Thailand in 1943, Thai strains are grown in other countries, such as Malaysia and Indonesia.

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There is a big variety, a big number of kratom strains, but in this article I am only focusing on the Malay strain, the Green Malaysian Kratom, one of the strongest strains.

The Green Malaysian Also known as Super Green Malaysian, Premium Malay, SGM, the Green Vein Malaysian is very well known and a pretty unique strain, with potency almost rivaling that of Maeng Da (Thai), and it is well-rounded, long lasting,  and energetic. The leaves of Malay Kratom are typically oval shades and have a dark green color, with an average size of 100-180 mm width and length. The veins of Malay Kratom leaves are either greenish-red or greenish-white with the latter being more potent.

Effects

  • Natural, all-day energy.
  • Mental concentration and clarity.
  • Excellent pain relief throughout muscles and joints.
  • Relief of stomach issues.
  • Anxiety relief.
  • Stress relief.
  • Muscle relaxer.
  • Help achieving a normal sleep schedule.
  • Calm state of mind.
  • Less social fear.
  • Ease of conversation.
  • Relief for chronic conditions like arthritis.
  • Sense of optimism.
  • Feelings of euphoria.
  • Lowered blood pressure

Green Malaysian has long been known as one of the longest-lasting strains due to leaf cell-wall density. Many people have remarks on this strain’s unique nootropic effects, which, despite heavy stimulation, can increase focus and patience for quite long periods of time. Interestingly, these effects are typically only noticed in retrospect due to its smooth character of effects. It helps in relieving chronic pain and aiding problems like osteoporosis, backache, migraine, etc. The most commonly found alkaloid in Malay Kratom leaves is Mitragynine, which is not soluble in water but is soluble in traditional organic solvents. The leaves of Malay Kratom act as powerful antioxidants, enhance the human body’s immunity and fight off damaged cells. Malay Kratom is useful for fighting off various cancers, and users have reported a boost in their chemotherapy results after simultaneously taking it. The alkaloids in the leaves are necessary to enhance mood and improve one’s health and balance hormones. When a user consumes Kratom, in whatever form, the effects that place usually happen simultaneously, meaning that shortly after eating or drinking Kratom, the user will experience euphoria (depending on the type of Kratom) alongside a boost in energy, an increase in appetite, relief from pain, etc. The problem with experiencing all these effects together is that they all go away together when the effects subside. Its main effect is to give energy, a boost in senses and a feeling of heightened happiness, joy or euphoria, as well as relief from chronic pain. The people suffering from a lack of concentration, boredom at work, anxiety, stress, and depression can use it to fix these issues. Naturally, it is the perfect strain for workaholics or professionals or even students. Also those suffering from chronic pain such as arthritis, osteoporosis, migraines, backaches, sciatica, etc. can significantly benefit from Green Malay Kratom pain relief properties. The effects of green Malay Kratom are the most long-lasting, which means extended relief from pain, heightened concentration and a boost in mood.

Dosage

A gram is the minimum dosage of Green Malay Kratom, whereas users say that 10 grams are the maximum dosage that a person can enjoy. Anything more than 10 grams in a day can be harmful to the human body. Reports from users show that the typical strain of green Malay Kratom ranges from 2 – 6 grams, with the most commonly reported dosage being of 2.5 – 4 grams. Keep in mind that smaller doses result in a more energetic experience, while larger doses tend to produce more calming and slow-speed effects. Green Malay Kratom dosage can also be taken according to one’s weight. If your weight is less than 70 kg or 150 pounds, then you should consume 2 – 3 grams per day. If your weight between 150 – 200 pounds, then you should take 3 – 4 grams per day, which amounts to 1.5 – 2 teaspoons a day. For those weighing more than 200 pounds, it is recommended that they start with 5 grams of kratom, which is equal to two and a half teaspoons of Green Malay kratom. These dosages are for those who are not very sensitive to kratom and are suitable for those wishing to experience milder effects. A precaution that one has to take with Green Malay kratom, due to its high potency, is not to take it on an empty stomach. Always eat something and take it one hour after eating, so that it does not sit on an empty stomach because this can lead to nausea, vomiting, dizziness and lack of concentration. If you do wish to take it on an empty stomach, the dosage should be 2 grams.

Preparation

There are a few popular methods of using powdered leaf, but the most common are “toss and wash“, mixing with food, and preparation as a tea. Even soap, or capsules can be made of kratom. But first of all, the leaves must be turned into powder. You can simply crunch up the leaves in your bare hand, being careful to collect the resulting dust on a piece of paper laid out on the table. You can also add dried leaves to an empty pepper mill (preferably a new one so no remnants of other spices remain), and grind them into a powder, or a small food processor or blender can accomplish the task well, though be sure to account for some kratom dust getting stuck to the blades. Here are some simple usage metods:

  • “Toss and wash” is basically just spooning the powder into your mouth and washing it down with a liquid. This is the most “difficult” method but likely gives the strongest effects. The powder is incredibly dry and will stick to your mouth and throat, causing many to gag or cough “blow” the dry powder out of their mouth. If using this method of consumption, it is best to spoon small amounts at a time.
  • Kratom can also be mixed into a food. One can mix it with ice cream or apple sauce, or mixing with chocolate milk or protein shakes. Keep in mind that kratom has a strong flavor and may not mix well in certain foods. Also, you will not reduce the efficacy of kratom if you take it with small amounts of food.
  • Preparation as a tea is convenient and effective. It is important to note that only powdered leaf should be used to make tea. Extracts should not be used. Start by measuring out between 1 teaspoon of powdered leaf. Boil 2-4 cups of water. The more water you use, the less strong the flavor, but as long as you drink it all the effects will be exactly the same. Put the kratom powder into a large cup or container with a pour lip, and pour the boiling water on top. Stir until it is thoroughly mixed. Be sure there aren’t any clumps of dry powder. Adding sugar it’s highly recommended, artificial sweeter, or honey (honey works the best to cut the bitterness), and stir. If using artificial sweetener, 2 packets is a good starting amount. Let sit until cool (at least 15 minutes), stirring occasionally. Once cooled, allow the powder to settle to the bottom. Pour the tea into a drinking cup, and enjoy! At this point you can add more sweetener to taste, or add water or ice cubes to dilute the flavor. As long as you drink all of the liquid, the effects will be the same.

Negative effects

Before you decide to jump in and give Kratom a try, it is important that you know what to expect from this botanical. Kratom effects can seem contradictory to the uninformed user. If more than 10 grams of Green Malay Kratom taken in one day, its adverse effects include slurred speech, difficulty in keeping track of thoughts, jitteriness, fidgeting and inability to concentrate on one thing. It can also make one extremely hyper, excessively talkative, nauseous or dizzy, especially if one suffers from vertigo or chronic migraines. Other users have reported excessive itchiness, sweating and red rashes on their legs. This is why, unless you are extremely tolerant, not more than 10 grams of Green Malay Kratom should be taken in a single day.

The users of Kratom strains recommend the use of Green Malay strain to experience a feeling of wellness and be able to go about your daily chores with a great amount of mental alacrity and soundness. However since the market is rife with a few adulterated varieties, it is often wise to check claims before making a purchase. Green Malay Kratom, if used wisely, is not only light for your pocket but also promises a host of other benefits as well.

Filed Under: Kratom (Mitragyna speciosa) Tagged With: green malay kratom, Green Vein Kratom, Kratom, Red vein Bali, Red Vein Kratom, White Vein Kratom

White Vein Thai Kratom

White Vein Thai Kratom

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February 21, 2017 By John Reed Leave a Comment

Of all different kratom varieties, white vein kratom is the most unique. This vein type has some of the most energetic strains of all and tend to be used in the mornings, or in draining situations where fatigue would be otherwise inevitable. However, while energetic, they overall tend to have less painkilling, analgesic properties than green and red vein strains.
Because of this, they have a very unique niche, and not everyone is suited for them. For those who haven’t tried this variety of kratom, there is a lot of potential within these strains, and shouldn’t be overlooked in favor of some other, heavier strain — sometimes the clean boost of white veins can be just what is needed.

White Vein Thai Effects

As briefly mentioned, the effects of this variety of kratom are unique in comparison to other vein types. The most common effects of white vein kratom are stimulation/energy, nootropic (cognitive boosting), endurance, and it has even been used for depression.

Stimulation, Energy and Endurance

One of the most common reasons that white vein kratom is used is for a clean pick-me-up. If you read through kratom forums, you’ll find many people who have replaced their morning coffee with a white with great effect. The energy that is provided from these strains tends to be much cleaner than the jittery energy of caffeine and other stimulants. The reason for this is the balancing of energetic and analgesic alkaloids, which also contribute to its endurance promoting effects by increasing energy and dampening the pain response.

Nootropic Effects

While not highly researched, many users of white vein kratom have experienced have experienced some unique cognition boosting effects. A few users have reported increased memory recall, but the most common effect reported has been increased focus. Many suspect the reason for this is the synergy between its energetic and analgesic effects, which appear to dampen background noise and promote natural focus. Because research in this area is so limited, it may be a while until we can delve more deeply into these areas.

Anti-Depressant

Similar to the nootropic effects, the anecdotal antidepressant effects of white vein kratom haven’t been researched much; however, user experiences across the board find that it is useful in this regard; however, whether it is useful for depression long-term is difficult to say at this point.

Alkaloids

The reason for different effects between white an red vein strains is their differing alkaloid profiles. Thanks to Raymond-Hamet, Beckett AH, Shellard EJ, Lee CM and Phillipson JD, we have some preliminary studies about alkaloidal differences between strains grown in different regions, and what alkaloids contribute to their effects.

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Sadly, there haven’t yet been any serious studies on vein type and alkaloid profile, but differences in effect seem to indicate similarities between strain alkaloid variation and vein type variation. Because of this, we have a much better idea of what alkaloids are found in this vein type, though it is far from complete and can vary depending upon what vendor or area you buy kratom from.

In this variety of kratom, we can expect to see a proportionally higher amount of mitragynine, and a lower amount of 7-hydroxymitragynine than is found in red vein strains, contributing to the energetic effects and reducing the painkilling effect. Additionally, we will likely see less speciogynine (a smooth muscle relaxer) and less ajmalicine (a anti-adrenergic sedative) than is found in red and green vein strains. Because this is far from complete, we will likely see a large number of other variations between different vein types.

Variability of White Vein

After years of previously selling kratom, we have noticed something that very interesting about this type of kratom: people tend to love them or get little to no effect from them at all. With other varieties, such as red veins, the effect from person to person is fairly even across the board, whereas white veined strains tend to play at brain chemistry in a very different way. Because of this, not every person may be particularly suited for them. However, like any other good thing, it is typically worth a shot, as the effects can be very helpful, and useful.

Additionally, white vein kratom dosage may be different than that of other strains, some who are sensitive to the effects may require less, whereas those who are less sensitive may require more. Because of this, it is a good idea to monitor dosage and start low if interested in this variety of kratom.

Popular Strains

Because white veined strains are found in all different regions and strains, there are a variety of different effects on can encounter depending on their choice. Some of the most popular are:

White Vein Borneo

As Borneo strains are typically more sedative in character than many other strains, this variety of borneo has a variety of properties unique to it. Anyone who has tried this variety knows that it tends to provide both energy and analgesia, given it is of sufficient potency. This blending of effects makes it very useful for those who require pain relief or anxiety relief, but don’t want to sacrifice performance or energy in order to achieve it. White vein borneo kratom is similar to Indo in this regard, and they share these common characteristics. However, each particular borneo and indo strain is different, so the effects can vary slightly.

White Vein Thai

Another common strain is white vein thai. The white veined varieties of kratom, on top of the already energetic effect of thai, can be a bit jittery for those who aren’t used to the sedation, but can also be highly effective for tedious work or jobs requiring a lot of energy. Sadly, the painkilling effects of this strain are not very pronounced. White vein maeng da is very similar to thai, however, it tends to have slightly more analgesic effect. However, this depends upon each individual plant and strain.

White veined kratom is one of the most unique of all strains and carries with it a variety of unique properties, which have given a broad range of good experiences. However, not everyone is affected the same way, so it may take some trial and error to find the ideal choice for yourself.

Filed Under: Kratom (Mitragyna speciosa) Tagged With: Kratom, Mitragyna speciosa, nootropic effect, Simulation, White Vein Kratom

Mitragyna Speciosa Korth Alkaloid Extract And Cytotoxicity Biology

Mitragyna Speciosa Korth Alkaloid Extract And Cytotoxicity Biology

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February 11, 2017 By John Reed Leave a Comment

Mitragyna Speciosa Korth Alkaloid Extract And Cytotoxicity Biology Essay

This essay has been submitted by a student. This is not an example of the work written by our professional essay writers.

Nonstandard abbreviations: MSE, Mitragyna speciosa alkaloid extract, DMSO, dimethyl sulfoxide; HEK293, human embryonic kidney cells; HepG2, human hepatocellular carcinoma cells; HCT116, colon carcinoma cells; SH-SY5Y, neuroblastoma cells; A498, renal cell carcinoma; SK-MEL-28, melanoma cells; MEM, Eagle’s Medium Essential Medium; FBS, fetus bovine serum; DMEM, dulbecco’s modified Eagle’s medium; IC50, half maximal inhibitory concentration .

Mitragyna speciosa has great potential to be used as opium substitute and treating opioid abstinence syndrom > Cytotoxicity of the methanolic extract was examined using XTT assay against 6 human cancer cell lines > Tested with 10 concentrations of plant extract from 0.05 to 300µg/ml > Acute and Chronic in vitro study > Acute dermatoxicity, chronic and moderate hepatotoxicity, nephrotoxicity and neurotoxicity were reported.

Abstract:

Ethnopharmacological relevance: Kratom, or Mitragyna speciosa Korth, has been reported as a mu- and delta- opiate receptor agonist producing similar effects as those produced by morphine. It has been traditionally utilized as an opium substitute or to alleviate opiate withdrawal symptoms. In spite of its relatively common usage, toxicological data of this plant is still lacking.

Aim: The aim of the study is to determine the acute and chronic cytotoxicity of Mitragyna speciosa Korth alkaloid extract in vitro in various human cancer cell lines.

Methodology: Cells were treated with 0.05 to 300µg/ml of Mitragyna speciosa Korth alkaloid extract. The effect of the alkaloid extract on proliferative responses of the cancer cell lines were assessed by cell proliferation cytotoxicity assay (XTT) after 24, 48 and 72 hours. Untreated cells were used as control.

Results and conclusion: Significant growth inhibitory activity of the alkaloid extract on cancer cell lines were noted. The Mitragyna speciosa alkaloid extract showed acute potential toxicity to the skin melonoma cells (SK-MEL-28) after 24 hours incubation with IC50 value of 16.15 ± 1.45µg/ml. Furthermore, moderate chronic hepatotoxicity, nephrotoxicity, neurotoxicity, embryotoxicity and colon toxicity was reported in this study.

Key words: Mitragyna Speciosa, cytotoxicity, XTT, cancer cell lines, IC50.

Introduction

Mitragyna speciosa Kroth (from the Rubiaeceae family) is an indigenous plant which is found mainly in the northern Malaysia peninsula and in central and southern parts of Thailand (Suhanya et al., 2009). It is known as “Biak-biak” and “Ketum” in Malaysia, and as “Kratom” in Thailand (Saidin et al., 2008). The major indole-alkaloid constituent found in the Mitragyna speciosa is mitragynine, a mu- and delta-opioid receptor agonist. (Juzaili et al., 2010). Studies have shown the psychoactive properties of mitragynine is linked with it’s high affinity for opiate receptors, hence indicating it’s potential for treating opiate addiction as replacement therapy (Babu et al., 2008).

Traditionally, leaves from this plant have been consumed by the Thai and Malaysian natives mainly to treat diarrhoea, and to produce a stimulant and euphoric effect to combat fatigue and to increase tolerance to the hot sun (Kavita et al., 2008). Furthermore, the leaves have been reported to possess opium-like properties in which it’s stimulating effect was found in low dose. High doses of the Mitragyna speciosa extract can cause analgesia and hallucination (Suchitra et al., 1998). Due to its unique medicinal properties, kratom has been widely used to treat pain and opium withdrawal symptoms since the nineteenth century. However, addiction and several opioid abstinence syndrome such as irritability, yawning, rhinorrhoea, myalgias, diarrhoea, tremor, nausea, nystagmus, and arthralgia were reported among the chronic users (Kavita et al., 2008). Anorexia, weight loss, skin darkening and psychosis have also been reported (Suwanlert, 1975).

Although, the pharmacolofical effects of Kratom in human and experimental animals are well established, the doses required to produce toxicity still remain poorly defined. The only toxicological study by Harizal et al. (2010), standardized methanol extract of Mitragyna speciosa Korth caused mild nephrotoxicity and severe hepatotoxicity at doses higher than 1000 mg/kg (Harizal et al., 2010). No acute neurotoxicity effects were found in the cortex and hippocampus of the rat (Harizal et al., 2010).

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The issue of misuse of the plant by the drug addicts has caused major concerns in Malaysia and Thailand. Consequently, Kratom plant has been listed as a controlled substance in Malaysia, Thailand and Australia. However, in other parts of the world, kratom is currently not strongly regulated. The availbility of kratom over the internet has caused significant drug abuse issue, such as self-treatment in opioid withdrawal and in chronic pain (Kavita et al., 2008; Somsmorn et al., 2008). The main objective of this study is to investigate the potential acute and chronic in vitro cytotoxicity of Mitragyna Speciosa Korth alkaloid extracts against different human cancer cell lines in order to estimate its potential toxicity to humans.

2. Methodology

2.1 Preparation of Mitragyna speciosa Korth alkaloid extract

Fresh leaves of Mitragyna Speciosa Korth were collected from the forest in Perlis, Malaysia. Methanol-chloroform extraction method was used to extract the alkaloid compounds. The leaves (5kg) were dried and soaked in methanol for 3 days. The methanol mixture was filtered and the filtrate evaporated using a rotary evaporator. The extraction and evaporation procedure was repeated three times. Following that, the crude methanol extract was re-dissolved in 10% acetic acid and then washed with hexane. The acidic layer was basified to pH 9 using ammonia hydroxide and extracted with chloroform. The collected organic layer was filtered through sodium sulphate anhydrous and the filtrate was extracted using a rotary evaporator to obtain 5.86g of crude alkaloid extract. The akaloid extract was then identified using Dragendorf test (Juzaili et al., 2010). Lastly, the extract was redissolved in dimethylsulphoxide (DMSO) to form the stock solution, following which, it was filtered using 0.2μm syringe filter before being tested on the different cell lines.

2.2 Cell Culture

The effect of alkaloid extract on cell viability was assessed in a cell culture system using cells from human embryonic kidney cells (HEK293), human hepatocellular carcinoma cells (HepG2), colon carcinoma cells (HCT116), neuroblastoma cells (SH-SY5Y), renal cell carcinoma (A498) and melanoma cells (SK-MEL-28) which were obtained from American Type Culture Collection (ACTT) and Aurigene Accelerating Discovery Ltd, Bangalore, India. HepG2, A-498, and SK-MEL-28 cell lines were grown in Eagle’s Medium Essential Medium (MEM); with 10% fetus bovine serum (FBS) and supplmented with 1% of 100x penicillin-streptomycin antibiotic, 2mM glutamine, 1% non-essential amino acid and 1% sodium pyruvate. Meanwhile, HEK293 cell line was grown in Dulbecco’s modified Eagle’s medium (DMEM) with high glucose content (4.5gL1). SH-SY5Y cell line was cultured in 1:1 mixture of MEM and Ham’s F12 medium. HCT116 cell line was grown in McCoy’s 5a medium. The medium for cryopreservation contained 20% FBS and 5-8% DMSO in growth medium. All the cell lines were maintained at 370C in a 5% CO2 atmosphere with 95% humidity. At 60-70% confluence, cells were trypsinized and seeded in 96-well plates in respective optimal cell density. Twenty-four hours after the cell seeding, cells were treated with various concentrations of plant extracts.

2.3 cell proliferation (XTT) assays

The cell viability of the cancer cell lines were determined by using cell proliferation XTT assays in which the viable cells were determined by the amount of mitochondrial dehydogenases released in the living cells. Mitochondrial dehydrogenese of the variable cells cleave the tetrazolium ring of XTT (2,3-bis[2-Methoxy-4-intro-5-sulfophenyl]-2 H-tetrazolium-5-carboxyanilide inner salt) yielding orange formazan cystals which can be measured by a spectrophotometer (Scudiero, 1988; Weislow, 1989). An increase or decrease in living cell numbers result in a concomitant change in the amount of formazan formed, indicating the level of cytotoxicity caused by the plant extract. The cells were seeded into 96 wells plates in respective optimal cell density and incubated for 24 hours to get 70% confluent. Following that, cells were incubated with various concentrations of plant extract (0.05-300µg/ml) for 24 hours, after which, plant extract was removed from each well and then washed with phosphate-buffered saline (PBS). After incubation, for every 100µl of serum free medium, 50µl of XTT solution with phenazine methosulphate (PMS) was added, and incubated for a further 4 hours at 37oC. The absorbance of the samples were checked at 465nm using fluorescence spectrophotometry. Untreated cells were used as control. Cell viability was determined after 24, 48 and 72 hours incubation time and defined as a percentage of cell survival (ratio of absorbance of treated cells to untreated cells). All data were recorded as mean ± SEM of triplicate measurements.

3. Results

3.1 Preparation of alkaloid extract

One kilogram of dried powdered mitragyna speciosa leaves (approximately 5kg of fresh leaves) gave a crude extracts of 105g methanolic extract. From the crude methanolic extract, 5.86g of alkaloid extract was obtained ( 0.12% yield of fresh leave weight). The amount of mitragynine exist in the alkaloid extract was approxiamately 22-24% (Juzaili et al., 2010)

3.2 Cytotoxic activity of Mitragyna speciosa alkaloid extracts on cancer cell lines

The results depicted in Table 1, Figure 1 and 2 summarize the cytotoxic effects of the alkaloid extract on HepG2, A498, SK-MEL-28, HEK293 HCT116, and SH-SY5Y cell lines. Table 2 indicated the classification of cytotoxicity for natural products. Untreated cells were used as control. The IC50 results (mean ±SEM) are listed as the percentage of cell survival after exposure to different concentrations of MSE and determined at three incubation times. Based on the figure 1 results, XTT assay showed that alkaloid extract caused a significant cytotoxic effect from 0.05 to 300 µg/ml.

3.2.1 HCT116 cells

Within 24hrs, there was a clear dose-dependent inhibition of cell proliferation compared to the control (Fig. 2a) and the effect become pronounced at the doses higher than 11µg/ml. By 48 hrs, proliferation of cells treated with lower concentration of alkaloid extract (≤ 33µg/ml) has recovered. However, cell proliferation inhibition remained observed at other extract concentration. Approximately 100% of mortality rate was observed with highest concentration of alkaloid extract, 200 µg/ml. The IC50 for the cell at 24 and 72 hrs period were 62 and 43µg/ml respectively (Table 1).

3.2.2 HEK293 cells

With HEK293 cells, alkaloid extract of Mitragyna speciosa caused a dose-dependent inhibition of cell proliferation at all incubation times. As with other cells, cell proliferation recovering was observed at lowest concentration after 48 hrs. At higher doses of extract (>33µg/ml), cell proliferation was inhibited. After 72 hrs, approximately 100% cells were dead at highest dose, >100µg/ml (Fig. 2b). The IC50 value in this cell was estimated as 46 µg/ml in 24 hr and 27 µg/ml in 72 hrs (Table 1).

3.2.3 SH-SY5Y cells

With SH-SY5Y cells, low doses of alkaloid extract (1.23 – 11.11 µg/ml) slightly increased the cell proliferation up to 48 hrs (Fig. 2c). However, higher doses (>33µg/ml) inhibited the cell growth substantially within 24 hrs. The IC50 of the cells after 24 and 72 hrs treatment were 66 and 34µg/ml, respectively (Table 1).

3.2.4 HepG2 cells

Alkaloid extract treated HepG2 cells had shown the same pattern of cell proliferation inhibition as other cell lines. At concentration higher than 33µg/ml, there was a prominent cell death throughout the experiment (Fig. 2d). Low or no inhibition was found at the two lowest dose. The IC50 for HepG2 cells at 24 and 72 hrs treatment were approximately 49 and 27µg/ml, respectively (Table 1).

3.2.5 SK-MEL-28 cells

For SK-MEL-28 cells, acute cytotoxicity was observed within 24 hrs treatment (Fig. 2e). Almost 100% of cell death was reported at 2 highest doses (100 and 200µg/ml). Low to moderate inhibition was noted at concentration lower than 33µg/ml. Simultaneously, cells were recovered at low concentration of extract. The IC50 for the cells was 16µg/ml approximately at all the time points (Table 1).

3.2.6 A498 cells

With A498 cells, dose-dependent inhibition of cell proliferation became prominent after 100 µg/ml (Fig 2f). Low or no inhibition of cell proliferation was observed at concentration lower than 33µg/ml. However, there was a sudden decreasing in cell proliferation after 48 hrs of high dose-treatment (100µg/ml). The IC50 reported in this cells were about 82 and 15µg/ml in 24 and 72 hrs treatment (Table 1).

DISCUSSION

The use of traditional medicines from natural products have become popular all over the world especially in the developing countries. Herbs were always presumed to be safe because of its “naturality”. However, as quoted famously by Paracelsus, “All substances are poisons; there is none that is not a poison. The right dose differentiates a poison and a remedy”. Self medication among the user without knowing its toxicity and not being aware of the dose that is being consumed is extremely dangerous. On the other hand, most of herbal medicines are given without a proper prescription, high doses or in combination with other medications may cause toxic effects.

Various types of pharmacological benefit from Mitragyna speciosa had been reported. However, due to it morphine-like properties, it has been aggressively misused among the drug addicts as opium substitute or to alleviate opiate withdrawal symptoms. Several countries such as Malaysia, Thailand, Myammar and Australia have legislated this plant due to its narcotism. Even throught, the potential toxicity of the mitragyna speciosa is still remain unclear. Therefore, toxicological assessment of this alkaloid extract was investigated in this study. The alkaloid compounds were extracted using the methanol-chloroform extraction method. Previous studies have identified that mitragynine was the most abundant alkaloid found. It has been well established to possess morphine-like effects on in vitro and in vivo studies (Idid et al., 1998; Matsumoto et al., 1996). Other indole alkaloids such as speciofoline, rhychophylline, stipulatine, isomitraphylline and ajmalicine have also been isolated from the leaves as well (Beckett et al., 1965). Besides, there was an interesting finding in which another alkaloid compound, 7-hydroxymitragynine, had been reported to have a stronger analagesic effect and a potent gastrointestinal transit inhibition in the mice when compared to morphine (Matsumoto et al., 2004a, 2006b). Tolerance and morphine-like withdrawal symptoms by 7-hydroxymitragynine and mitragynine have also been reported.

In the present study, the cytotoxic effects of Mitragyna speciosa alkaloid extract was evaluated using several human cancer cell lines in vitro. Due to its fast, easy growing and other special mammlian characteristic, cancer cell lines were widely used as primary screening for the in vitro cytotoxicity. For example, HepG2 cells are the transfected cells which showing metabolic activities such as cytochrome P450s metabolism and hydroxylation (Wu et al., 2006). Besides, µ- and δ- types opiate binding side are presented on SH-SY5Y cells. HEK293 cells are the kidney embryonic cells which consist of many cell characteristics.

In addition, the use of the XTT assay greatly simplifies the procedure for measuring proliferation as compared to the MTT assay, whereby the solubilization step that is present in the MTT assay was avoided. There was a limitation to the high concentrations of Mitragyna speciosa alkaloid extract used since extremely high concentrations of Mitragyna speciosa interfered with assay fluoroscence measurement (Saidin et al., 2008). However, there was a dose dependant toxicity trend seen with the alkaloid extract at the doses of concentration ≤ 300µg/ml.

Regardless of incubation times, In vitro screening of alkaloid extract demonstrated that skin melanoma cell SK-MEL-28 was the most sensitive cell line examined. The IC50 after 24hrs treatment of SK-MEL-28 was 16.9µg/ml. Epidemiology study showed that darkening of the skin was found in chronic consumers the of Mitragyna speciosa extracts, but the mechanism remain unclear. However, most properly, it was caused by the dark pigment, melanin which produced by activation of melanocytes in response to the melanocyte-stimulating hormone (MSH) stimulation. MSH was released by pituatray gland as response to the mitragynine-estimulating corticotropin-releasing hormone (CRH) release from hypothalamus.

Apart from the acute cytotoxicity effects (24 hr treatment), another major finding in this study was the chronic cytotoxicity effects by Mitragyna speciosa extract as determined by 72 hrs treatment. Moderate cytotoxicity on kidney, liver, colon and nerve cancer cell lines were observed. However, cell proliferation was completely inhibited when treated with the dose ≥200µg/ml. There were some differences in the IC50 values for the HepG2, HEK293 and SH-SY5Y in this study from those of Saidin et al., (2008). The study of Saidin et al. (2008) showed that mitraynine was most toxic to SH-SY5Y and moderate cytotoxicity to HEK293 and HepG2. The IC50 results in Saidin’s study was relatively higher than the present study. Variation such as manner of preparation and extraction methods can also contributed to the data variability. Uncontrollable factors such as climate, growth and storage condition might affect the quality of the substrates as well (Akansha et al., 2008; Hanapi et al., 2010). Besides, the use of relative IC50 and absolute IC50 remain controversial among the researchers. Relative IC50 showed the concentration required to bring the curve down to the point half way of the maximum and minimum plateaus of the curve. Whilst, absolute IC50 is defined as the concentration required to give 50% of inhibition. However, relative IC50 was more commonly used compare to absolute IC50 because the potency of the drug is ignored in the determination of absolute IC50.

Harizal’s study showed that oral administration of standardized methanolic extract of Mitragyna speciosa resulted in severe hepatotoxicity and mild nephrotoxicity in high doses. This had been proven by histological and biochemical examination of Mitragyna speciosa extracts treated liver cells. Kupffer cells, enlargment of nucleus (karyomegaly), and significant elevation of ALT level was found (Harizal et al., 2010). Metabolic activation of xenobiotic was believed to be one of the factors that had caused the hepatotoxicity. Besides, consumption of the the Mitragyna speciosa extract by rodents has been found to cause an increase in blood pressure (Harizal et al., 2010). There is a likelihood that the effects produced are due to α2-adrenoceptor antagonists effect, which is the case with yohimbine (Verwaerde et al., 1997). On the other hand, in vivo acute treamtment of Mitragyna speciosa did not bring any damage in axons and dendrities of the hippocampal neurons (Harizal et al., 2010). High dose of administration among the chronic user are categorized as high risk user because of the drug tolerance and addiction effects.

It has been noticed that mitragynine is structurally similar to yohimbine, an alkaloid with stimulant and aphrodisiac effects which is found naturally in Pausinystalia yohimbe (from Rubiaeceae family) (Fig.3). Yohimbine is an α2-adrenoceptor antagonist which has been used to treat idiopathic and medication-induced erectile disorder (Benjamin et al., 2007). Several similarities in side effects mitragynine and yohimbine such as tremor, irritability, hallucination, dizziness, skin flushing, seizure and renal failure have been reported in the literature (Quinton, 1963; Eric et al., 1989; Lydia et al., 2001). An interesting antinociceptive study had demonstrated that pre-treatment of yohimbine completely blocked the opiate receptor agonist such as morphine (mu-opioid receptor agonist), U-50,488 (kappa- opioid receptor agonist) and SNC80 (delta- opioid receptor agonist) (lydia et al., 2001). Based on the chemical structure of yohimbine, ester group and hydroxy group at the C-17 position have the stronger affinity to the α2-adrenergic receptor, serotonin and dopamine receptor. Thus, this indicated that yohimbine have high potential to be competitive agonist to the opiate receptor. Minor differences in their chemical structures such as the molecular weight, polarity, indoloquinolizidine structure, total of rings, might given some changes in the pharmacological effects as well.

In conclusion, Mitragyna speciosa alkaloid extract showed most sensitive cytotoxic effect on skin melanoma cells after 24hr of drug treatment. Chronic and moderate cytotoxicity was reported in the human liver, kidney, colon and nerve cancer cells. This finding supports the result of the hepatotoxic and nephrotoxic effects from in vivo study of Harizal et al. (2010). Futher studies on other active compounds in the alkaloid extract are necessary in order to identify the most toxic chemical components in the extract. Besides, metabolic activation, especially cytochrome P450 metabolism activation by the extract must be carried out in order to get a better understanding of the mechanism of toxicity.

Filed Under: Kratom (Mitragyna speciosa) Tagged With: akaloid extract, Kratom, kratom toxicity, Mitragyna speciosa, Preparation of Mitragyna speciosa Korth alkaloid extract

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