Pre-Trip Ingredient Research Summary

This is a deep analysis summarizing the published anti-nausea, anti-anxiety, and cardiovascular supportive benefits of all the ingredients in the formula. It is DENSE, especially meant for the nerds out there 🙂

Ingredient Deep Dive.

• 500 mg Ginger Extract (20% gingerols + shogaols):  
  The extreme potency of the chosen ginger extract was a perfect fit for use in the capsules. The primary active compounds within Ginger root (Zingiber officinale) are the Gingerols and Shogaols. These compounds have many effects, but our goal is to block the 5-HT3 receptors, also known as the serotonin 3 receptors . Side effects of large activity at serotonin 3 receptors can include nausea. Gingerols and Shogaols act by gently blocking these receptors (the same target as Zofran), helping to soothe the stomach. The compounds also have shown potential to bolster cognitive health, mood, and memory. The use of this high potency gingerol + shogaol containing ginger extract far exceeds what can be found in other products on the market.
  • Ginger’s Anti-Nausea research:
    • A 2015 literature review on ginger for nausea from various causes noted a strong trend towards improvement in nausea & vomiting across different populations, including pregnancy-related conditions, chemotherapy-related issues, hospital operation-related issues, and immunotherapy-related issues.¹ In one of the pregnancy-related studies covered by the literature review, ginger was able to improve combined nausea and vomiting symptoms by 49%.¹
    • A 2022 meta-analysis pools data from 5 studies in pregnant women to compare ginger and vitamin B6 in their ability to decrease nausea and vomiting². First, the effectiveness of ginger itself is noted, then the authors compare ginger to vitamin B6, with a trend for ginger being slightly more powerful than vitamin B6, but with both ingredients being more effective than placebo treatments.²

• Ginger’s Anti-Nausea Mechanisms (What compounds in ginger cause this effect?):
  • In a 2018 study titled “Natural Negative Allosteric Modulators of 5-HT3 Receptors”, Multiple different compounds within ginger were determined to block the 5-HT3 receptors, which is a mechanism of action shared by some of the most common nausea-reducing medications.³ These compounds include: 6-gingerol, 8-gingerol, 10-gingerol, 6-shogaol, and Zingerone.³ This is exactly why the ginger extract in our Pre-Trip product is standardized to a whopping 20% combined gingerols & shogaols. 
  • Non-extracted dried ginger root powder, which is the form used in human studies thus far, contains an average of only ~0.8% gingerols & shogaols⁴. Our ginger extract contains ~24.8 TIMES more of the important bioactive compounds by mass. We can only speculate about the implications of this much more potent ingredient, but in theory it is able to much more effectively decrease activity through the 5-HT3 receptors, and improve a sense of ease in the stomach*.
  • Comparison of 6-gingerol to ondansetron (Zofran): A 2019 study found 6-gingerol, one of the strongest bioactives in ginger extract, to be equally effective to ondansetron in a rat-model of nausea.⁵ The 6-gingerol is dosed much higher by mass than ondansetron, but the higher dose makes up for the reduced potency.
  • Although blockade at the 5-HT3 receptors is thought to be the primary mechanism for ginger’s effects, there is some preliminary research to suggest additional blockade at the muscarinic cholinergic M3 receptors.⁶ This means ginger may be working through more than one mechanism when improving stomach comfort*.
• Ginger’s Anti-Anxiety research:
  • A 2021 research paper diving into ginger’s cognitive health applications also notes data from preliminary studies describing reductions in what they refer to as “anxiety-like behavior”.⁷ In simple terms, ginger may also contribute to the calming effect on the mind*.
  • Some of ginger’s effects on the mind may be through the blocking of 5-HT3 receptors. Ginger, through blocking 5-HT3 receptors may also synergize with the mood-lifting effects of psychedelics*, due to increasing mood through a unique mechanism. A 2021 research paper discusses the role of blocking 5-HT3 receptors in supporting lower stress levels*, through models they call “chronic unpredictable mild stress” models.⁸ 
• Ginger’s Pro-Cognitive research: As discussed in a 2011 research article, Ginger has also been researched to benefit cognitive health.⁹ There are multiple proposed mechanisms, including the inflammation-regulating and oxidation supportive pathways that ginger works through.⁹ Pre-Trip is targeted to improve as many aspects of the psychedelic experience as possible, and the improved mental clarity* is an added benefit from ginger extract in terms of retaining more memory of the trip experience.

• Vitamin B6 (as 48 mg pyridoxal-5-phosphate)
  The active form of vitamin B6 is the preferred choice for any formulation, but it was not thrown in our formulation just to look pretty. Vitamin B6 has been shown to go head to head against ginger as a natural anti-nausea ingredient, yet through a completely different mechanism. In addition, B6 acts as a cofactor in many enzymatic cascades, particularly as a cofactor in the production of GABA, the dominant calming neurotransmitter. This ingredient is included not only to help quell an upset stomach, but also to support a calming mental environment.
  • Vitamin B6 Anti-Nausea research:
    • In the same meta-analysis discussed in the section on ginger, vitamin B6 was still shown to be significantly effective at reducing nausea compared to the placebo condition.²
    • A 2023 systematic review on the use of vitamin B6 for pregnancy-related nausea & vomiting reviews 8 studies where B6 alone was confirmed to improve symptom severity.¹⁰
    • Efficacy of vitamin B6 in a non-pregnancy condition: While not a human study, we wanted to also provide some preliminary evidence showing a benefit to stomach comfort in non-pregnancy related symptoms. A 2013 veterinary medicine study on cats found vitamin B6 to significantly decrease vomiting induced by a commonly veterinary sedative.¹¹ They administered the B6 prior to the administration of the nausea-inducing medication, showing preliminary evidence for the use of vitamin B6 to have immediate stomach-soothing effects.*
  • Vitamin B6 Anti-Anxiety Research and Mechanism:
    • A 2022 research paper using 478 people found vitamin B6 supplementation to decrease “self-reported anxiety”.¹² The paper also dives into the mechanism by which vitamin B6 may be reducing stress, due to its role as a cofactor nutrient in the production of the calming neurotransmitter GABA.¹²
• 300 mg L-Theanine
  This amino acid is found naturally within green tea, but at much smaller quantities than what we have included in the capsules. There are many fascinating effects served by L-theanine, but it is included to promote GABA activity, support alpha brain waves, and generally promote relaxation.
  • L-Theanine’s Anti-Anxiety research:
    • L-theanine has been shown to decrease measures of stress in humans, as reported by a 2019 randomized controlled trial on the effects of L-theanine.¹³ The study only used 200 mg of L-theanine,¹³ and Pre-Trip contains 300 mg. 
    • A 2022 systematic review examined dosages of 200-400 mg of L-theanine, and they claim that L-theanine can help with stress reduction “in people exposed to stressful conditions.”¹⁴
  • Alpha brain wave research: In a 2008 research study, L-theanine was shown with EEG readings in humans to increase alpha brain waves, which according to the authors of the paper, “relaxes the mind without inducing drowsiness”.¹⁵
  • GABA mechanism: Mechanistically speaking, a 2007 paper reports that L-theanine exerts some of its effects through the GABA A receptors, which when activated are known to have stress-relieving properties.¹⁶ The researchers determined this by using a GABA A antagonist (which blocks GABA receptor function) in combination with L-theanine and found an elimination of L-theanine’s neuroprotective benefits.¹⁶
• 310 mg Magnesium (from Sucrosomial magnesium & magnesium Taurate)
  Minerals are all over the place, but magnesium deserves extra attention. Serving as a cofactor in over 300 enzyme processes, it has many roles. For our purposes, it is one of the key calming ingredients, both physically and mentally. Magnesium can help prevent over-activation of stress-inducing glutamate receptors. It promotes muscle relaxation to provide a calming sensation across the body, and improves mood as well. The patented Sucrosomial form of magnesium has excellent bioavailability and eliminates the gastrointestinal issues often experienced with other magnesium salts*. The sucrosomial form encloses magnesium oxide molecules within a sucrosome- which is a lipid-sucrose bilayer. This allows the magnesium to directly pass into our cells and better increase magnesium levels throughout the body.
  • Magnesium’s Anti-Anxiety research: A systematic review into human studies of magnesium supplementation for anxiety reduction found a consistent trend towards improved anxiety scores.¹⁷
    • There is also research to suggest the combination of vitamin B6 with magnesium may increase the positive effects.¹⁸ This synergistic effect may even further describe the rationale for including both of these ingredients in Pre-Trip.
  • NMDA receptor antagonism: Magnesium, despite being a simple essential mineral in our diets, has a critical function in blocking open NMDA receptor channels. As discussed with one of our other ingredients, agmatine, these are types of glutamate receptors, and excessive signaling through these receptors is associated with higher stress. Magnesium ions must be removed from the NMDA receptor for transmission to occur. In simple terms, magnesium acts as a simple barrier against excessive stimulation- a gentle lock on one of the doors leading to stress. This is a huge reason why magnesium is included in Pre-Trip*.
  • Muscle relaxation effect (jaw clenching): Magnesium is often touted as a muscle relaxant, as seen with things like Magnesium sulfate epsom salt baths. This is due to magnesium’s counteracting effect on calcium entrance into muscle cells. A 2023 research review discusses magnesium’s possible effects on reducing clenching of the jaw muscles.¹⁹ It is a common issue with psychedelic use to have a troublesome time relaxing the jaw musculature, and magnesium’s inclusion in Pre-Trip may be able to support this muscle relaxation*
  • Blood pressure: A 2016 meta-analysis examining magnesium’s effects on blood pressure found small but significant reductions.²⁰ Psychedelic substances are known to possess unwanted cardiovascular effects, and magnesium’s inclusion in Pre-Trip may help to support cardiovascular health*
• 920 mg Taurine (from Magnesium Taurate)
  This conditionally essential amino acid is produced within our own bodies, but daily production is limited and we need to obtain some from our diets for optimal function. Taurine is similar to L-theanine in its ability to support a calming effect by promoting GABA receptor activity, but it also has fascinating benefits for heart health, eye health, and many other physically calming effects within the body. In addition, Taurine improves the bioavailability of Magnesium, one of our core ingredients.
  • Anxiety research:
    • A 2023 research article discusses the use cases of taurine, including its application for anxiety.²¹ For example, Taurine has exhibited benefits in animal models of chronic stress, lead-induced stress, and other types of stress.²¹
    • A 2016 study found that Taurine can reduce anxiety-like behavior in zebrafish.²²
  • Glycine Mechanism: In a 2007 study using mice, the authors found that the anxiety-reducing effect of taurine may occur through the glycine receptor, and memory function is preserved, showing a high safety profile.²³ Many stress-reducing ingredients, including taurine, work through GABA receptors, but it is very unique to act through glycine receptors. 
  • GABA mechanism: A 2019 study reports that Taurine is a weak agonist of GABA A receptors, quite likely contributing to its relaxing effects.²⁴
  • Blood pressure research: In humans, a 2018 meta-analysis of research using wide ranges of taurine administration shows a significant decrease in blood pressure.²⁵ Taurine’s inclusion in Pre-Trip may help to support cardiovascular health* when using psychedelic substances. 
  • Taurine may improve magnesium levels: In an animal model administering taurine to rats, the researchers discovered higher blood magnesium levels after dosing taurine.²⁶ As we described, magnesium is a key ingredient in Pre-Trip for its stress-relieving and bodily-relaxing properties*, and Taurine not only adds its own benefits, but may enhance magnesium’s effects as well!
• 250 mg Agmatine
  This amino acid derivative of Arginine is a lesser-known ingredient in supplements, but it certainly belongs in this formulation. Agmatine promotes calming effects through a different mechanism from Taurine & L-theanine, by helping restrict Glutamate (NMDA) receptor activity, which is our main system involved in excitation. Agmatine also promotes a positive mood. In addition, agmatine may support cardiovascular health by increasing nitric oxide levels- increasing blood vessel diameter. This is perfect in the context of cardiovascular reactions seen with psychedelics.
  • Agmatine’s Blood pressure research:
    • A 2018 review article references agmatine’s ability to reduce blood pressure and heart rate.²⁷ One of the mechanisms for this effect is the increase in nitric oxide (NO) levels, along with some complex effects involving one of the adrenaline receptors. Supporting heart health is one of the reasons for the inclusion of agmatine in Pre-Trip.* 
    • NMDA antagonism research: The same 2018 paper exploring agmatine’s role in the neurologic system references agmatine’s ability to block the NMDA receptors, the main glutamate receptors.²⁷ While magnesium also blocks NMDA receptors, agmatine can do this through a different mechanism. By doing this, agmatine in Pre-Trip may decrease feelings of overstimulation and promote a sense of calm*. 
  • Agmatine’s Depression research: According to a 2021 review article, agmatine is currently being explored for its potential ability to rapidly enhance mood*, based on many promising animal studies.²⁸ In the paper, agmatine is compared to the well-known substance ketamine for its fast ability to boost mood.²⁸ There is one very small human pilot study that found agmatine to have significant mood improving qualities²⁹.* 
• 400 mg Palmitoylethanolamide (PEA): This is a key ingredient in our formula that mimics many of the effects of CBD. PEA is a cannabinoid-like compound that occurs naturally in our bodies, and is a strong inflammation supportive agent that relaxes the body and the mind.
  • Fatty acid amide hydrolase (FAAH) inhibition: This mechanism slows the natural breakdown of the endocannabinoid transmitters that circulate normally in the body. There is a theoretical nausea supportive effect from the PEA alone, but also a proven calming effect:
    • Palmitoylethanolamide’s Anti-Anxiety research: A 2022 research study found an improvement of anxiety-type symptoms in a mouse model of neuroinflammation.³⁰ They noted a reduction of inflammatory markers, and possible increase in GABA levels.³⁰ They also found PEA to counteract overactivation of the HPA axis (decreases cortisol release).³⁰
      • Anxiety/depression symptoms were also reduced in a 2013 study administering PEA & luteolin to mice.³¹ It is difficult to parse out the benefits of just the PEA alone when luteolin was also given, but this is more preliminary research on the stress-managing effects of PEA. 
    • PEA’s Mood research: In a 2018 human randomized controlled trial, PEA improved depression scores when added to SSRI treatment.³² This means that PEA in Pre-Trip may have beneficial effects in increasing mood*.
    • Theoretical nausea mechanism: A 2015 paper discusses how FAAH inhibition reduces nausea through the PPAR alpha receptors and CB1 receptors.³³ 
    • A 2016 paper confirms palmitoylethanolamide’s ability to inhibit the FAAH enzyme.³⁴ While FAAH inhibition is in its infancy in the modern research, the goal of Pre-Trip is to target as many synergistic and complementary pathways as possible in supporting the optimal trip*: 
• 90 mg Vitamin C
  Why vitamin C? This is one of the most widely accepted antioxidants, but it also supports a positive mood, and may help as an additional layer of mild nausea protection.
  • Vitamin C’s Anti-Nausea research:
    • A 2014 human study found vitamin C to improve seasickness (a type of nausea) by lowering levels of histamine.³⁵ As seen in our breakdown of all these different mechanisms, there are many biochemical pathways that can lead to stomach discomfort. Pre-Trip includes Vitamin C to help target this histamine-lowering mechanism* and relieve stomach discomfort through a different mechanism.*
    • A 2020 human study found taking vitamin C before surgery to reduce scores of nausea.³⁶ This is further human research that helps to show the reasons behind the inclusion of Vitamin C in the Pre-Trip product. 
  • Vitamin C’s Mood research:
    • A 2021 meta-analysis found Vitamin C to have a mild effect on elevating mood in certain populations of people.³⁷ This is simply a possible added benefit of Vitamin C’s inclusion in the Pre-Trip product*. It is worth noting that Vitamin C is a necessary cofactor in the production of the neurotransmitter dopamine, which is essential for a positive mood. 
  • Shelf Stability: A 2023 scientific paper discusses how Vitamin C also has the added benefit of increasing shelf stability of foods due to its antioxidant properties.³⁸ This is yet another reason to include Vitamin C, to improve the long-term stability of the capsule components of Pre-Trip*.
• Ginseng Extract (200 mg of 20% ginsenosides): Ginseng is a super common ingredient, but we never see it discussed for its enhancement of stomach-comfort! Ginseng serves a dual purpose of reducing stomach distress and enhancing mood.*
  • Ginseng’s Anti-Nausea Human research:
    • A large 2021 meta-analysis of ginseng use across 28 randomized controlled trials and 2503 total participants found an improved quality of life, including reduced levels of nausea and vomiting.³⁹ Ginseng is often included in many traditional Chinese medicine formulations that address stomach comfort, and this meta-analysis helps to confirm the potential efficacy of ginseng for easing the stomach*.
  • Ginseng’s Anti-Nausea mechanism:
    • Ginsenoside compounds within ginseng root have been identified in a 2007 research paper to block the same 5-HT3 receptors we keep talking about!⁴⁰ They bind to unique sites on the receptors, helping to decrease the stomach uneasiness induced by these receptors through a unique and complementary mechanism, working alongside ginger, CBD, and linalool in the Pre-Trip formulation*.
  • Ginseng’s Mood effects:
    • Ginseng also helps to support mood by decreasing stress and increasing positive aspects of mood. Ginseng has been found to act as an adaptogen (an herb or compound that helps regulate stress levels), and according to a 2017 research paper, it is a more effective adaptogen at reducing stress compared to other adaptogens.⁴¹ Ginseng does this through a unique mechanism by directly affecting the HPA axis, which is a hormonal pathway involving cortisol.⁴¹ Ginseng can decrease the inflammatory cascade induced by the stress response, further helping to calm the mind* in Pre-Trip.
• Quercetin phytosome (200 mg of patented QuerceFit Indena Phytosome) Quercetin is being researched for its unexpected stomach-comfort enhancing properties. This ingredient adds a unique blend of effects that helps ease the stomach through multiple biological pathways.*
  • Animal Research on Quercetin’s Anti-Nausea Effects:
    • A 2023 animal study using Quercetin on chickens found a significant reduction in nausea and vomiting, even in combination with known anti-nausea medications.⁴² Quercetin also showed a dose-dependent effect⁴², meaning more quercetin was more effective at improving symptoms. 
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  • Quercetin’s Anti-Nausea mechanism:
    • The same 2023 study on chickens found that quercetin blocks peripheral dopamine D2 receptors,⁴² which is a unique pathway to nausea relief hit by some pharmaceuticals such as Domperidone, but not commonly seen as a mechanism in supplement options. This discovery of a unique stomach-comfort enhancing ingredient* was revolutionary in the development and testing of the Pre-Trip product. 
    • Even more interestingly, the same quercetin study finds that Quercetin ALSO blocks the 5-HT3 receptor,⁴² meaning there is yet again ANOTHER ingredient in the formula that can block this receptor and binds at unique positions on the receptor.  
    • The same study finds that Quercetin ALSO blocks the M1 through M5 muscarinic acetylcholine receptors,⁴² which are receptors that are also involved in stomach distress. If all of this wasn’t enough, the study also notes quercetin’s known ability to protect the gastrointestinal tract from toxins.* 
  • Enhancing bioavailability: In the study on chickens, the authors administered high doses of quercetin orally, and they note that the oral bioavailability of quercetin is quite low. This is why we chose to use the Indena patented Quercetin Phytosome.
    • In a 2018 study on the pharmacokinetics of quercetin phytosome compared to regular oral quercetin, the 250 mg dose of the phytosome preparation produced a ~10.5 TIMES higher area under the curve of blood concentration than the 500 mg dose of non-phytosome.⁴³ 
    • The dose of quercetin phytosome in Pre-Trip is 200 mg, which in theory will provide over 8 TIMES the total blood concentration compared to the 500 mg regular quercetin dosage seen in the average supplement.* As we know from the chicken study, higher doses of quercetin yielded stronger effects at soothing the stomach, which is what we are going for!
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• CBD (cannabidiol): Cannabidiol (CBD) offers a unique blend of mentally calming and stomach-soothing effects, acting through unique mechanisms. CBD can help protect the nervous system from damage, and does not have ANY psychoactive potential, even though it lies in the category of cannabinoids.
  • CBD’s Anti-Anxiety Research:
    • A 2019 review article on various doses of CBD for different types of anxiety found a consistent ability of CBD to provide “acute reduction” in symptoms of stress⁴⁴, and they classify it as having a “promising role”⁴⁴ in helping people struggling with these issues. The doses evaluated in the review range from as low as 6-12 mg all the way up to over 400 mg of CBD per dose.⁴⁴ The Pre-Trip product contains a nice level of 70 mg of CBD, which falls comfortably in this range to provide a mild reduction of stress and easing of the mind alongside the other ingredients.*
    • A 2024 systematic review and meta-analysis by Han et. al confirms the findings of the 2019 review article. They refer to CBD as having a “considerable effect size” on stress reduction.⁴⁵
    • CBD’s Calming Mechanisms:
      • CBD has been shown in animal models to increase adult neurogenesis.⁴⁶ This is an added complementary benefit of Pre-Trip*, but likely also helps with the stress reduction effects.
      • CBD acts on the vanilloid receptors called TRPV1, the same receptors activated by capsaicin.⁴⁶ This activity is partially responsible for the pain-relieving effects of CBD, but interestingly, also is involved with the stress-reducing and mood-lifting properties of CBD*.⁴⁶
      • CBD also acts on the Serotonin 1A(5-HT1A) receptors, which are receptors that are known to be involved in decreasing stress and lifting mood.⁴⁶
      • CBD also functions as a positive allosteric modulator of GABAA receptors.⁴⁶ This means that the other ingredients in our formula that exert calming effects through GABA A receptors (L-theanine, Taurine, Vitamin B6, and Linalool) will be made slightly more effective by the inclusion of CBD.*
  • CBD’s Anti-Nausea Research:
    • Nausea mechanisms: CBD is thought to work against nausea primarily through activating the Serotonin 1A (5-HT1A) receptors. However, in the research article that outlines the 5-HT3 blocking effects of our other ingredients (gingerols, shogaols, and linalool), it was also presented that CBD has a very potent ability to block the 5-HT3 receptors as well.³ 
    • It is important to note that while the CBD dosages for reducing stress can far exceed the dosage found in Pre-Trip, the effective dose window of CBD for stomach-comfort is narrow,⁴⁷ and lower doses are more effective than higher doses. Pre-Trip is calculated to fall within the appropriate dosage range to soothe the stomach.*
• 30 mg CBDA: Cannabidiolic acid (CBDA) is a novel non-psychoactive hemp-derived cannabinoid that shows MUCH stronger stomach-soothing potential compared to CBD itself. This may be one of the most powerful ingredients included in Pre-Trip.
  • Higher Potency of anti-nausea effect in animal models
    • CBDA has been demonstrated to produce anti-nausea effects in animals that are 1000x more potent than the anti nausea effects of CBD itself.⁴⁸ CBDA has also been shown in animal models to enhance the efficacy of compounds that block 5-HT3 receptors.⁴⁸ The mechanism by which CBDA is theorized to reduce nausea is through activation of 5-HT1A receptors, similar to CBD.⁴⁸
    • CBDA, unlike CBD, has been shown in animal models to still be effective for motion-induced stomach unease,⁴⁸ demonstrating another point of evidence to suggest a significantly higher stomach-soothing potential.*
    • It is very important to emphasize that the current research suggests higher doses of CBDA to still retain efficacy for stomach-comfort⁴⁷, unlike the narrow dose range of CBD. While research suggests extremely low doses of CBDA to still be effective⁴⁷ due to the 1000x higher potency than CBD, we decided to include a relatively high dosage of CBDA in Pre-Trip, in order to maximize the theoretical stomach-soothing benefits as well as the stress support benefits.
  • Potency of CBDA’s anti-stress effect in animal models: In a 2020 research study, CBDA has been shown to be somewhat more effective than CBD in certain types of stress, however CBD may be more effective at other types of stress.⁴⁹ This is a big reason for the inclusion of BOTH CBD & CBDA in Pre-Trip.*
  • CBDA’s Higher Bioavailability compared to CBD: Animal research from 2020 appears to suggest that CBDA is about 2-3 times more effectively absorbed into the bloodstream than CBD.⁵⁰ This higher bioavailability ensures we can capture a high level of effect from CBDA in Pre-Trip.*
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• 25 mg Linalool: Linalool is the primary terpene constituent of lavender essential oil, which has shown consistent efficacy in calming the mind when taken orally.
  • Lavender’s Anti-Anxiety research:
    • When referencing a systematic review of a patented oral product containing lavender essential oil, we see a consistent, reproducible effect on supporting stress levels.⁵¹
  • Linalool’s Anti-Anxiety Mechanism:
    • According to a 2022 research review article, Linalool acts through several mechanisms, including NMDA antagonism, 5-HT1A activity (similar to CBD), as well as possible activity through GABA receptors. ⁵²
  • Linalool’s Stomach-soothing mechanism:
    • Linalool binds to a different allosteric site of the 5HT-3 receptors to potentially further decrease nausea through this pathway.⁵³ 
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