Kratom, or Mitragyna Speciosa, is a tropical evergreen plant of the Rubiaceae family, much like coffea and cinchona. It is endogenous to various regions of Southeast Asia, namely Malaysia, Thailand, Indonesia and Burma. Mitragyna has been cultivated for millennia and serves a multitude of applications in both traditional and modern herbal medicine. However, as of late, the plant has become increasingly popular among the nootropic and cognitive enhancing community, primarily as an anxiolytic and anti-depressant. Though generally, the most popular use is in the cessation of opioid and alcohol addiction. Kratom has proven to be extremely effective in treating opiate dependence and reducing relapse potential 1. This is possible because mitragyna contains unique opioid alkaloids. Now, this fact has produced a great deal of contention and is largely responsible for the DEA’s attempt to ban the drug in late 2016, however for reasons that will be elaborated on in detail later, a drug’s pharmacological classification alone could not mean less when assessing it’s potential risks. That isn’t to say they do not exist, anything has the potential to be abused and kratom certainly isn’t exempt.
This guide’s purpose is to serve as an educational resource for those looking to use mitragynine as a nootropic and/or therapeutic agent, while it is effective for the treatment of addiction, we will not be covering this particular application in depth. It is also intended that this guide will separate and distinguish the prominent misconceptions from what research publications have determined to be correct.
Pharmacology of Kratom
The pharmacokinetics of kratom are quite complex as the plant contains a variety of active alkaloids. The compounds of highest concentration include mitragynine, paynantheine, speciogynine, 7-hydroxymitragynine, mitraphylline and rhynchophylline. The concentrations of each vary greatly between regional subspecies (or strains), consequently, different kratom strains can offer a wide spectrum of benefits and potencies.
Mitragynine is the most abundant alkaloid found in mitragyna speciosa, comprising approximately 66% of the total alkaloid content and ~2.1% of dry leaf weight 2. The compound is an indole-based opioid that functions as both a selective and full μ-opioid receptor agonist, evidence suggests its affinities for the δ and κ receptors are effectively negligible. Mitragynine also modulates the 5-HT2a and postsynaptic α2-adrenergic receptors in various regions of the brain, these interactions are speculated to be in part responsible for kratom’s mood elevating and stimulatory effects, respectively3. Despite being largely responsible for the plant’s psychoactive activity, this is merely due to its concentration as it is quite weak relative to its hydroxylated and metabolic analogues.
(7-)Hydroxymitragynine is the second most prominent alkaloid found in mitragyna speciosa, comprising only ~2% of the total alkaloid content and ~0.037% of dry leaf weight4. As its name describes, 7-hydroxymitragynine is the hydroxylated analogue of mitragynine, as such, it too is an indole-based opioid-agonist. Though hydroxymitragynine’s binding affinity is considerably poorer than that of mitragynine, consequently it only functions as a partial agonist of μ-opioid receptor. In spite of this, not only are its analgesic effects 30 times more effective than mitragynine, they are 17 times higher than morphine. While it’s abundance is far too low for this potency to be apparent, studies have found that the isolated administration of this compound failed to produce discernible adverse effects in the standard equivalent doses of morphine, whereas morphine resulted in digestive issues and dependence5. This isn’t to say that hydroxymitragynine is free of side effects, they’re just significantly less apparent than traditional opioids and imperceptible at therapeutic/nootropics doses.
Mitraphylline (MTP), is an oxindole derivative and apparent analogue of mitragynine, it comprises less than 1% of the total alkaloid content and ~0.012% of dry leaf weight. While the compound hasn’t been studied extensively, it has been found to have many applications. It can function as a vasodilator, anti-hypertensive, muscle relaxant, diuretic, anti-inflammatory, anti-amnesic, anti-leukemic and immunostimulant6. Few of the mechanisms behind these behaviors are well understood, however of the studies that exist, all posit that mitraphylline is a promising prospect in the development of future medicine, notably in the field of cancer treatment. In vitro testing, mitraphylline has been found to selectively induce apoptosis (programmed cell death) in human breast cancer, sarcoma7 and leukemia cells8. There is ongoing research exploring it’s antiproliferative and cytotoxic efficacy in other forms of cancer.
Rhychophylline is an oxindole-based alkaloid found in mitragyna speciosa that is quite similar to mitraphylline and present in the approximately the same quantities. The pharmacology of rhynchophylline is largely non-psychoactive, however the compound does function as a non-competitive NMDA antagonist9, neuroprotectant and neurogenic10. Studies in rats have found that its administration not only mitigated various neurological deficits in reducing infarct volume and brain edema but also increased claudin-5 and BDNF (brain-derived neurotrophic factor) expressions11. Rhynchophylline’s other effects include acting as a vasodilator, anti-hypertensive, anti-aggregant, anti-inflammatory, anti-pyretic, anti-arrhythmic and anti-thelmintic. Though much like mitraphylline, the mechanisms for these functions have not yet been conclusively determined.
Mitragynine pseudoindoxyl is the oxidative rearrangement of 7-hydroxymitragynine and is not produced organically by mitragyna speciosa, but rather by its fermentation. From the little research that exists, it’s understood that the compound is significantly more potent than the analgesics found naturally in kratom and functions as both a μ-opioid receptor agonist and δ-opioid receptor antagonist. Fermented kratom is widely reported to be more stimulating, euphoric and pain-relieving than unadulterated kratom. Due to the lack of research on this synthetic arrangement’s safety in humans, we cannot advise the consumption of kratom preparations that contain it.
Other Notable Alkaloids
The following table describes the effects of notable but also less abundant alkaloids found in Mitragyna, note that alkaloid concentrations can greatly differ between strains, those listed are only the ones reported in analytical research papers.
|Mitragynine||66%||Adrenergic, Anxiolytic, Analgesic, Antitussive, Antidiarrheal, Antimalarial|
|Hydroxymitragynine||2%||Anxiolytic, Analgesic, Antitussive, Antidiarrheal|
|Mitraphylline||<1%||Neuroprotectant, Anti-amnesic, Immunostimulant, Anti-carcinogen, Anti-inflammatory, Vasodilator, Anti-hypertensive|
|Rhynchophylline||<1%||Cerebrovasodiator, Neuroprotectant, Neurotrophin, Immunostimulant, Anti-Hypertensive, Anti-Aggregant, Anti-Inflammatory, Anti-Pyretic, Anti-Arrhythmic and Anti-Thelmintic|
|Ajmalicine||<1%||Cerebrovasodiator, Neuroprotectant, Sedative, Anti-Convulsant, Muscle Relaxant|
Applications of Kratom
In traditional herbal medicine, mitragyna speciosa is generally used for the stimulation of immune functions12, alleviation of pain13, promotion of wakefulness14, improvement of cardiovascular health15 and even the regulation of blood sugar16. Clinical research provides credible biological bases for these applications. More recently, kratom has been used as an anxiolytic, antidepressant, metabolic stimulant, aphrodisiac and, as previously mentioned, a method of effective and healthy drug cessation.
There is also research being conducted on the efficacy of isolated mitraphylline in the treatment of breast cancer, sarcoma and lymphoblastic leukaemia. In 2005 it was discovered that this particular alkaloid was capable of inducing apoptosis in various forms of cancer, apoptosis being the process of programmed cell death. The compound also exhibits antiproliferative and cytotoxic effects exclusively in these cancers that could be independent of the apoptotic induction.
Nootropic Characteristics of Kratom
The most pronounced nootropic qualities of kratom are its stimulating properties when taken in lower doses. Without going into extraneous detail, the boost in energy often produced by kratom is the conjunctive result of increased blood flow to various regions of the body and the modulation of metabolic processes. The energy is often described as much “cleaner” than caffeine or nicotine, though that isn’t to say that kratom is more effective than either of the two. In fact, caffeine and kratom are considered to be quite synergistic.
Kratom is also an incredibly effective anxiolytic and antidepressant. Due to the opioidergic and adrenergic nature of several of its most abundant alkaloids, kratom modulates several neurotransmitters; namely serotonin and GABA. These play significant roles in the regulation of mood, motivation and the reduction of anxiety.
Additionally, the increase in serotonin and epinephrine can enhance both long and short term memory. Serotonin has been found to greatly contribute in the process of learning, development of memory and the consolidation of existing memory. Epinephrine also elevates focus and is capable of the retrograde enhancement of long-term memory.
Several studies have also found that kratom has neuroprotective benefits. Rhynchophylline, in particular, is arguably the most interesting alkaloid produced by mitragyna speciosa, namely because it functions as a neuroprotectant (protects and extends neuron lifespan), neurotrophin (stimulates neurogenesis and nerve growth), NMDA antagonist and calcium channel blocker (mitigates high blood pressure).
Rynchophylline is a promising candidate for the treatment of several nervous system and cardiovascular diseases, though little research exists regardings its efficacy for these applications. Mitraphylline, as stated earlier, has anti-carcinogenic, anti-viral and immunostimulatory properties, however it also functions as a neuroprotectant and memory enhancer by reducing neuroinflammation and elevating the rate of oxygen delivery to the brain.
Similarly, Ajmalicine acts as a cerebrovasodilator and anti-neuro-inflammatory17, although due to the minute presence of this alkaloid (less than 1% concentration), it’s unclear whether it notably contributes to kratom’s neuroprotective benefits.
The Strain Spectrum
As a member of the Rubiaceae family, mitragyna speciosa has existed for an extremely long time, far longer than other flower species. Over this period it has spread throughout various regions of what is now southeast Asia. Naturally, due to the environmental disparities, numerous subspecies have emerged – each of which contains unique alkaloid concentrations and, consequently, a different effect profile.
Kratom is generally divided into three categories; white, green and red. The color doesn’t necessarily describe the color of the ground product, but rather the color of the leaves’ vein color. Note that this color becomes more apparent as the plant matures, if you’re growing kratom yourself it may take several months to determine kind of kratom it is (if the seeds you purchased didn’t specify a strain). White strains are typically more stimulating and mood-elevating, whereas red strains are sedating and analgesic. Green strains are the middle ground and are a great place to start if you are new to kratom and unsure. There are also vendors who advertise “yellow” strains, however if you’re at all familiar with color theory you’ll likely suspect that this is more or less a novelty marketing ploy, which it both is and isn’t though this will be expanded upon later on.
Of the three, white vein kratom has the highest nootropic potential by far. White strains are largely associated with stimulation, focus, endurance and clean energy. Conservative doses of white kratom can be significantly more effective than a standard cup of coffee and are even suitable for many as an alternative to caffeine entirely. Although for this reason, it would be advisable to avoid its use later in the day as it can inhibit sleep.
While all kratom strains have both mood-enhancing and anxiolytic properties, white veins are widely considered to be the most effective in these regards. Combined with the clean stimulation, white kratom can vastly improve motivation and task management, or more generally, productivity as a whole.
Like any type of kratom, white strains will induce sedation in higher doses, though to a notably lesser degree than green or red kratom. If you’re intending to use kratom as a cognitive enhancer, remember that less is more when it comes to dosing, especially if you’re using it by itself. The sedation can be overcome by stacking kratom with caffeine, an ampakine or any wakefulness promoter (except for s-modafinil, r-modafinil, adrafinil or fluorene – see final notes).
The following ratings are rough approximations of effect amplitudes derived from keyword usages in a series of user reviews. This is by no means an empirical or objective means of measuring effect profiles, however it should give you a general idea of what to expect from these strain types.
White veins are not ideal for pain relief, if you are interested in kratom for this particular application, it is highly advised that you stick to red veins, or better yet, extracts (see preparation and consumption section further down).
Red strains are characterized as sedating, relaxing, pain relieving and euphoric. They’re generally used for their strong analgesic effects and in the cessation of opiate/opioid addiction. Reds are largely responsible for kratom’s recent influx of popularity as they are a viable alternative to prescription painkillers, not only due to their effectiveness but also because they are far less expensive, and indisputably healthier. Red strains are also quite novel in spite of their analgesic efficacy, much like the white and green strains, they produce very few adverse effects, are less addictive and their magnitude of withdrawal is comparable to caffeine.
The following ratings are rough approximations of effect amplitudes derived from keyword usages in a series of user reviews.
While red strains have no acute nootropic benefits, the neurogenic, neuroprotective and neurotrophic compounds of kratom are present in marginally higher concentrations than in the green and white strains. Though this benefit is trivialized considering that it can be achieved in the same capacity with green or white strains simply by taking more – with the added benefit of stimulation and focus.
Green strains provide a balance between stimulation and sedation, they are generally associated with relaxed mental clarity and enhanced mood. Green strains are the ideal place to start if you are new to kratom, as they will give you a general understanding of the benefits it offers. From here you can determine whether the level of sedation or stimulation is satisfactory, if not, you can incrementally transition to either end of the “strain spectrum” until you find what suits your needs best.
The following ratings are rough approximations of effect amplitudes derived from keyword usages in a series of user reviews.
Preparation and Consumption
Kratom can be consumed in a variety of ways, each of which has their advantages and drawbacks, however we’ll discuss each in fair detail. The most common ways of consuming kratom include:
- Toss n’ Wash Method
To make it abundantly clear, kratom cannot be smoked. In fact, if this route of administration came to mind, it is very likely that kratom will disappoint you. Kratom is not a recreational drug, associating it with, or treating it as, such only hurts the public perception of this truly benign plant, and it is ultimately jeopardizing the legality of its use. We thank you for being mindful of this.
The Toss n’ Wash Method
The Toss n’ Wash is possibly the most widely favored method for consuming kratom, simply due to the convenience and effectiveness. It entails dumping a spoonful of the desired dose directly into your mouth and quickly washing it down with a chaser. Make no mistake, while this is preferred by many, it can be absolutely treacherous for beginners. Your sinuses are not designed to be within close proximity to masses of near micron-sized granules18. It is important not to breathe through either your nose or mouth when doing this, otherwise the powder will make you cough or, far worse, sneeze.
Alternatively, you can mix the kratom in a glass with a drink (ideally grapefruit juice or lemonade) before dumping it into your mouth to avoid having loose powder in your mouth. This will also more effectively mask the taste, as the powder will largely stick to the surfaces of your mouth if unmixed. Regardless, I wouldn’t recommend this method unless you are familiar with the taste of kratom, while it isn’t awful, it has been known to make the unacquainted gag.
This method is as about as straightforward as it gets. Mix the given dose of kratom with hot water, let it steep for several minutes and then strain it with a coffee filter or (if you’re using leaves) a french press.
The advantages of using tea are the pleasant taste and rapid onset of effects, whereas the common deterrents might be the preparation time and the slight waste of kratom. When you consume the powder by itself (e.g. via Toss n’ Wash), you’re ingesting all of the plant material, however when you make tea, not all of the alkaloids present in the powder are dissolved, so inevitably you’re only getting a fraction (albeit a sizeable one) of what you would otherwise. To most this difference is negligible – assuming that you let your kratom steep for a reasonable period, of course.
Kratom tea without any additional flavorings isn’t fantastic, though there are many recipes that complement the, rather bitter, taste of kratom quite well. We’d recommend the following two.
Kratom Chai Tea is quite popular as chai blends generally contain cardamom and star anise, which have incredibly strong flavors that can effectively mask the bitterness of kratom, even in quite high concentrations. The procedure for making it is identical to the standard tea, although simply use the kratom tea as the water for your chai tea and add milk, honey or sugar to taste. If you care more for flavor than potency, in theory, you should steep the chai tea before the kratom, as the water only has a limited solvency. If you tend to use less water in your tea, it will become saturated quite quick – reducing mitragynoid dissolution.
Kratom Black Lemon Tea is also a recommended recipe for those who take lower doses (>2g) as it tastes more or less like regular tea. Camellia sinensis (the primary component of black tea) has a distinct but rather mild taste and isn’t ideal for masking the taste of larger kratom doses. Making it is exactly same as the chai kratom tea, only you use black tea – adding lemon and honey/sugar to taste. Black tea also contains a fair amount of caffeine, which is great for mitigating the drowsiness induced by green/red strains, however those who use white strains may find this too stimulating.
Arguably the most convenient way to consume kratom is in capsule form. You can take capsules wherever you go, which, for those who take kratom for chronic pain or anxiety, is a necessity.
Many websites sell kratom capsules (generally at a premium) however you can make them yourself with a filling device which is ideal if you experiment in mixing strains. Capsule fillers can be bought rather inexpensively in many health stores. The only notable drawback to using capsules is the onset period, which largely depends on whether you’ve eaten prior to taking them. Additionally, capsules are commonly gelatin based and can cause bloating or heartburn if you are allergic. Both of the aforementioned issues can be solved by using vegetarian capsules, which not only dissolve quicker but are more easily dealt via digestion.
Tinctures are simply alcohol-based extracts that are saturated with plant alkaloids. Throughout history, they were the most widely used technique for the extraction and delivery of medicinal plant alkaloids. While tinctures are less common today, they are still worth your consideration.
The advantages of using tinctures are the lack of preparation, ease of measurement/consumption and potency. Since the alkaloid concentration is about as uniform as possible, gauging doses and adjusting accordingly is far easier than it would be with powder as several factors can facilitate its loss in potency (such as air exposure and humidity). When the compounds are suspended in solution, they can go far longer before decomposing or becoming chemically inert. Naturally, this option would be best for long-term storage. The drawbacks to using tinctures would be the lack of selection and cost. A majority of the tinctures sold online are “full-spectrum” tinctures, which use both white, green and red strains for extraction. While this seems like a neat idea, anecdotal reports describe them as nearly “heroin-like”, causing extreme tolerance increases and flu symptoms. It would be advisable to either make your own tinctures or stick strictly to single strain tinctures and dilute of necessary.
Solid Kratom Extracts
Aside from tinctures, two other forms of extracts exist; resins and oils. Powdered extracts are made in several ways, the most common of which being boiling the raw plant material and then dehydrating it. This process is often repeated, sometimes with multiple solvents, to further increase potency.
Extract potency is typically denoted by a multiplier relative to standard powder, such as 1x, 5x,10x or even 15x. Using extracts would not be advisable for beginners as they can result in far worse side effects than other forms of kratom when dosed improperly. Additionally, much like tinctures, they can drastically increase your tolerance. This often cannot be solved by cycling as most extracts are full-spectrum. Kratom extracts and resins should ideally only be used if you have chronic pain or are recovering from opiate addiction.
Bentuangie (Fermented Kratom)
As with most plants, kratom can be fermented. This process converts many of the active alkaloids into unique analogues, namely mitragynine pseudoindoxyl.
Mitragynine pseudoindoxyl hasn’t been extensively studied, so again, we cannot advise consuming any preparations that contain it. With that said, Bentuangie is widely reported to be exceptionally potent and is simultaneously more stimulating than white strains and more analgesic than red strains. Interestingly, these characteristics do not seem to differ regardless of what type of kratom is used for fermentation. Bentuangie has arguably the most well balanced effect profile of any kratom type, and would be worth researching as a possible alternative to full spectrum extracts.
There are hundreds of reported ways to increase the effectiveness of kratom and more easily conserve it in the process. Few of these have pharmacological explanations regarding how they would interact with kratom, though several exist that do work.
Grapefruit juice is not only useful in masking the taste of kratom but also for enhancing its effects. Grapefruits, along with some other citrus fruits, contain a class of compounds called furanocoumarins which are capable of inhibiting several metabolic enzymes including CYP3A4, which is critical for the process of drug metabolism. For the unfamiliar, drug metabolism is the breakdown process by which compounds are structurally modified by the liver’s enzymic systems. Many mitragynoids are rendered psychoactively inert through this process and will ultimately reduce the general effectiveness of its consumption. Naturally, inhibiting the responsible enzyme will negate this.
It is recommended to use either freshly squeezed grapefruit juice or white grapefruit juice – whether it’s from concentrate hasn’t been found to effect potentiation. Juices labeled as “ruby red” will generally be diluted with other fruit juices, despite being deceptively marketed as “100% Grapefruit Juice”. Anecdotally, it works best to take 200ml 15-20 minutes before ingesting kratom.
Cimetidine is a prescription pharmaceutical that is similar in function to furanocoumarins. It inhibits an array of metabolic enzymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and most importantly, CYP3A4. Cimetidine is a highly effective potentiator for opioidergic drugs, and as such, should be treated with the utmost respect, as doing otherwise could easily lead to overdose with prescription painkillers. While kratom is far weaker, taking it in tandem with cimetidine without determining an appropriate dose will result in potentially overwhelming effects.
Dextromethorphan (often referred to as DXM) has been found to radically improve the effects of μ-opioid receptor agonists19. DXM is a morphinan-derived cough-suppressant that has a wide range of pharmacological mechanisms that cause it to behave as a stimulant, sedative and dissociative in appropriate dosages. These mechanisms include:
- Uncompetitive NMDA receptor antagonist
- σ1 and σ2 sigma receptor agonist.
- Nicotinic-aceylcholine receptor antagonist.
- μ, δ, and κ-opioid receptor agonist
- SERT and NET inhibitor
- NADPH oxidase inhibitor
- Sodium channel blocker
Interestingly, 3-Hydroxymorphinan – a metabolite of DXM, has been found to have both neuroprotective and neurotrophic benefits20 and is currently being investigated as a novel therapy for Parkinson’s disease.
Much like cimetidine, mixing dextromethorphan with any drug should be done with care. Taking a standard dose of DXM with kratom is safe, however serious adverse reactions can occur when it is mixed with monoamine oxidase inhibitors or serotonin reuptake inhibitors.
Tolerance and Adverse Effects
As with most psychoactives, taking kratom consistency, especially in high doses, will result in a tolerance buildup. For this reason, it’s important to either not take kratom on a daily basis or take frequent breaks – such as one week on, one week off. Otherwise you will have to continue to increase doses to achieve the same effect, which is a route that could very well lead to addiction. To be clear, kratom’s capacity for physiological dependence is rather mild, similar to caffeine, however, much like anything, it can be abused.
Kratom can be an incredibly effective cognitive enhancer and has a wide range of applications. It has been shown in clinical testing to substantially improve memory and focus regarding logic orientated tasks. It has proven to be a safe, natural alternative to prescription opioids and antidepressants. If you struggle with anxiety, depression, chronic pain, or are simply interested in boosting productivity, kratom would certainly be worth your consideration.
- Mitragyna speciosa for opioid withdrawal in drug cessation and substitution therapy
- Typical Alkaloid Potencies in Mitragyna Speciosa
- Pharmacology of Kratom’s Stimulatory Mechanisms
- 7-Hydroxymitragynine Content Reports (EMCDDA Profile)
- Involvement of μ-Opioid Receptors in Antinociception
- A plant alkaloid with therapeutic potential for cardiovascular and central nervous system diseases
- Cytotoxic Effect of the Pentacyclic Oxindole Alkaloid Mitraphylline on Human Ewing’s Sarcoma and Breast Cancer Cell Lines
- Apoptosis in proliferating, G0/G1-arrested and bcl-2-expressing acute lymphoblastic leukaemia cells
- Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytes
- Isolation of Neuroprotective Compounds from Uncaria rhynchophylla against Beta-Amyloid-Induced Neurotoxicity
- Neuroprotective effects of rhynchophylline against ischemic brain injury via regulation of the Akt/mTOR and TLRs signaling pathways
- Indole Alkaloids as Potential Leads against Infectious Diseases
- Pharmacology of Analgesic Alkaloids from Mitragyna Speciosa
- The informal use of Mitragyna Speciosa in Malaysia
- Antioxidant and α-glucosidase inhibitory activities of traditional medicinal plants
- Acute and long-term effects of alkaloid extract of Mitragyna speciosa
- Molecular Docking Studies of Rhizophora mucronata Alkaloids Against Neuroinflammatory Marker Cyclooxygenase
- Obligatory: Cinnamon Challenge
- Dextromethorphan differentially affects opioid antinociception in rats
- 3-Hydroxymorphinan, a metabolite of dextromethorphan, protects nigrostriatal pathway against MPTP-elicited damage both in vivo and in vitro.