(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.

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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.

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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!