(Note: Originally posted by reddit user pippleripple on the kannagrowing subreddit - slight formatting edits by Gidaz on lemmy)

This gives a more favourable alkaloid profile (to me) so fermenting is worth doing.

1. Harvest your scelly. The best time to harvest for high alkaloid is when it's flowering.

2. The whole plant contains alkaloids so take everything. Commercially (and traditionally) they take the whole plant including roots. Definitely include stems because they are way higher in alkaloids. If you want your plant to keep producing obviously don't include roots.

3. Wash everything under the tap to remove dirt/dust. Let it drain for a little bit.

4. Put your harvest into a ziplock bag. Crush the plant thoroughly so everything is mashed.

5. Leave in a sunny window for a week. While it's fermenting you'll need to vent gas or it will pop open and make a mess. Use the opportunity to crush it up some more while venting.

6. After a week put the green sludge into a glass tray. Dry in the sun or use a dehydrator (faster and easier). Once it's dry scrape it up.

Congrats, you now have delicious scelly ready for use.

Tip: Run it through a coffee grinder and put back into drying if you want to make extract to make sure it's crispy dry.

(Note: This post was written by tfgust on reddit)

This post will thoroughly discuss the safety of kanna (sceletium tortuosum) and any potential adverse effects.

I am writing this because a number of people have been recently complaining about mild to moderate withdrawals from taking kanna. Additionally, an individual has been fear-mongering by spreading exaggerated information about the dangers of kanna, incorrectly citing studies to back false claims that it is more dangerous than amphetamines. Therefore, I think the actual risks of kanna need to be elucidated.

Kanna is generally recognized as safe for human consumption, however, like virtually all psychoactive substances, there are risks. This will be broken into 6 sections: 1) Medicinal vs. Recreational Usage, 2) Is Kanna An Empathogen, 3) Kanna Withdrawals, 4) Toxicity, 5) Potential for Addiction, 6) Combining Drugs With Kanna.

I. Medicinal vs. Recreational Use + Safe Dosing

Kanna has a long history of being used for both medicinal and recreational purposes. Typically, medicinal usage is less likely to cause harmful side effects than recreational usage. This begs the question: what is the difference between medicinal and recreational use of kanna?

Medicinally, it is used for treating anxiety, depression, and mild pain. Recreationally, it is used as a mood-elevating stimulant (with sedating effects in higher doses) that may produce mild euphoria.

The difference between medicinal and recreational usage ultimately is determined by two things: the method of administration and the dosage.

• Medicinal Usage
  • Method of Administration: Oral, possibly sublingual. There is some research suggesting that taking kanna sublingually, possibly via a medicated chewing gum, might be an acceptable way of taking kanna for medicinal use. Despite this, kanna is usually taken orally for medicinal purposes.
  • Dosage: 50mg - 200mg daily of dried, botanical raw material. Studies conducted on kanna suggest a starting dose of 50mg of botanical raw material in the morning, which can be titrated up to 100-200mg in the morning within a few days. In cases of severe depression, a prominent doctor in the field of kanna research suggests using dose increases in 50mg increments every 3 days up to a maximum dose of 800mg twice daily. He, however, noted that doses above 200mg per day may cause side effects and withdrawals.
• Recreational Usage
  • Method of Administration: Intranasal, sublingual, smoking, rarely oral. Kanna is often processed into a snuff, which people snort for short-lasting recreational effects. Traditionally, indigenous peoples chewed fermented leaves of the kanna plant for mild recreational effects but also for medicinal purposes- in fact, they called fermented kanna "kougoed", which means "something to chew." Historically, kanna has often been combined with alcohol or marijuana for recreational purposes. Sometimes, kanna is smoked, especially when it is combined with marijuana. Kanna that is high in mesembrine content is viewed as more desirable for recreational use.
  • Dosage: Oral, 500mg - 2000+mg of dried, botanical raw material. Intranasal, 15mg - 40mg of highly refined kanna extract (with about 3%-6% mesembrine content). Sublingual, 50mg - 500+mg of dried, botanical raw material. Some people take doses that far exceed those listed.

​

>RESPONSIBLE DOSING OF KANNA > >In theory, and according to current research, you should only take 50mg - 200mg of botanical raw material per day, either orally or sublingually. A dose of 800mg taken orally twice per day should be considered an absolute maximum for responsible usage, and even then, you should be aware that you may experience side effects and/or withdrawals. > >Taking a dose over 200mg daily may cause adverse effects or withdrawals, and the safety of doses over 200mg/day in humans is not well known. > >If you are intent on abusing kanna for recreational purposes by snorting it or taking massive amounts, please don't take kanna every day and avoid using kanna recreationally more than once per day. Kanna is considered safe and fairly non-addictive, similarly to caffeine. But if you take anything in excess it will do harm.

​

II. Is Kanna an Empathogen?

Arguably, yes, kanna is a mild, atypical empathogen. This is likely why kanna is frequently and unfortunately marketed as "herbal molly." This marketing is devious because kanna's mechanisms of action and safety are very different from MDMA. Despite kanna being an empathogen, it is not significantly toxic nor anywhere near as powerful or dangerous as MDMA.

Why?

Kanna contains several psychoactive alkaloids, the most notable being mesembrine and mesembrenone. Mesembrine in particular acts as a potent VMAT-2 upregulator, a potent serotonin reuptake inhibitor (which is stronger than fluoxetine), and a PDE-4 inhibitor.

Because mesembrine potently increases VMAT-2 in the brain, kanna acts as a moderately strong trimonoamine releasing agent. Mesembrine not only causes the release of dopamine, serotonin, and norepinephrine into the synapse, but it also releases GABA and histamine.

Empathogens (entactogens) are a class of drugs that 1) act as trimonoamine releasing agents, 2)increase serotonin levels in the synapse to a greater extent than dopamine and norepinephrine, and 3) elicit feelings of empathy, interconnectedness, and tactile enhancement. Kanna is 1) a mild, atypical trimonoamine releasing agent, 2) a serotonin reuptake inhibitor as well as a serotonin releasing agent which therefore increases serotonin in the synapse to a greater extent than dopamine or norepinephrine, and 3) reported to cause mild feelings of empathy and tactile enhancement in high doses. Thus kanna arguably qualifies as an empathogen.

All empathogens besides kanna are toxic, dangerous, and at least somewhat addictive. Kanna, however, does not work the same way as any other empathogen. It is extremely atypical, and much less dangerous.

Despite being a monoamine releasing agent, kanna is considered significantly safer than amphetamines, including Adderall, meth, MDMA, fenfluramine, etc. This is likely because kanna's mechanism of action is nearly the opposite of amphetamines. Amphetamines work by inhibiting VMAT-2 and reversing monoamine transporters, whereas kanna increases VMAT-2 and does NOT reverse monoamine transporters. Increased VMAT-2 is thought to have neuroprotective effects against monoamine releasing agents, and kanna literally works by increasing VMAT-2. Further, kanna is a relatively mild monoamine releasing agent in comparison to amphetamines like Adderall. Kanna is therefore thought to have far fewer adverse effects than amphetamines. It also has been shown to have far less addictive potential.

For more information about kanna's alkaloids and pharmacology, see the other post on Kanna's Pharmacology.

III. How Severe are Withdrawals from Kanna?

If you have been taking a normal medicinal dosage of kanna (below 200mg of raw plant material), you likely will not experience withdrawals at all. If you have been taking above 200mg of plant material or you use kanna recreationally on a regular basis, expect to experience withdrawals.

Kanna withdrawals are usually similar to but weaker than withdrawals from prescription SSRI antidepressants. This is because kanna and SSRI's have a shared mechanism of action. The withdrawals from kanna tend to be weaker and shorter because kanna's main effects only last for 4-6 hours, whereas prescription SSRIs tend to last more than 24 hours.

If you have been taking kanna multiple times a day or have been taking very high doses, you may feel a moderately severe withdrawal syndrome. The withdrawal is not physically dangerous in any way, but it can cause you to feel depressed, tired, lethargic, anxious, and in very severe cases, even suicidal. Withdrawal usually persists for only 2-5 days. But if you have been taking irresponsibly high doses of kanna, the withdrawal theoretically could last for 3 weeks or even more (the typical timeframe for SSRI withdrawals).

If you have been taking high doses of kanna, it is recommended that you taper off. If you are taking dried, raw kanna, then you should gradually reduce your dosage by 50mg until you are only taking 50mg of kanna. Once you are taking only 50mg, you should be able to quit without withdrawal. It also will help if you switch from a high-mesembrine kanna product to a high-mesembrenone kanna product like Zembrin (mesembrenone is weaker, and won't cause recreational effects). Zembrin is a well studied kanna extract- Zembrin is a 2:1 extract, so 25mg of Zembrin is equal to about 50mg of raw kanna. Withdrawals can be avoided with responsible usage.

IV. All About Kanna's Toxicity

Kanna is generally considered non-toxic and safe to consume. It has been fairly well-studied in humans at the dose of 50mg/day. 50mg/day is safe for human consumption for at least 6 months, and has no toxic effects.

In rats, cats, and dogs, studies show that very high doses of kanna had no apparent toxic effects. One study subjected rats to insanely high doses of kanna (the equivalent of 84,000mg in a 70kg human) every day for weeks. No toxic effects were observed. The study concluded that a daily dose of 840mg is safe for a 70kg human. Previous studies observed no major effect on genotoxicity, hepatoxicity, or bacterial reversion in mammalian cell lines. ( Murbach, Timothy S., et al. "A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin®) in rats." Food and chemical toxicology 74 (2014): 190-199. )

Doses of kanna above 200mg in humans have been shown to cause side-effects including headaches, nausea, and potential withdrawals. These side-effects are very typical for serotonin reuptake inhibitors like kanna, and are not considered very serious. Additionally, very high doses of kanna may cause mild ataxia, pupil dilation, and mild feelings of intoxication.

Kanna does contain low amounts of the alkaloid Δ-7 mesembrenone. Δ-7 mesembrenone was found to exhibit a high risk for cytotoxicity in isolation. This effect is probably due to the fact that it is an antioxidant, and very high doses of antioxidants can harm cells. (Tunstall, Rebecca; 2019) Kanna likely does not contain enough Δ-7 mesembrenone to cause toxic effects when taken within the clinically accepted dose range. Damage from kanna due to this effect has never been reported, and low levels of antioxidants can even be a good thing.

Taking kanna daily for many weeks theoretically may cause downregulation of SERT expression and downregulation of VMAT-2 in the brain. This impact is similar to the long-term effect of the commonly used antidepressant citalopram.

Unfortunately, very little is known about the pharmacokinetics of kanna in humans. We will not grasp a full picture of kanna's safety or effects until we understand its pharmacokinetics.

V. Can I Get Addicted to Kanna?

No, at least not physically. Kanna can cause dependence. This can be seen in the withdrawal syndromes caused by high doses (you might want to take kanna to relieve the withdrawal).

Kanna does not, however, cause addiction.

Addiction is marked by biochemical changes in the brain after continued substance use that leads people to compulsively and irrationally continue craving/taking the substance. Dependence, on the other hand, involves physical withdrawals and psychological feelings that you need the drug to function well. To understand the difference, think of antipyschotics. Antipsychotics are not addictive (they actually tend to cause aversion/avoidance, which is the opposite of addiction), but they do cause dependence because they cause withdrawals and some people feel like they aren't able to fall asleep without their antipsychotics.

Kanna does not cause preference nor aversion in rats in conditioned place preference, a classic model used to gauge whether drugs are addictive or not. Statistical analysis revealed that amphetamine displayed much higher preference scores in rats in comparison to kanna and mesembrine. Haloperidol displayed higher aversion scores in comparison to kanna. Kanna tended to produce slightly aversive scores. ( Loria, Melissa J., et al. "Effects of Sceletium tortuosum in rats." Journal of ethnopharmacology 155.1 (2014): 731-735.)

Further, surveys of people who regularly took kanna sublingually for recreational purposes indicated that people did not experience cravings for the plant. Individuals expressed that they sometimes did not "feel" like taking kanna, and would therefore not take any for a while, then resume using it later if they felt like it.

Evidence suggests that kanna, unlike many other monoamine releasing agents, does not cause significant physical addiction in humans. It is no more addictive than coffee.

VI. Combining Kanna With Other Drugs

Kanna should not be combined with MAOIs, SSRIs, SNRIs, many antidepressants, and many serotonergic drugs. These drugs have strong interactions. Also, the combination of these drugs could result in a rare but serious condition called serotonin syndrome, which could cause brain damage or even be fatal. If you have been taking SSRIs and plan to replace them with kanna, look up the half-life of your antidepressant medication. Stop the SSRI and wait at least 2-3 half-lives before starting the kanna.

Kanna has historically been combined with alcohol and marijuana for recreational purposes. Anecdotal evidence suggests that there is a synergistic reaction between alcohol and kanna, and that kanna strongly potentiates the effects of marijuana. Unfortunately, very little relevant data exists on the safety of combining these substances. No deaths or serious adverse effects have been reported from these combinations, but that does not mean that it is safe.

Because kanna upregulates VMAT-2 and acts as an SRI, it interacts with a LOT. It interacts with MAOIs, SSRIs, SNRIs, tricyclics, amphetamines, trace amines, dopaminergic agonists like Modafinil, certain benzodiazepines, some GABAergics, alcohol, marijuana, other cannabinoids, reuptake inhibitors like Ritalin, cocaine, Straterra, etc, psychedelics, MDMA, other empathogens, cathinones, histaminergics, etc. So basically everything. Most of these interactions are minor, but that does not mean that you should not be careful.

KANNA + AMPHETAMINES

Don't combine kanna with amphetamines like Adderall. Firstly, combining these poses a small risk of getting serotonin syndrome. Secondly, amphetamines inhibit VMAT2 whereas kanna increases it. Obviously, there is a direct interaction between the two drugs. Kanna may theoretically reduce amphetamine toxicity at first, but as the kanna wears off, VMAT-2 levels in the brain will be reduced, which will increase the toxicity of amphetamines.

Thirdly, anecdotal evidence suggests that the combination of Adderall-like drugs with kanna can cause extremely euphoric, MDMA-like effects for some people. "How the fuck is this legal?", wrote one user after combining the two. Any drug combination that causes euphoria like this is bound to be either addictive, dangerous, or bad news. One user indicated that after days of combining the two, they experienced a withdrawal that was even worse than the after-effects of MDMA. They reported craving the drugs afterwards. This combination has not been studied well.

So, combining amphetamines with kanna is likely toxic, dangerous, addictive, and causes withdrawals. So please do not combine these without proper medical supervision.

Summary

• The safe dose of kanna is 50mg - 200mg of raw, dried botanical product per day. Doses up to 840mg/day appear to be safe when taken orally, but may cause withdrawals or side effects. The absolute maximum dosage that has been suggested is 800mg twice per day orally. Going above that dosage is likely not responsible.
• Kanna can cause mild to moderate withdrawals when taken at doses above the normal clinical dose range (more than 200mg of raw botanical product).
• When taking more than 800mg/2 times a day of dried kanna, or snorting/smoking kanna, you run the risk of having severe withdrawals that can last for weeks. These withdrawals are not physically dangerous, but may result in lethargy, anxiety, depressed mood, and even suicidal thoughts.
• Kanna is NOT addictive. It may cause mild physical dependence, but is not addictive and does not cause preferential behavior in conditioned place preference tests. It has been shown to be far, far less addictive than amphetamine.
• Kanna is not toxic for humans in low doses\\.\\ Medium to high doses are likely not toxic, but have not been studied well in humans.
• Kanna can cause side effects like headaches, nausea, anxiety (even panic attacks when taken in too high of a dose), and pupil dilation.
• Be careful when combining kanna with other substances. It interacts with a very large number of medications/supplements. Kanna strongly potentiates/synergizes with certain drugs like marijuana and Adderall in powerful and unpredictable ways.

I will try to cite the rest of my sources later. Hope this helps!

(Note: This post was written by Polytrewq on reddit)

Sceletium tortuosum more commonly known as Kanna is a succulent plant originating in South Africa. Kanna has been used by San and Khoi tribes of South Africa for centuries to relief thirst or hunger, to combat fatigue, as a medicine, and for social and spiritual purposes. After the harvest it was left to ferment and then used as a quid(chewed) or smoked with other herbs. Nowadays it can be used orally in a pill or tea form, sublingually, intranasally or smoked/vaped. Most popular forms of Kanna are extract powders, fermented leaf/tea cut, fermented powder and recently liquid tinctures ideal for vaping.

Effects

Effects and their intensity vary slightly depending on the route of administration, dosage and people's biochemistry. In general Kanna has anxiolytic, calming, anti-depressive, empathogenic and mood lifting effects. It enhances touch, libido and colours slightly and music noticeably, especially when snorted. It might make you more talkative and social, improve your motivation, suppress your appetite or offer mild pain relief. Kanna is both stimulating and sedating. Higher doses generally become more sedating.

Kanna rush is most noticeable when snorted and lasts about 10-15 minutes that gradually fades into a happy calm feeling with this ROA. It is not easy to describe since Kanna is it's own thing but most people compare it to a sudden and rapid entactogen(MDMA, benzofurans, etc) or psychedelic comeup with relatively strong euphoria, slight dizziness/vertigo, stimulation with urge to move or dance when listening to music. Some people find the rush overwhelming and anxiety inducing, which can be mostly attributed to anxiety prone personality, due to underestimating the effects of Kanna or incorrect dosage.

Side effects might include nausea, laxative effect, which should subside after regular use, sweating, pupil dilation and mild headache. Some people report trouble sleeping and anxiety.

Dosages

Dosage varies depending on the ROA, the form and each person's biochemistry. Some people experience reverse tolerance meaning they have to take Kanna several times before they feel the effects. This is called priming. Unfortunately few people don't experience any effects from Kanna even with priming. Biggest mistake new users do is underestimating the effects and taking very high dose their first time. Start with the dosages mentioned below and adjust accordingly.

Insufflation - start with 10-15mg of extract powder or 30-40mg of non-extract powder. Snorting fermented leaf/tea cut is not recommended. Crush the extract as much as possible before insufflating. When snorting, use only little more force than you do when breathing, so it doesn't end up in your throat. Using saline nasal spray before insufflating improves absorption since less powder gets to your throat. You should also use it after the snorting to keep your nose healthy. The effects manifest in 5-10 minutes and last up to 1-2 hours. Insufflation is best for recreational use.

Sublingual - start with 20-30mg of extract powder or 100mg of fermented leaf/tea cut or fermented powder. Keep under the tongue for at least 15 minutes without swallowing the saliva. If you have fermented leaf/tea cut you can try chewing it. The effects become noticeable in 20-40 minutes and can last up to 4 hours. Sublingual use is ideal if you want anxiolytic, anti-depressive and calming effects.

Oral - start with 200mg of leaf/tea cut or fermented powder. Dosing extracts orally is not very cost-efficient but if you still want to try, start with 60-75mg. Oral ROA is usually less consistent than sublingual or insufflation. Effects typically last 3-6 hours. Some users experience elevated mood even next day. Most popular oral product in a pill form is Zembrin, which is mainly focused on anxiolytic effects. It is standardized extract with few clinical trials.(1, 2, 3)

Smoking - most common practice is to sprinkle some extract on weed/tobacco. If you have leaf/tea cut you can mix it with the weed/tobacco.

Pharmacology

Kanna contains up to 32 psychoactive alkaloids which have distinct pharmacological profiles and effects. The dominant, and clinically significant alkaloids in Sceletium tortuosum are mesembrine, mesembrenone, ∆7-mesembrenone, mesembrenol and tortuosamine, though the minor alkaloids undoubtedly play important roles in the overall pharmacological effect too. The distribution and variability of these alkaloids differs from plant to plant due to factors such as cultivar, season, geographical and climatic factors, growing conditions and age.

Mesembrine is the most notable psychoactive alkaloid present in Kanna. Mesembrine acts mainly as a VMAT-2 upregulator, serotonin reuptake inhibitor and PDE4 inhibitor. It is assumed mesembrine is responsible for the Kanna rush.

Mesembrenone is an SRI and PDE4 inhibitor. Mesembrenone-based extracts are most useful in therapeutic utility, because the rush they produce is not intense or barely noticeable.

For a more in-depth pharmacology profile check this great post, originally written by reddit user tfgust.

Interactions and synergies

Although Kanna is well tolerated with many substances, it should NOT be combined with antidepressants(SSRI, SNRI...), strong MAOIs and serotonin releasers(entactogens like MDMA, 6-APB, 3-MMC etc.). Kanna and weed/alcohol will potentiate each other. Other good synergies include coffee, kratom, phenibut, damiana or blue lotus. Interaction with classical psychedelics like mushrooms, LSD seem mainly positive, but there have been a few negative reports. According to anecdotal reports Adderall and Kanna have also good synergy, but it's important to start with small doses.

Safety

Kanna is generally considered non-toxic, safe to consume and doesn't cause addiction. There are mixed reports on withdrawal symptoms when taken regularly over longer period of time(3+months). Some people report stopping cold turkey without any symptoms, while others notice brainzaps or symptoms similar to stopping prescription antidepressants, although weaker.

For a more thorough information check another good post originally written by tfgust on reddit.

FAQ

Is Kanna like natural MDMA? No. The only slightly similar thing Kanna has with MDMA is the initial rush, which is only a part of the whole experience. Kanna is it's own thing.

I took Kanna and don't feel anything. Most common issue if you don't feel anything is the quality of the product. There are a lot of bunk products on the market. Another reason might be reverse tolerance.

Can i redose Kanna? Redosing in short period of time usually doesn't work or has diminished effect. Waiting at least 4 hours between doses is recommended.

Can i use Kanna daily? Yes. Taking Kanna daily should be safe if you don't overdo it. However you might develop tolerance to it. Listen to your body.

I take Kanna regularly and still want to take MDMA sometimes. How should I go about it? Since Kanna appears to have relatively short half life, not taking it 2 days before your roll should be fine. If you want to be super safe wait a week before rolling.

I take xy prescription antidepressant. Can I take Kanna? It is not recommended to mix Kanna with antidepressants since both work as serotonin reuptake inhibitors. The only common antidepressant that should be safe with Kanna is Bupropion(Wellbutrin).

Can I combine Kanna with xy substance? See the section Interactions and synergies.

Can I drive while on Kanna? Don't drive during the initial Kanna rush, since it can make you disoriented. After that it should be safe.

Will Kanna show up on drug tests? No, it won't. It shouldn't cause false positives either.

Can I grow my own Kanna? Yes. Kanna is quite easy to grow. You can buy seeds in various shops online or from a fellow member u/salviasammich

I have harvested my own Kanna. How do I ferment it? Here/) is a good guide copied from reddit user pippleripple.

 

List of vendors is here. Share your experience in that thread.

 

More reading available at:

• Sceletium.org
• https://Kanna-info.com
• https://sceletium.com/chemistry-pharmacology/
• links to scientific publications https://examine.com/supplements/sceletium-tortuosum/research/#citations

(Cross-posted from the subreddit - HUGE shout out to tfgust on reddit who wrote this entire thing like 3 years ago)

Kanna (sceletium tortuosum) contains multiple psychoactive alkaloids which have distinct pharmacological profiles and effects. Kanna products and extracts can have vastly different alkaloid compositions depending on the strain of the plant, time harvested, and preparation methods used.

Different kanna products often standardize for one or several of these alkaloids. For example, the makers of the kanna supplement Zembrin specifically attempt to reduce the amount of mesembrine in their product to achieve a certain affect. Liftmode, however, attempts to have a high amount of mesembrine in some of their products.

This post will be broken into 3 parts. The first will cover the general effects of kanna. The second will discuss the major psychoactive alkaloids present in kanna, their pharmacological profiles, and their subjective effects. The third will explain the pharmacological functions of kanna and their effects.

I. Your Guide to the Effects of Kanna

This section summarizes the known effects of kanna and all of its alkaloids.

Common Subjective Effects

These effects vary based on the dosage, ROA, and alkaloid composition:

• Antidepressant effects (comparable in strength to prescription SSRI medications)
• Anxiety suppression (significant)
• (Very) Mild physical euphoria (in high doses or when smoked/snorted)
• Mild cognitive euphoria (in high doses or when smoked/snorted). Don't expect to get "high" like you would from alcohol, marijuana, or hard drugs. This effect is often described as a feeling of "tranquility", "bliss", or "post-orgasm", and although quite noticeable, the sheer euphoria itself from kanna is not very intense. Please note that the combined effects of kanna are not mild.
• Dose-dependent sedation or stimulation
• A "rush" of stimulation (especially when smoked/snorted)
• Increased or decreased heart rate, as well as either vasodilation/vasoconstriction
• Tranquil "afterglow"
• Appetite suppression
• Mild pain relief
• Mild tactile enhancement
• Pupil dilation (usually mild, but acute in some people)
• Mild empathogenic effects (e.g. empathy, affection, feelings of interconnectedness)
• Increased sociability
• Increased libido
• Motivation enhancement
• Mild motor control impairment (when taken in extreme doses)
• IN VERY HIGH DOSES (8x the minimum noticeable dosage, NOT recommended):
  • Extreme pupil dilation
  • Very blurry vision, light sensitivity
  • May worsen pre-existing HPPD
  • Increased body temperature
  • Heavy sweating
  • Mild discomfort in chest
  • Muscle relaxation
  • Inexplicable numbness in teeth or facial region (locals once used kanna to treat toothaches)
  • Mildly-moderately strong, unique state of intoxication - no impairment of motor function. Mildly resembles dissociation. Sounds will feel far away.
  • Euphoria does not appear to increase with higher doses - it is still mild.
  • Panic attacks or feelings of anxiety are likely to occur.

Duration of Action

Relatively little is known about the half-life of kanna's alkaloids in humans. Subjective reports indicate that when taken orally, kanna's duration of action is 4-6 hours long, and its onset occurs after 30-60 minutes. When taken via intranasal administration (snorted), the effects of kanna lasts for 30-90 minutes (peaking around 5-10 minutes) and its onset occurs between 0-5 minutes.

Kanna's apparently brief duration of action is the primary reason it is seldom used as an antidepressant in modern medicine. SSRI medications are thought to work by slowly increasing neuroplasticity due to their long duration of action, and therefore, kanna was initially (and perhaps wrongfully) dismissed for its supposed inability to affect neuroplasticity like typical SSRIs. It has since been shown that kanna may actually cause increases in neuroplasticity more quickly than typical SSRI medications due to its PDE4 inhibition and VMAT-2 upregulation. In other words, whereas most antidepressants supposedly take 4-6 weeks to start working, kanna might begin working immediately.

II. Pharmacology of Kanna's Alkaloids

Mesembrine

Mesembrine is the most notable psychoactive alkaloid present in kanna. Mesembrine acts as a VMAT-2 upregulator, serotonin reuptake inhibitor, PDE4 inhibitor, mild MAO-A inhibitor (this effect is nearly negligible), and a mild reversible AChE inhibitor. VMAT-2 upregulation appears to be the primary function of mesembrine, although this alkaloid is also a very potent serotonin reuptake inhibitor (SRI).

Mesembrine-rich kanna extracts/products have antidepressant and anxiolytic activity that feels similar to clinically used SSRIs. Mesembrine may prevent drug and food cravings, and may have other medical applications besides the treatment of depression. In addition, however, mesembrine-rich kanna can cause a stimulating "rush", mild euphoria, and mild intoxicating effects (these are most notable when mesembrine-rich kanna extracts are insufflated/snorted). Mesembrine is why some people are able to get mildly "high" on kanna. Despite this mild "euphoria", mesembrine has been shown to have minimal to negligible abuse liability and does not cause physical addiction nor withdrawal (long term use of kanna may cause a minor withdrawal syndrome that is similar to but weaker than that of clinically used SSRIs). Mesembrine can also induce mild empathogenic effects and tactile enhancement in high doses. Mesembrine does not have hallucinogenic effects (despite incorrect reports of kanna acting as a psychedelic from older research, which have been disproved). For some people, acute high doses of mesembrine can induce transient anxiety or even panic attacks (these negative side-effects fade away quickly). Many people compare the feeling induced by mesembrine to either microdosing MDMA or very powerful coffee mixed with an antidepressant. This is why kanna is frequently marketed as a legal "MDMA alternative", although this marketing is blatantly misleading as kanna's potency, safety profile, and mechanisms of action are all very different from MDMA. In small doses, mesembrine is stimulating, but in higher doses, mesembrine can cause sedation.

Mesembrenone

Mesembrenone is an SRI and a PDE4 inhibitor, but does not appear to affect VMAT-2. Its strength as an SRI is weaker than that of mesembrine. Mesembrenone-rich kanna extracts have consistently been shown to be effective at treating anxiety in multiple studies, and research indicates that they may also be effective at treating depression. Mesembrenone-based extracts are most useful in their therapeutic utility, especially because they typically do not create the transient anxiety that mesembrine causes in some people. Mesembrenone lacks the craving reduction, weight-loss potential, and some neuroprotective properties of mesembrine. It also may be less effective at treating severe depression due to lack of VMAT-2 activity and being a weaker SRI. Mesembrenone does not cause a stimulating "rush" and is generally not thought to produce the mild euphoria associated with mesembrine.

Mesembrenol

Mesembrenol has the exact same functions as mesembrenone (but is weaker?).

Mesembranol

No information found at this time, but mesembranol has been shown to have notable psychoactive effects.

III. Kanna's Pharmacological Functions

Serotonin Reuptake Inhibition

It is well known that kanna is a powerful serotonin reuptake inhibitor (SRI). It works in a nearly identical fashion to selective serotonin reuptake inhibitors (SSRIs), i.e. citalopram, fluoxetine, etc. Please note that SSRIs are SRIs, and that the only difference between the two is that SSRIs only inhibit serotonin transporters, whereas SRIs do the exact same thing but can do other things as well. SSRIs are used in the clinical treatment of depression, anxiety, and OCD. They, like kanna, work by preventing serotonin from being transported back into the presynaptic neuron from the synapse via inhibiting the activity of serotonin transporters (SERT). This increases the amount of serotonin in synapses in the brain, boosting serotonergic activity. Kanna's activity as an SRI has been shown to be more powerful than several synthetic antidepressant medications that are used as first-line treatments for depression, and kanna has been shown to be as effective in treating acute depression as the antidepressant citalopram in several case studies. Mesembrine's binding affinity for SERT is almost as high as citalopram (it has an IC-50 of 4.3 for SERT inhibition). A large body of peer-reviewed research definitively shows that certain kanna extracts are clinically effective at treating anxiety. A small number of studies report that kanna, like other potent SRIs, may cause a withdrawal syndrome in some individuals after long-term use, however, this withdrawal syndrome is more mild than that of clinically used SSRIs and other research indicates that kanna doesn't cause any withdrawal symptoms.

VMAT-2 Upregulation

Recent, preliminary research has shown that kanna increases the activity of VMAT-2. VMAT-2 is a the primary protein that selectively carries serotonin, dopamine, norepinephrine, GABA, and other monoamines out of the presynaptic neuron and into the synapse. By boosting the levels/activity of VMAT-2, kanna effectively causes monoamine release into the synapse, meaning it acts as a mildly to moderately strong monoamine releasing agent. Most monoamine releasing agents usually act via alternative mechanisms and are often selective for specific monoamines, thus having a variety of applications that include treating ADHD, treating binge eating disorder, potentially treating depression, potentially treating autism, and recreational drug abuse. Adderall, fenfluramine, MDMA, and other amphetamines all are monoamine releasing agents.

The mechanism causing kanna's monoamine release, VMAT-2 upregulation, is fairly unique among known drugs. This VMAT-2 upregulation may be what causes the mild "euphoric" effects of kanna in high doses as well as some of its stimulant effects. It further may cause mild empathogenic effects and tactile enhancement. It should be noted that these mildly euphoric, intoxicating effects are only found in certain kanna strains/products, not all of them. Unlike many amphetamines, however, kanna has negligible liability for abuse and research consistently shows that kanna does not cause physical addiction. Further, VMAT-2 upregulation may have neuroprotective properties (especially against amphetamine toxicity), be a potential treatment for depression, be a potential treatment for obesity (may cause weight loss), and may reduce both addiction to and abuse of stimulant drugs (like cocaine and methamphetamine).

Note: There is a large amount of interest among the pharmaceutical industry in creating drugs that potently increase the activity of VMAT-2 for the treatment of addiction and mental disorders because "none are known to exist", yet I personally have found very little research done into mesembrine's ability to upregulate VMAT-2. Again, this function makes kanna quite unique.

PDE4 Inhibition

Kanna strongly inhibits phosphodiesterase 4 (PDE4). PDE4 is predominantly responsible for breaking down cyclic adenosine monophosphate (cAMP) within both immune cells and cells in the central nervous system. cAMP is used for intracellular signal transduction, for example, it transfers the effects of hormones like adrenaline into cells. "PDE4 inhibitors are known to possess pro-cognitive (including long term memory-improving), wakefulness-promoting, neuroprotective, and anti-inflammatory effects. PDE4 inhibitors have been investigated as treatments for a diverse group of different diseases, including central nervous system disorders such as major depressive disorder (clinical depression), anxiety disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, multiple sclerosis, attention deficit-hyperactivity disorder, Huntington's disease, stroke, autism and inflammatory conditions such as chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis." (Wikipedia, information verified from alternate sources) Kanna's ability to inhibit both SERT and PDE4 has attracted especial attention, as this combination may be particularly useful in treating depression.

Other Mechanisms of Action

Mild Inhibition of MAO-A: Kanna mildly inhibits MAO-A. This inhibition, however, is so weak as to nearly be negligible. MAO-A is an enzyme that helps break down certain neurotransmitters, including dopamine, norepinephrine, and serotonin. In people with chronic depression, MAO-A levels may be elevated, and dysfunction of this protein is also implicated in bipolar disorder, Alzheimer's, aggression, panic disorder, and ADHD.

Mild Inhibition of AChE: Kanna is a mild reversible inhibitor of acetylcholinesterase (AChE). AChE inhibitors or anti-cholinesterases inhibit the cholinesterase enzyme from breaking down ACh, increasing both the level and duration of the neurotransmitter action. Reversible AChE inhibition may have applications in the treatment of Alzheimer's. Note that kanna is a reversible inhibitor rather than an irreversible one, as irreversible AChE inhibitors are used in chemical warfare as nerve agents.

Anti-inflammatory: Kanna has anti-inflammatory activity (in other words, it reduces inflammation or swelling), possibly due to its PDE4 inhibition. Anti-inflammatory agents make up over half of analgesics (for example, aspirin or naproxen). This may explain why case studies report that kanna can provide relief from bee stings.

Limits Reuptake of Dopamine and Norepinephrine at High Doses: When taken in high doses, kanna may mildly limit the reuptake of dopamine and norepinephrine into the presynaptic neuron by their respective transporters. This action is slightly similar to that of NDRIs (like Ritalin), however, this effect is quite weak and only occurs in very high doses.

Cannabinoid Receptor Inhibition: Plain kanna has been shown to inhibit cannabinoid receptor type 1 (CB1). It is currently unclear which alkaloid in kanna affects CB1. CB1 inhibition may cause antidepressant and anorectic effects.

Sources

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