These were used to assess connectivity for the whole task and both conditions separately by entering them in the original GLM, as well as for psycho-physiological interaction PPI analysis as implemented in SPM8 to assess differences between conditions. The resulting contrast maps were entered in the separate full-factorial models to test for DRUG effects in functional connectivity of the bilateral amygdala with the threat circuit ROI-corrected.
No other main effects or interactions were observed using this statistical threshold. All effects are whole-brain FWE-corrected with an extend threshold of 20 voxels unless stated otherwise. Coordinates refer to MNI space. Using two independent fMRI designs, we show that Zembrin compared with placebo administration reduces anxiety-related Bishop et al , amygdala reactivity and attenuates amygdala—hypothalamus coupling.
These results not only have importance as the first evidence on the dampening effects of Zembrin on the brain's threat system but support further work on the clinical applicability of dual PDE4 and 5-HT reuptake inhibitors for the treatment of anxiety disorders and depression. Anxiety is characterized by hyper-responsivity to mild threats.
The task we used to assess amygdala reactivity directly taps into this mechanism as mild threats, ie fearful faces, had to be ignored in favor of a cognitive task, ie letter detection. Although clinically anxious individuals show such threat interference in general Bar-Haim et al , , healthy individuals can successfully ignore task-irrelevant stimuli under high task demands Lavie, In line with this, the amygdala is activated by unattended facial fear, particularly under low perceptual load conditions Silvert et al , , which is further increased by state anxiety Bishop et al , In the present study, this amygdala reactivity to facial fear under low-load conditions was significantly attenuated after Zembrin administration.
Although we did not observe general subjective mood effects, the effects noted here arguably reflect a reduction of responsivity of the threat system related to the anxiolytic properties of S. Crucially, this does not affect our interpretation of the fMRI effects as behavioral performance was previously shown to be independent from state anxiety and its relation to the amygdala's BOLD signal Bishop et al , Attenuation of threat responsivity, as measured with the BOLD signal, can result from reduced basal threat responding, as well as increased cognitive control over these threat responses.
Our results are in line with the former as during the matching of threatening facial expressions a decrease in functional connectivity of the amygdala and hypothalamus was observed after Zembrin administration.
This effect was marginally stronger when contrasted with the shape-matching control condition, whereas cortical areas showed no such main or interaction effects even when using a less stringent statistical threshold.
The amygdala and hypothalamus are connected through the bed nucleus of the stria terminalis, which is heavily involved in anxiety-related behaviors Walker et al , , thus arguably, this effect reflects anxiolytic actions of Zembrin on basal threat responding in this subcortical threat circuit. Combined, these results provide support for the anxiolytic potential of dual 5-HT reuptake and PDE4 inhibitors Harvey et al , This combination has previously been argued to have synergistic potential in the treatment of anxiety and depression Cashman et al , , with the added value that lower doses can be used to reduce side effects Duman et al , ; Rock et al , Although we cannot separate these pharmacological actions in the present results, the effects seem to compare well with the literature on both the mechanisms Harmer et al , Harmer et al , Acute SSRI administration has been shown to increase amygdala reactivity in tasks that required explicit evaluation of threatening facial expression Bigos et al , but generally reduces amygdala reactivity to unattended facial expressions of threat Del-Ben et al , ; Murphy et al , The first effect is marginally supported in the present data and is usually interpreted as an effect of increased agitation and increased sensitivity for social information in general after first use of SSRIs Anderson et al , ; Harmer et al , , which normally disappears after long-term administration Pringle et al , The second effect has been interpreted as the underlying mechanism for the anxiolytic properties of SSRIs in long-term administrations, which are often described in terms of functional coupling of prefrontal areas with the amygdala Fisher et al , ; McCabe and Mishor, ; Pringle et al , In the present data, this is further supported as the reduction of amygdala reactivity was particularly observed in a contrast that has previously been linked to state anxiety Bishop et al , Finally, although we did not find evidence for the effects on PFC—amygdala coupling in the present study, these effects might be observed in future studies of long-term Zembrin administration.
FMRI studies on PDE4 inhibitors are, to our knowledge, currently not available, but PDE4 inhibitors can be specifically linked to anxiolytic functions in the subcortical threat circuit.
Although PDE4s can be found in cortical as well as subcortical areas Korff et al , , especially the sub-types PDE4B and PDE4D Perez-Torres et al , , which are particular the targets of Zembrin Harvey et al , , can be found in the olfactory nucleus, ventral striatum, hypothalamus, and midbrain of mice Cherry and Davis, Moreover, PDE4B has been argued to be associated with acute effects on the noradrenergic stress system Cherry and Davis, , has been linked to panic disorder Otowa et al , , and the prototypical PDE4 inhibitor rolipram has been shown to affect the amygdala Rutten et al , ; Werenicz et al , , possibly through its enhancing effect on Fos-like immunoreactivity Bureau et al , Future fMRI research should establish how these effects are reflected in amygdala reactivity to threat, but taken together these data do suggest that PDE4 inhibitors target the subcortical threat circuit, which is further supported by our results.
In sum, we show here that the dual 5-HT reuptake and PDE4 inhibitor Zembrin reduces amygdala reactivity to unattended facial fear and also decouples amygdala—hypothalamus connectivity. These results support the potential anxiolytic actions of Zembrin and provide a foundation for exploring the clinical potential of dual PDE4 and 5-HT reuptake inhibitors for the treatment of anxiety disorders and depression.
This study was made possible by funds from H. The other authors declare no conflict of interest. National Center for Biotechnology Information , U. Journal List Neuropsychopharmacology v. Published online Aug Prepublished online Aug 1. Author information Article notes Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people and subsequently by European colonial farmers as a psychotropic in tincture form.
Keywords: anxiety, amygdala, hypothalamus, phosphodiesterase, serotonin, sceletium. Open in a separate window. Figure 1. Figure 2. Figure 3. Figure 4. Supplementary Material Supplementary Information Click here for additional data file.
Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study. Psychol Bull. MRI atlas of the human hypothalamus. Acute 5-HT reuptake blockade potentiates human amygdala reactivity. Neural mechanisms underlying selective attention to threat.
Ann NY Acad Sci. Neural processing of fearful faces: effects of anxiety are gated by perceptual capacity limitations. Cereb Cortex. Neuroanatomical and pharmacological assessment of Fos expression induced in the rat brain by the phosphodiesterase-4 inhibitor 6- 4-pyridylmethyl 3-nitrophenyl quinoline. Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression.
Bioorg Med Chem. Cyclic AMP phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol. The amygdala: vigilance and emotion. Mol Psychiatry.
Too much serotonin in the nervous system can cause a condition called serotonin syndrome. In minor cases, people experience symptoms like tremor, twitching, anxiety, insomnia, and increased heart rate. If serotonin levels get high enough, this syndrome can cause seizures, delirium, and extremely high body temperature.
In extreme cases, a person suffering from serotonin syndrome can fall into a coma. The symptoms of this condition vary from person to person, and they range from mild to life-threatening [ 44 , 45 ].
Many antidepressants work primarily by increasing the amount of available serotonin in the brain. Similarly, kanna increases available serotonin; it may be dangerous in people who are already taking antidepressant medication [ 25 , 46 , 5 ].
This class of drugs includes [ 47 , 48 , 49 ]:. This class of drugs includes [ 47 ]:. If you are taking any medication for depression or anxiety, talk to your doctor before using kanna.
Very few drugs and substances have specifically been tested for interactions with kanna. Some anecdotal evidence suggests that it may enhance the effects of alcohol and cannabis [ 20 ].
Kanna is a serotonin reuptake inhibitor, like the SSRIs listed above. Such medications interact dangerously with many other substances, such as [ 54 ]:. We recommend caution when combining bioactive supplements with medication. Talk to your doctor to avoid adverse effects and unexpected interactions.
Many researchers have investigated the interaction of SSRIs with genetics. Because kanna shares a mechanism with this class of drugs, the genes that affect SSRIs may affect kanna in a similar way.
Note, however, that these genes have not been connected specifically to kanna; more research is required to confirm any direct interactions [ 55 ]. This claim is highly controversial, but SLC18A2 certainly affects the amount of dopamine stored, released, and available in the brain [ 57 , 58 ].
This gene codes for the VMAT2 protein. In one study, kanna increased the amount of the VMAT2 protein in human and mouse cells. Scientists explored a region near the SLC18A2 gene that affects its activity promoter region. Some combinations of variants can increase the expression of this gene, while one combination of variants can decrease it [ 59 ]. People who have higher gene activity may also be more sensitive to the psychoactive effects of kanna; people with lower VMAT2 transcription may benefit more from kanna, as this herb may raise VMAT2 levels in their brains and potentially offer some protection against cognitive dysfunction [ 59 ].
However, affordable whole-genome sequencing may make this data available to consumers in the near future [ 59 ]. The most widely available commercial form of kanna is Zembrin. Zembrin is a standardized extract of Sceletium tortuosum ; it is sold as a powder and in single-dose capsules.
Multiple companies sell Sceletium tortuosum as an extract or in tea. Alternatively, you may be able to find Sceletium tortuosum sold as a houseplant. This succulent shrub can be grown from seed or bought as a seedling and re-potted. The fermentation process changes the chemical profile of the herb, increasing mesembrine and decreasing mesembrenone [ 60 ]. The smell of kanna is compared to that of tobacco and its taste described as very bitter.
Traditional healers warn that fermented kanna should only be chewed for about 15 minutes and then removed from the mouth. Any longer than that and the user will become intoxicated [ 20 ].
The recommended dosage of Zembrin, a commercial Sceletium tortuosum extract, is 25 — 50 mg per day for cognitive effects. Some South African psychiatrists prescribe kanna for major depression and anxiety; these patients receive between — mg per day, taking half with breakfast and half with lunch [ 61 , 62 , 41 , 20 ].
In a rat toxicology study, researchers concluded that up to 6 mg per kg of body weight per day would be completely safe to consume.
For an average adult human, that works out to mg per day, far above the effective dose [ 41 ]. According to tradition, fermented kanna should be chewed for about 15 minutes and then removed from the mouth for the best result. If chewed for longer, they say, it will intoxicate the user [ 20 ].
Much of the traditional knowledge of Sceletium tortuosum has either been lost or has yet to be scientifically verified. Of the work that does exist, a significant proportion belongs to a single researcher for whom kanna and other traditional South African medicines are a passion project. While his work and interest predate any corporate partnership, he is currently a Director of the company that makes Zembrin, a commercial extract of Sceletium tortuosum.
Effects which have been demonstrated in cell studies may not have been tested in live animal or clinical human studies. Some clinical human studies, furthermore, suffer from small sample sizes. Anecdotal reports of some benefits are, by their nature, selective: only the success stories are presented. Kanna is the fermented product of the whole Sceletium tortuosum plant: a small succulent that grows wild in South Africa.
Kanna has antidepressant and anti-anxiety properties and may improve executive function and cognitive flexibility. It is traditionally used as a mild painkiller and to decrease appetite.
There are a few categories of substances of medications that should be whenever using Kanna. Kanna has the same mechanism of effects as erectile dysfunction medications like Viagra or Cialis. This type of interaction is called an agonistic interaction. When two or more substances are taken together that do the same thing, it significantly increases the chances of experiencing side effects. The potential side effects of these drugs can be severe — ranging from priapism painful erection lasting 6-hours or more to hearing loss or severe headaches.
Kanna may negate the effects of drugs used to treat high blood pressure and could lead to side effects when combined with high blood pressure medications by causing blood pressure to drop too low. This can cause feelings of dizziness and lead to fainting. Kanna should be avoided when taking any antidepressants. The alkaloids in Kanna inhibit the reuptake of serotonin — which is the same mechanism used by most antidepressant medications. Mixing Kanna with drugs like Zoloft, Prozac, Celexa, or Lexapro could increase the chance of side effects, including nausea, loss of libido, blurred vision, fatigue, and more.
Kanna is not inherently addictive in the classical sense of the word. With that said, any substance that provides a sense of euphoria or escape from discomfort or depression can become habit-forming and eventually lead to issues with addiction if used for the wrong intention. Kanna is an excellent herb for self-growth, focus, sexual performance, and buffering our mood during times of stress. Kanna should not be used as a crutch or a bandaid for managing mental illness or trauma without addressing the underlying cause first.
This produces rapid onset of effects and is a more efficient means of using Kanna than other methods — like smoking or making tea. You need about a quarter of the dose when snorting as you do for oral methods of consuming the plant. Other side effects include a loss of your sense of smell, pain in the nasal cavity, frequent nosebleeds, headaches, and recurring sinus infections. One of the best aspects of Kanna is how easy it is to grow some yourself.
Surprisingly few psychoactive plants can be cultivated easily at home. Kanna can be grown easily from seed or cuttings in a small pot inside your house. Plant these seeds like you would any other. It works great in a humidity dome with seed-starting soil and lots of light. It can take several weeks for the seeds to sprout, so be patient.
This plant is super easy to grow. The main cause of failure is overwatering. You have to remember that Kanna is a succulent that thrives in a part of the world that gets very little rain. Kanna is legal in most parts of the world — but it can be difficult to find.
This herb has only recently started to gain traction outside South Africa. There are no countries that have banned this herb specifically. Serotonin and the serotonin receptors are very well studied. Researchers have shown that there are unique genetic SNPs in the human body that affect how we respond to serotonergic substances — such as Kanna [ 4 ].
This is a field still being explored and is highly speculative — but could explain why some people respond to Kanna very strongly and others very weakly. What is Kanna? These alkaloids target other neurotransmitters aside from just serotonin. Some studies suggest Kanna also acts through the endocannabinoid system in a similar way to CBD. Here are the most common dosage ranges for Kanna depending on the method of consumption: Chewed fermented Kanna leaves —— mg chewed with gum for 15 minutes and then spat out Sublingual powder — — mg, held in the mouth for 15 minutes before swallowing Zembrin commercial kanna concentrate — 25—50 mg per day Insufflation snorted — 20—50 mg per dose Smoked — — per session Kanna Tincture — Equivalent dose of — 0.
What Does Kanna Do? Does Kanna Cause a Hangover? How Long Does Kanna Last? How Does Kanna Work? What Does the Research Say? Serotonin Reuptake Inhibition Serotonin is an important neurotransmitter most active in the brain and gut.
The effects of Kanna are subtle. You may not even notice them. Kanna vs. The effects of kava and Kanna are very similar despite having unique mechanisms of action. Kratom Kanna and kratom Mitragyna speciosa are also very similar in their effects on the body — however, kratom is much stronger than Kanna in just about every category. Marijuana Kanna and marijuana Cannabis sativa share a few key similarities. Can you take too much Kanna? Kanna Drug Interactions There are a few categories of substances of medications that should be whenever using Kanna.
Erectile Dysfunction Medications Kanna has the same mechanism of effects as erectile dysfunction medications like Viagra or Cialis.
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