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Science Dangerous combinations etc

mr peabody

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TripSit's Guide to Drug Combinations (Click to Enlarge!)

Dangerous combinations

Psychonaut Wiki

Although many substances are safe on their own, they can become dangerous and even life-threatening when combined with other substances. Certain combinations may be safe in low doses of each but still increase the potential risk of death. Independent research should always be done to ensure that a combination of two or more substances is safe before consumption.

Substance related deaths most commonly occur when combining depressants. Depressants affect the parts of the nervous system responsible for breathing, and an overdose or combination of these substances can result in fatal levels of respiratory depression. Death may also occur when a victim falls into deep enough unconsciousness to aspirate on their own vomit. Lying in the recovery position can prevent one from suffocating on their own vomit.

Another possibly fatal combination of substances are serotonergic substances, which might cause serotonin syndrome. This can also be caused alone by an overdose of said substances. Serotonin syndrome is a result of excess serotonin in the brain, which can cause seizures, anxiety, tremors, nausea, coma and possibly a deadly fever. Usually this is caused when a user has used an anti-depressant within the last 2 weeks of consuming said substance. These kind of antidepressants include monoamine oxidase inhibitors (MAOIs), serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRI).


Benzodiazepines +
  • Depressants (1,4-Butanediol, 2-methyl-2-butanol, alcohol, barbiturates, GHB/GBL, methaqualone, opioids) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If nausea or vomiting occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If nausea or vomiting occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Stimulants - It is dangerous to combine benzodiazepines with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of benzodiazepines, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of benzodiazepines will be significantly increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only dosing a certain amount of benzodiazepines per hour. This combination can also potentially result in severe dehydration if hydration is not monitored.

Opioids +

  • Depressants (1,4-Butanediol, 2m2b, alcohol, barbiturates, benzodiazepines, GHB/GBL, Ketamine, methaqualone) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If nausea or vomiting occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If nausea or vomiting occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Stimulants - It is dangerous to combine oxycodone, a depressant, with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of oxycodone, which is the main factor most people consider when determining their level of intoxication. Once the stimulant wears off, the effects of oxycodone will be significantly increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only taking a certain amount of oxycodone.

Alcohol +

  • Depressants (1,4-Butanediol, 2-methyl-2-butanol, barbiturates, benzodiazepines, GHB/GBL, methaqualone, opioids, Ketamine,phenothiazines[1]) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation, sedation and amnesia caused by one another and can lead to unexpected loss of consciousness at high doses. There is also an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If nausea or vomiting occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Dissociatives - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If nausea or vomiting occurs, users should attempt to fall asleep in the recovery position or have a friend move them into it.
  • Stimulants - It is dangerous to combine alcohol, a depressant, with stimulants due to the risk of excessive intoxication. Stimulants decrease the sedative effect of alcohol, which is the main factor most people consider when determining their level of intoxication. Alcohol also appears to have addictive effects on stimulants compared to taking either of them alone. For instance a study found that concentration d-methylphenidate concentration in the brain are increased by up to 30% when mixed with alcohol. Another study had also found that when there is concurrent administration of methamphetamine (30 mg intravenously) and ethanol (1 gm/kg orally over 30 minutes) increased heart rate by 24 beats/minute compared to methamphetamine alone. Once the stimulant wears off, the effects of alcohol will be significantly increased, leading to intensified disinhibition as well as other effects. If combined, one should strictly limit themselves to only drinking a certain amount of alcohol per hour. This combination can also potentially result in severe dehydration if hydration is not monitored. It also interacts with cocaine in vivo to produce cocaethylene, another psychoactive substance.[2]
  • MAOIs - This combination can result in dangerous reactions through the way in which tyramine, a chemical commonly found in alcoholic beverages, causes increased blood pressure.

Psychedelics +

NOTE: Because of the relatively high unpredictability of psychedelics, it is usually advised (especially if the person has little or no experience) to avoid mixing them with any other substance, even if the mix is considered physically safe. Even a substance like Alcohol, which tends to dull the psychedelic effects, could trigger a state of confusion which might cause the person to have a negative experience.
  • Cannabis - This combination is very unpredictable. Some people like and advise to smoke during a trip to make the experience more relaxing, but in many cases it seems to potentiate the psychedelic effect and/or make the experience more intricate and confusing. This is usually not physically dangerous, but very well might cause a Bad trip by making the experience too overwhelming and disorienting.
  • Stimulants - This combination tends to increase anxiety, thus increasing the possibility of having a negative experience. If the psychedelic substance used is already stimulating on its own (for example a Phenethylamine) a mix like this could cause an increase in heart rate and/or other unpleasant physical and psychological symptoms.

Monoamine oxidase inhibitors (MAOIs), serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRI) +

  • Empathogens (MDMA) - This combination can result in serotonin syndrome, which is a result of excess amount of the neurotransmitter serotonin in the brain. Symptoms include headaches, agitation, hypomania, confusion, anxiety, hallucinations, coma, shivering, sweating, nausea, twitching and tremors. These symptoms can be fatal.
  • Dissociatives (Dextromethorphan) - This combination can result in serotonin syndrome, which is an excess amount of the neurotransmitter serotonin in the brain. Symptoms include headaches, agitation, hypomania, confusion, anxiety, hallucinations, coma, shivering, sweating, nausea, twitching and tremors. These symptoms can be fatal.
  • Other antidepressants - This combination can result in serotonin syndrome, which is an excess amount of the neurotransmitter serotonin in the brain. Symptoms include headaches, agitation, hypomania, confusion, anxiety, hallucinations, coma, shivering, sweating, nausea, twitching and tremors. These symptoms can be fatal.

 
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mr peabody

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Known Dangerous Combinations

MAOIs (e.g. Phenelzine, Tranylcypramine, Selegiline) +

X
All phenthylamine psychedelics (e.g. DOx, 2C-x, 3C-x, TMA-x, 25x-NBOMe)
X aMT (alpha-Methyltryptamine)
X MDxx (e.g. MDMA, MDA, MDEA)
X Other serotonin releasers (e.g. 6-APB, 5-APB, 5-API, 5-IAI, MDAI)
X All cathinones
X DXM (Dextromethorphan)
X Ibogaine
X SSRI/SNRI antidepressants (e.g. Sertraline, Seroxat)
X Methoxetamine
X Tramadol
X 5-HTP


SSRI/SNRI antidepressants (e.g. Sertraline, Seroxat) +

X
aMT (alpha-Methyltryptamine)
X 2C-T-7
X Ayahuasca/Pharmahuasca
X Other MAOIs (e.g. Phenelzine, Selegiline)
X DXM (Dextromethorphan)
X Ibogaine
X Tramadol
X 5-HTP


Anticonvulsants (e.g. Lithium, Valproate) +

X
All classical psychedelics (5HT-2a agonists like LSD, mushrooms, 2C-B)
X All phenethylamines
X Ibogaine


Beta-blockers (e.g. Propranolol, Atenolol) +

X
All stimulants and empathogens (e.g. Amphetamine, Cocaine, MDMA, Mephedrone)
X aMT (alpha-Methyltryptamine)
X LSD/LSA
X Datura/Belladonna/Brugmansia


Triptans (e.g. Sumatriptan, Rizatriptan, Zolmitriptan) +

X
aMT
X 2C-T-7
X Ayahuasca/Pharmahuasca
X Other MAOIs (e.g. Phenelzine, Selegiline)
X LSD/LSA


5-HTP +

X
aMT (alpha-Methyltryptamine)
X 2C-T-7
X Ayahuasca/Pharmahuasca
X Other MAOIs (e.g. Phenelzine, Selegiline)
X All SSRIs/SNRIs (e.g. Sertraline, Seroxat)
X MDxx (e.g. MDMA, MDA, MDEA)
X Other serotonin releasers (e.g. 6-APB, 5-APB, 5-API, 5-IAI, MDAI)


Alcohol (e.g. Beer, Wine, Vodka) +

X
Ibogaine
Additionally, tyramine-containing alcoholic beverages such as draught beer and wine should not be combined with any of the following:

X aMT
X Ayahuasca/Pharmahuasca
X 2C-T-7
X Other MAOIs (e.g. Phenelzine, Selegiline)


Ibogaine +

X
Alcohol
X DXM
X All SSRIs/SNRIs (e.g. Sertraline, Seroxat)
X MDxx (e.g. MDMA, MDA, MDEA)
X Other serotonin releasers (e.g. 6-APB, 5-APB, 5-API, 5-IAI, MDAI)
X All other stimulants (e.g. Amphetamine, Cocaine, MDPV)
X All anticonvulsants (e.g. Lithium, Valproate)
X Antibiotics
X Grapefruit Juice
X Quinine (Tonic water)


Serotonin releasers (e.g. MDMA, MDA, MDEA, 6-APB, 5-APB, MDAI, Mephedrone, Methylone) +

X
aMT (alpha-Methyltryptamine)
X 2C-T-7
X Ayahuasca/Pharmahuasca
X Other MAOIs (e.g. Phenelzine, Selegiline)
X DXM (Dextromethorphan)
X Ibogaine
X 5-HTP


Stimulants (e.g. Amphetamine, Cocaine, MDPV, Methcathinone) +

X
Beta-blockers
X Ibogaine

-----

Potentially/Likely Dangerous Combinations

Adrenergic autoreceptor antagonist antidepressants (mirtazapine, yohimbine) +

X
Dissociatives (DXM, ketamine)
X Ibogaine


Serotonin releasers (e.g. MDMA, MDA, MDEA, 6-APB, 5-APB, MDAI, Mephedrone, Methylone) +

X
5-MeO-MiPT and 5-MeO-DiPT
X Methoxetamine


Stimulants (e.g. Amphetamine, Cocaine, MDPV, Methcathinone) +

X
All of the NBOMe series (e.g. 25C-NBOMe, 25I-NBOMe)
X 5-MeO-MiPT and 5-MeO-DiPT
X Bromo-DragonFLY
X aMT (alpha-Methyltryptamine)
X 2C-T-7
X Ayahuasca/Pharmahuasca
X Other MAOIs (e.g. Phenelzine, Selegiline)


Alcohol (e.g. Beer, Wine, Vodka) +

X
Dissociatives (e.g. Ketamine, DXM, PCP, Methoxetamine)
X 5-HTP
 
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mr peabody

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The risk of combining MDMA with Ritonavir or Cobicistat

SPIRIT PHARMACIST | 16 April 2020

Dear Spirit Pharmacist: What are the risks of combining ritonavir or cobicistat with MDMA?

Answer: MDMA is potentially unsafe in combination with ritonavir or cobicistat. This is supported by case reports, unpublished manufacturer data, and data available for similar amphetamine compounds. Persons interested in MDMA should not suspend HIV medication use in order to use MDMA. Instead discussion of treatment strategies should involve the prescriber of their HIV medication.

So…What if I want to undergo MDMA therapy to work on my mental health?

MDMA, ritonavir, and cobicistat: A deeper dive


The medications in query, ritonavir (Norvir) and cobicstat (Tyboost), are used in the treatment of Human Immunodeficiency Virus (HIV). They are often combined with other HIV anti(retro)viral medications, which boosts their levels in the blood. They do this by blocking metabolism of drugs in the liver, which prolongs and increases antiviral effects, producing better results and decreasing chances of resistance developing to medication. They are known as ‘pharmacokinetic enhancers’ when leveraged this way. The risk or downside to this approach is that it leaves the user susceptible to drug interactions with other substances/medications.

Other HIV combination medications that have either ritonavir or cobicstat in them include*
  • Genvoya
  • Stribild
  • Symtuza
  • Evotaz
  • Kaletra
  • Prezcobix
*This list may not be all inclusive as the genesis of HIV medications continues. Check your current formulation for ritonavir or cobicistat to be sure. It should also be noted that this discussion of drug interaction is limited to the ritonavir or cobicistat component and other components of certain formulations may introduce their own risks*

There have been at least two cases reported of serious toxicity or death from combining ritonavir with MDMA

In case one, a 32 year old male ingested 180mg of MDMA at a night club and suffered a fatal serotonergic toxicity. The user had ingested MDMA several times previously without toxicity according to his partner. The user had started 600mg of ritonavir/day twice daily two weeks prior and had a history of liver dysfunction secondary to alcohol use. It should be noted that the standard dose of ritonavir as a pharmacokinetic booster is 100mg/day whereas this user was taking 1200mg and it relies of the liver to be metabolized itself. Upon autopsy, blood concentrations of MDMA were 10x higher than expected given the amount ingested.

In case two, a 23 year male taking ritonavir 100 mg/day, atazanavir 300 mg/day, and tenofovir/emtricitabine 300/200 mg/day took two tablets of ecstasy spaced 3 hours apart. After dancing for 4 hours he became progressively ill and was admitted to an intensive care unit (ICU) with hyperthermia, seizures, and impairment of consciousness. He developed renal and liver failure, was put on life support or mechanical ventilation to support breathing, and required 11 days in the ICU or 3 weeks in the hospital to recover enough to return home. Analysis of blood concentrations demonstrated concentrations 9x higher than what would be expected from a single 150mg dose of MDMA, although the individual reportedly took two tablets so may represent closer to~4-5x increase in blood concentrations compared to what could be expected.

In case three, a 29 y/o male with history of HIV/AIDS (CD4 count 24: history of neutropenia, Karposi’s sarcoma, Pneumocysstisti carinii pneumonia, and thrush) was switched to sasquinavir 400mg twice daily and ritonavir 400mg twice daily and ingested two tablets of MDMA about 4 days later. He experienced prolonged stimulant effects, insomnia, and agitation lasting about a day, which prompted him to take some GHB, which resulted in respiratory failure and being placed on life support. Upon awakening and stabilization he was adamant that he had used both substance previously at similar doses on a previous HIV regimen lacking ritonavir.

MDMA is primarily metabolized to either active or inactive metabolites by CYP2D6 although other liver enzymes have been implicated in its metabolism. Ritionavir and cobicistat are well known to inhibit CYP3A4 although have effects on many other liver enzymes including CYP2D6 and are notorious for drug interaction potential overall. In comparing the profiles of drug inhibition or pharmacokinetic enhancement profiles of ritonavir or cobicstat, there is not anything that would support they are much different in risk as far as combining with MDMA. While ritonavir and cobicstat have some differences, the differences they have would not be predicted to decrease risk of MDMA. Adulterants or substance misrepresentation is also of concern as many other amphetamines and related compounds interact strongly.

The manufacturer of ritonavir stated that they had studied theoretical interactions and predicted that for the average person a 2-3x increase in MDMA blood concentrations could be expected. However, they added that for a fraction of the population the increase could be as high as 5-10x depending on genetics or concurrent illnesses. In the two cases described above, concentrations found were 9-10x the expected concentration from a single 150mg dose of MDMA. All of this strongly signals potential risk in combination, however there are several caveat variables in understanding what happened in these cases and why the outcomes were so severe. In case 1 the subject was taking antiretroviral rather than booster dose of ritonavir, had pre-existing liver impairment, and ingested in a nightlife setting. In case 2 the subject re-dosed ecstasy and reportedly danced for 4 hours straight. The hot environment, fluid loss, excessive intake or lack of intake of water, and physical stress of dancing are known risk factors for exacerbation of hyperthermia and precipitation of severe toxicities. Cases of death resulting from ingestion of ecstasy as low as 2x the usual blood concentrations have been reported in these types of environments, underscoring the ability to exacerbate risk. In case 3 the subject was also on a larger dose of ritonavir than is standard today and had a history of advanced AIDS, may increase medical risks of drug use.

Interaction Risk Management

From what is currently known about drug interactions between ritonavir or cobicistat with MDMA, it seems there is likely risk of problematic drug interaction and proceeding with MDMA use may not be safe. The question then becomes about potential management strategies. Current HIV treatment guidelines shed little light on a management strategy and recommend behavioral interventions that “are used for other drugs use disorders” in the context of MDMA use as a “club drug.”

HIV medications are never tapered, because low levels of the drug in the system creates opportunity for HIV to develop drug resistance. HIV medications are also not supposed to be skipped temporarily for similar reasons around development of drug resistance. There are a few things that could be considered:

1. Discuss desire to undergo MDMA therapy with HIV provider, explain it will take a few months as there are typically a few sessions spaced a month apart with intense psychotherapy work between. Ask if:

a. There is another HIV medication without ritonavir or cobicistat that you could switch to

b. If the CD4 count is high enough and viral load low enough then a structured treatment interruption for the duration of the MDMA therapy

*These may be the best strategies. Please involve your HIV treatment provider to help manage decisions appropriately. These decisions are very personal and highly technical, do not attempt to make them by yourself. Treatment interruptions or poor adherence to HIV medication can increase the risk of drug-resistant HIV developing or transmission of HIV to others, thus is not recommended once taking antiretroviral therapy.

2. Shifting focus to a different psychedelic. Psilocybin would not be predicted to have this same problem with drug interaction. Ketamine would also have strong interaction potential with ritonavir or cobicstat and increased ketamine blood concentrations ~2-4x could be expected. If the dose was adjusted and ketamine was administered in an monitored medical setting, this could still be a safe option. Use of ketamine in unmonitored settings in combination with ritonavir or cobicistat could be unpredictable or dangerous.

3. A dose adjustment strategy could be applied to MDMA. It could be an appropriate precaution to start at 25% of the usual dose if combining with ritonavir or cobicistat, which would be 25mg if considering 100mg as normal. Given the wide estimations in effects on blood concentrations of MDMA (2-10x increase), this would equate to taking 50-250mg of MDMA. Single doses > 125mg have not been used to start in clinical trials of MDMA, thus this strategy still risks overdose and potential physical adverse effects or toxicity. Hot environments, prolonged physical activity, should be avoided as well as over or under hydration. Avoidance of re-dosing or booster doses is another reasonable strategy to lower risks. While this may help mitigate physical risks, there is also a chance it could introduce psychological risks. For example, in clinical trials of MDMA assisted psychotherapy, one participant that received low dose MDMA as an active control (30mg) became suicidal. Therefore, this strategy is likely fraught with safety concerns and is not preferable.

 
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Why taking psychedelics while on antidepressants could make treatment ineffective

by Tyler Koslow | DoubleBlind | 8 May 2020

How LSD, psilocybin, MDMA, ayahuasca, and ketamine interact with SSRIs.

Similar to how cannabis legalization was galvanized by its ability to reduce suffering during the Eighties AIDS epidemic, medical professionals are starting to cast a more favorable eye upon psychedelics due to promising effects on those suffering from depression and other mental health conditions.

We’ve seen psilocybin spread its spores into state legislatures and clinical trials, MDMA demonstrating promising results for patients with PTSD, and a growing movement of people interested in microdosing LSD to boost their mood and productivity. But for those patients who are prescribed antidepressants, there could be a disadvantage when it comes to benefiting from the guiding force of psychedelics.

Further research is needed to explore the interaction between certain selective serotonin reuptake inhibitors (SSRIs) and psychedelics such as psilocybin, LSD, MDMA, DMT, and ayahuasca, among others. However, preliminary evidence has presented a cruel irony of sorts. What if those who can benefit the most from psychedelic-assisted psychotherapy may be hindered by their present, and perhaps even their past use of SSRIs.

Dr. Julie Holland, a New York-based psychiatrist specializing in psychopharmacology, certainly believes that the question mark surrounding SSRIs and psychedelics is the elephant in the room for early clinical trials. Without solid information on how a history of antidepressant use impacts the effects of psychedelics, there’s no way of knowing how effective psychedelic-assisted treatment is for depression and anxiety.

“Wouldn’t it be terrible if it turns out that the people who need psychedelics the most benefit from it the least?” Dr. Holland tells DoubleBlind. “I’m certainly not willing to say that at this point, but I am willing to say that this is something to look at. It’s concerning.”

While peer-reviewed research remains sparse, there’s a bevy of available data that provides insight into how antidepressants may blunt the effectiveness of psychedelic-assisted treatment. Here’s a breakdown of what we know about the interaction between SSRIs and psychedelics.

Serotonin receptors: Where SSRIs and psychedelics meet

Before we explore the sparse research regarding antidepressants and various types of psychedelics, we should establish a general understanding of how SSRIs interact with and even blunt the effects of certain substances.

According to the National Center for Health Statistics, in 2017, 12.7 percent of the U.S. population over the age of 12 were taking antidepressants. SSRIs are the most commonly prescribed type of antidepressant, accounting for approximately 80 percent of the antidepressant market.

The primary function of SSRIs is to inhibit the serotonin transporter (SERT), which increases levels of serotonin in the brain by preventing it from leaving synapse. Over time, as SSRIs inhibit the serotonin transporter, the system attempts to self-regulate and serotonin receptors like the 5HT2A receptor aren’t expressed as much.

These serotonin receptors are where tryptamines (LSD, psilocybin, and DMT), phenethylamines (MDMA), and MAOI-containing substances like ayahuasca work their magic and lead us to the type of profound experiences that have changed so many lives. But, when these receptors are reformed by SSRIs, the way the body interacts with certain psychedelics may change.

In a chart compiled by psychopharmacologist Benjamin Malcolm on his website Spirit Pharmacist, existing evidence on the interaction between antidepressants and psychedelics has been categorized and matched with as much readily available information as possible. The guide itself should not be the basis of medical decisions, but it does provide interesting guidance regarding how patients may need to taper off their antidepressants in order to benefit from the effects of psychedelics.

According to the chart, for phenethylamines, tryptamines, and MAOI-containing psychedelics, subjects may be safer or have more potent experiences by tapering off of Paroxetine (Paxil), Sertraline (Zoloft), Citalopram (Celexa), Escitalopram (Lexapro), and Fluvoxamine (Luvox) for at least two weeks, while those on Fluoxetine (Prozac) should wean off for period of at least six weeks.

Tapering off SSRIs can be dangerous, however, and shouldn’t be done without consulting with your doctor beforehand. Suddenly reducing SSRI dosages can induce several harsh symptoms, including dizziness, fatigue, and insomnia, as well as less common symptoms like nausea, diarrhea, flu-like effects, irritability, and anxiety. Coming off of antidepressants could also stir up suicidal thoughts, so it may not be worth the potentially enhanced psychedelic experience.

SSRIs and LSD

One of the earliest studies providing insight into the interaction between psychedelics and antidepressants came courtesy of Katherine Bonson, a pharmacologist with the U.S. Food and Drug Administration (FDA). In a 1996 study published in Neuropsychopharmacology, Bonson and her research team collected first-hand accounts from volunteers who self-administered LSD while also taking an antidepressant.

When asked to describe the hallucinatory and psychological effects of the LSD, 88 percent of the subjects who had taken an SSRI over a three week period reported a significantly diminished or eliminated response to LSD. One of the 32 subjects, who had fluoxetine administered for one week, had an increased response to LSD. In a previous study, Bonson and her team noted increased responses to LSD in subjects taking lithium or tricyclic antidepressants, which are commonly used for patients who do not tolerate SSRIs.

These findings certainly provide some insight, but should be taken with a grain of salt. After all, the study consists of self-reported experiences from volunteers through a questionnaire—a far cry from a double-blind clinical trial. Anecdotal evidence scattered throughout the internet has followed a similar theme to Bonson’s research.

Similarly, anecdotal accounts also claim that there’s a diminished response when people on antidepressants take DMT. There’s no major research on the interaction between DMT and SSRIs, but these claims make sense considering that DMT also takes action within the serotonin receptors.



SSRIs and mushrooms

Like LSD, psilocybin is also classified as a tryptamine. Thus, there’s a similar concern that antidepressants could also cause a blunted response in psilocybin-assisted treatment.

Various psilocybin-assisted treatment retreats, such as the Amsterdam-based Synthesis, openly refuse to accept visitors on SSRIs, and do not accept guests who have been administered SSRIs and other prescription medication over the last 6 weeks (although, based on the huge need and potential to benefit, Synthesis is working with consultants and experts to determine how they can safely expand their support to this population and plan to announce something about this before the end of 2020). In Jamaica, the psilocybin-assisted retreat MycoMeditations requires applicants to thoroughly report medications and mental illness. At this retreat, the team starts with conservative psilocybin doses to account for factors such as SSRI interactions and anxiety.

While most accounts suggest that someone currently on SSRIs will likely experience a blunted response to psilocybin, there’s still the question of whether tapering off will provide a clean slate for an effective experience. Dr. Holland expresses concern that even years after the fact, past use of SSRIs could potentially hinder the potency of psychedelic-assisted treatment.

But not all experts have found that prior use of SSRIs will damper the effects of psilocybin. According to Dr. Matthew Johnson, professor of psychiatry and behavioral sciences at Johns Hopkins University, his team hasn’t seen a diminished response when psilocybin treatment is administered to subjects with a history of SSRI use.

“Anyone with that chronic use history would have had to go off for several weeks before having a session,” Dr. Johnson tells DoubleBlind. “In terms of someone still having a blunted response even after that period, we have not specifically analyzed this, but I doubt if there is anything substantial as we’ve seen many cases of powerful sessions with folks in that situation.”

While studies show that SSRIs restrain the psychedelic experience sparked by shrooms and LSD, there’s no evidence suggesting that mixing the two is necessarily dangerous. In fact, a group of researchers have proposed that SSRIs and psychedelics modify the serotonergic system in two different ways, and therefore could still lead to therapeutic outcomes when taken in a complementary fashion. This 2017 study theorized that SSRIs and other antidepressants enhance the 5-HT1AR pathways, while 5-HT2AR-agonist psychedelics like shrooms enhance the 5-HT2AR pathways.

SSRIs and MDMA

Although MDMA is not usually what comes to mind when you think about classical psychedelics, this stimulating hallucinogen has nonetheless emerged as a potentially effective treatment for both depression and PTSD. On top of that, there’s more clinical research on the interaction between MDMA (also referred to as ecstasy) and the serotonin system than with any other psychedelic.

In a 2007 study published in the Journal of Pharmacology and Experimental Therapeutics, researchers conducted a double-blind, placebo-controlled trial with 12 healthy male subjects. Over a three day period, they were either given 20 milligrams of paroxetine or a placebo before taking 100 milligrams of MDMA. Researchers found that subjects who had been given the three-day dose of antidepressants experienced a notable decrease in the physiological and subjective effects of MDMA, even though they showed a 30 percent increase in MDMA plasma concentrations, indicating a metabolic interaction between antidepressants and MDMA. They concluded that the “decrease in the effects of MDMA could lead users to take higher doses of MDMA and to produce potential life-threatening toxic effects.”

Another study found that lab rats pretreated with the SSRI citalopram did not experience reductions in aggressive and exploratory behavior when administered MDMA, suggesting that the SSRI appeared to render the MDMA treatment as less effective for certain behaviors. Furthermore, other lab studies discovered that the SSRI fluoxetine may enact certain neuroprotectant effects that reduce the neurotoxic effects of MDMA and also restore serotonin levels. Dr. Holland explains that this is why some people believe that taking an SSRI six to eight hours later may help prevent the rather unpleasant MDMA “crash.” However, there’s no solid evidence to suggest that this practice is effective in cushioning the come down.

Further studies looking at how SSRIs modulate the effects of MDMA are still ongoing. Dr. Holland has been working with the Multidisciplinary Association for Psychedelic Studies (MAPS) as a medical monitor on a study focused on MDMA treatment for PTSD patients.

“For MDMA, there’s no question,” says Holland. “I can state with a good amount of confidence that if you want a full experience from MDMA you have to get off SSRIs to do that.”

The multi-center clinical trials, which have yet to be published, found that people who had a history of being on SSRIs demonstrated a blunted response to MDMA. Not only could this cause someone to over-consume in an attempt to achieve an equally potent experience, but could potentially lead to the onset of serotonin syndrome.

Serotonin syndrome can happen when certain serotonergic medications or substances are combined, causing the body to over-produce serotonin. This leads to extreme nerve cell activity and symptoms that include confusion, restlessness, nausea, vomiting, loss of muscle control, rapid heart rate, and in some extreme cases, seizures and uneven heartbeat.

Now, while evidence suggests a correlation between people who take SSRIs having a blunted response to psychedelics, that doesn’t necessarily mean that antidepressants are the culprit. Holland cautioned that it’s important not to conclude that SSRIs are causing the diminished effects, as there are numerous unknown factors at play.

“You can’t definitively conclude because you don’t know what came first: the chicken or egg,” says Dr. Holland. “It may be that the kind of people who end up on SSRIs for years and years are the kind of people who are not going to have a robust response to MDMA for some reason, due to their pre-existing serotonergic state."

SSRIs and ayahuasca

Another mystical psychedelic that has shown promise in the treatment of depression is ayahuasca, a South American brew made from Psychotria viridis leaves and the stalks of the Banisteriopsis caapi vine. Historically used by Amazonian tribes for spiritual purposes, ayahuasca is now being looked at in the clinical setting.

In 2018, Brazlian scientists conducted a double-blind, placebo-controlled trial involving 29 patients with treatment-resistant depression. After giving subjects a dose of ayahuasca or a placebo, researchers found significant evidence that ayahuasca was effective in lowering depression levels.

Despite the increasing interest in ayahuasca, researchers have cautioned against combining this mystical plant-based brew with SSRIs due to the risk of serotonin syndrome. Still, there’s no concrete evidence that combining the two will cause serotonin syndrome. As the story often goes with psychedelics, more research is needed to fully understand the interaction.

Similar to most psilocybin retreats, organizations that run ayahuasca ceremonies also commonly turn down applicants who are prescribed SSRIs. The Peruvian ayahuasca retreat Lotus Vine Journey, for instance, advises that visitors stop taking SSRI medications (with the blessing of their doctor, of course) at least six weeks prior to their workshop.

The silver lining: Ketamine treatment shows promise

You might be thinking about how a majority of these studies are highly discouraging for people using antidepressants and looking to incorporate psychedelics into the healing process. It’s important to reiterate that more research is needed to fully comprehend whether different psychedelics are effective in treating depression, as well as how antidepressants could stifle these apparent benefits.

One promising sign for those suffering from depression is the early success of ketamine treatment. A medication commonly used for starting and maintaining anesthesia, ketamine induces a trance-like state and is increasingly being used to treat depression and pain.

Unlike studies involving most other psychedelics, studies involving ketamine have found it to be an effective replacement for traditional antidepressants. Moreover, evidence suggests that people on SSRIs can still reap the benefits of ketamine treatment without any diminished response.

In 2019, the FDA approved the first ever ketamine-based antidepressant, a major milestone in the search for alternatives to SSRIs. While antidepressants often take months to be effective and must be taken regularly to work, a single dose of ketamine has proven to have lasting effects on subjects suffering from depression.

Although ketamine has proven itself to be a viable tool in depression treatment, we still have a long way to go before we can assuredly say the same about psilocybin, LSD, MDMA, ayahuasca, and other psychedelics.

“You can be on antidepressants and still have a full ketamine experience,” Dr. Holland says. “But what happens when you’re on antidepressants and you have psychedelics? It seems, from what I’m hearing from some people, that there’s a blunted response, but there’s no double-blind, placebo controlled randomized trial to back up what I’m hearing from people anecdotally.”

 
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Pain and psychedelics: Drug interactions with analgesics

SPIRIT PHARMACIST | 10 Dec 2019

This is the second of two installments on pain and psychedelics. In the first installment or Part I (above), I cover mechanisms of psychedelic action in the context of pain, suffering and philosophy. In this installment I cover drug interactions with different classes of analgesics.

Pain and analgesics: Psychedelic healing, set, and setting

There are many different types of analgesics and pain medications available, each of which has different mechanisms, effects, risks, and interactions with psychedelics. Therefore, we’ll take a class by class approach in this guide. Generally speaking, psychedelic healing works via the heightening of senses, expression or feeling of emotion, and (hopefully) resolution of repressed emotions. Pain relievers or analgesics are drugs that act to suppress pain signals or modulate emotions in a way that suffering is decreased. From this perspective, there is a possibility for counterproductive effects between analgesics and psychedelic-assisted psychotherapy. Counterproductive effects may be further increased by agents that have strong effects in the Central Nervous System (CNS) such as opioids. On the flip side, analgesic agents may increase physical comfort and reduce sympathetic nervous system (fight or flight) arousal due to painful conditions. This could confer beneficial effects on user ‘set’ and the depth of their experience.

When pain conditions are present, the psychedelic user should inquire into and reflect upon any drug or non-drug based modifications that would preserve user ‘set’ or improve user ‘setting’. Adjustments can be made to the physical setting, such as allowing an individual with orthopedic hip and knee injuries to use a comfortable chair to sit in opposed to having them sit on the ground. Many pain medications have the tendency to cause physical or psychological dependence. Discontinuing pain medication may be so damaging to user ‘set’ that they aren’t able to actively participate in their experience. For example, if the user has advanced illness or severe chronic pain (e.g. cancer) it may not be reasonable (due to physical and psychological dependence as well as medical necessity) to discontinue opioid or other pain medication. For others, use of pain medication may be problematic or unwanted. They may be approaching psychedelics in hopes of using less or stopping the use of pain medications. In these cases substance use treatment mind sets may improve outcomes and stopping use of pain medication may be intentional. In most cases (with the exception of ibogaine and ayahuasca which harbor severe physical risks in combination with analgesics), use of pain medication is primarily a risk vs. benefit decision the user can assess based upon their pain condition and goals of analgesic use. A comprehensive assessment of pain conditions as well as their treatments is an essential part of preparing for a therapeutic psychedelic experience.

Over the counter (OTC) analgesics

There are a few different classes of pain relievers that are sold over the counter (OTC) in the United States including acetaminophen/paracetamol (Tylenol), ibuprofen (Motrin, Advil), naproxen (Aleve), and Aspirin. Generally, these medications do not pose any risk of physiological danger in combination with psychedelics, including psychedelics that contain MAOIs such as ayahuasca.

Acetaminophen (Tylenol, paracetamol)

Interestingly, there is an emerging body of research, particularly with acetaminophen (Tylenol) demonstrating that OTC pain relievers can have effects on emotional processing and behavior. It was demonstrated that acetaminophen (Tylenol) has the ability to blunt emotional processing to both positive and negative stimuli. It can also reduce effects of pain secondary to things like social rejection. It appears that it can interfere with our judgement of errors and make us more apathetic to mistakes. The site of interference in error evaluation appears to be in the cortex, which is a site in the brain targeted by psychedelics via their stimulation of 5HT2A receptors. Evidence for an effect on emotional processing is less well established with other OTC analgesics, although ibuprofen has also been shown to have a sex specific effect on emotional processing. How strong these effects on the interference of emotional processing are and whether they could influence psychedelic healing processes in a clinically significant manner is unknown. OTC analgesics have been permitted to be used in protocols of clinical trials utilizing psychedelics to date.

Non-steroidal anti-inflammatory drugs (NSAIDS)

Another more theoretical area of drug interaction involves effect on the immune system and inflammatory responses. Non-steroidal Anti-Inflammatory Drugs (NSAIDS) such as ibuprofen, naproxen (and several other prescription agents such as meloxicam, diclofenac etc.) work by blocking the production of pro-inflammatory mediators termed prostaglandins. Psychedelics are known to have immunomodulatory and anti-inflammatory effects, thus there could be an immune system mediated interaction. The significance of this interaction, if any, is unknown.

Aspirin

Aspirin has a similar mechanism of action to NSAIDS, although low daily doses are often used for advanced cardiovascular conditions. Therefore, when use of low-dose or daily aspirin is reported, a contraindicated condition to psychedelic use may be present.

Due to the benign nature of OTC analgesics from a physical perspective when used with psychedelics and lack of perceptual psychoactive effects, their benefits still likely outweigh risks of interference with emotional processing for minor aches and pains before or after psychedelic experiences. For example, OTC analgesic use prior to psychedelics to relieve menstrual cramps may improve ‘set’ of the user enough to be worth the risk of blunted emotional processing. Similarly, a mild-moderate tension headache is a common side effect the day after psilocybin use and if adequately relieved by an OTC analgesic, it may allow for a less distracted period of reflection in the immediate post-use period, creating a compelling benefit. Conversely, for a new pain or a pain that becomes exacerbated by psychedelic use without an explanatory provocation, it may be preferable to attempt working through pain using psychosomatic processing or other non-drug related methods rather than taking analgesics.

Neuropathic analgesics

Nerve pains are often described as stabbing, shooting, tingling, or burning types of pains and are treated with a variety of analgesics. These analgesics are almost universally active in the CNS and many share therapeutic overlap with other psychiatric or neurologic illnesses including depression, anxiety, and seizure disorders. The only neuropathic agents that are not CNS active involve topical remedies.

Antidepressants

I discuss interactions with antidepressants used for nerve pain such as duloxetine (Cymbalta) and amitriptyline (Elavil) elsewhere. Psychedelics, either in macro or micro doses, may be effective agents in pain conditions. It’s a logical hypothesis to test: if antidepressants work for depression, anxiety nerve pain, or fibromyalgaia and psychedelics also work for depression, anxiety, and have anti-inflammatory effects, that they may have potential to impact nerve pain too.

Gabapentinoids

The gabapentinoids include the agents gabapentin (Neurontin) and pregabalin (Lyrica). They are used for neuropathic pain and anxiety disorders primarily, although gabapentin is also an antiepileptic agent. There is likely some mild interaction potential between gabapentin, pregabalin and psychedelics that may blunt the experience, although user anecdotes don’t support a strong interaction and in a clinical study of MDMA for PTSD, they allowed users to remain on gabapentin when used for pain. There is no rationale to believe that gabapentin or pregabalin would have a high risk of serotonin syndrome or other severe adverse reactions if combined with ayahuasca. Speculatively, they may diminish effects of ibogaine or ketamine due to GABAergic activity.

Both gabapentin and pregabalin have dependence when taken for extended periods of time and can cause withdrawal syndromes if not tapered appropriately. Therefore, in persons with neuropathic pain that are getting a beneficial effect from these agents, it is reasonable to simply continue them. For persons using lower doses for anxiety disorders, tapering the medication over a period of a few weeks may be considered instead.

Opioids

Opioids is an umbrella term that encompasses drugs that produce an analgesic effect by binding with μ-opioid receptors. It includes both naturally derived drugs such as codeine, morphine, and heroin (opiates) as well as synthetics such as oxycodone, methadone, buprenorphine, tramadol, and others. Opioids are notorious for leading to dependence, tolerance, and substance use disorders (addiction) and harms associated with opioids are currently epidemic in the US. They are regulated as controlled substances and produce sedative effects on the CNS, which can lead to fatal respiratory depression in overdose. Drugs that depress CNS activity, tend to generally have blunting effects on psychedelics, although how significant this effect is may depend on individual factors such as tolerance, dose, or the agent(s) used. If an underlying opioid use disorder is present, then the psychedelic ibogaine would likely be of most benefit, although is limited by potential for fatal arrhythmia.

Opioids are oftentimes used for the short-term management of severe pains associated with post-surgical pain, acute physical trauma, or pain flares associated with various medical conditions. For these indications they may be offered ‘as needed’ and taken for such a short period of time or so sparingly that physical dependence does not occur. For the opioid user that doesn’t have a physical dependence on opioids, it is likely best and relatively easy to avoid them for at least 72 hours prior to psychedelic use, which is the timeframe that it could be expected that most opioids used on an as needed basis are eliminated from the body. If persons are experiencing an acute pain flare requiring as needed opioids, it may be best for user set and setting to simply postpone the psychedelic session until the individual is no longer in high amounts of pain and using opioids.

In users of opioids for the treatment of chronic pain in which a substance use disorder is not present, then the choice of psychedelic and management approach is important. Some opioids are contraindicated with ayahuasca or ibogaine. For life-threatening illness or illness in which opioids are medically necessary, continuation of long-acting opioids may be necessary for comfort in user ‘set’.

Which opioids can you combine with ayahuasca?

While opioids all share their activity at μ-opioid receptors, some of them have additional pharmacology at serotonin and norepinephrine reuptake pumps that could introduce serious drug interaction potential with MAOI containing psychedelics such as ayahuasca. The opioids methadone (Dolophine), meperidine (Pethidine), tapentadol (Nucynta), and tramadol (Ultram) and dextromethorphan all have some weak affinity for the serotonin reuptake pump and have been implicated in cases of serotonin syndrome when combined with MAOIs. Therefore, these agents should be either avoided or discontinued at least 5 half-lives ahead of ayahuasca use. The opioids hydrocodone, oxycodone, buprenorphine, morphine, hydromorphone, oxymorphone, heroin and codeine do not have activity at the serotonin reuptake pump and have not been implicated in cases of serotonin syndrome.

Have opioids and psychedelics ever been combined in clinical trials with other psychedelics?

It is relatively common for opioids to be prescribed for pain associated with illnesses such as late stage cancers. In clinical trials of psilocybin assisted psychotherapy for life-threatening illness in which many participants had late stage cancer, the use of long-acting opioid medications (e.g. sustained release morphine or oxycodone) administered every 12 hours were permitted to be used concurrently per the clinical trial protocol. The protocol stipulated that psilocybin administration would be timed 6 hours after the ingestion of their opioid and 6 hours prior to their next dose of opioid. Therefore, it appears their strategy was to time the dose of psychedelic the farthest possible from the previous opioid dose, while still allowing time for the psilocybin experience to unfold prior to the next opioid dose. For serotonergic psychedelics that do not contain an MAOI, such as MDMA, psilocybin, or short-acting inhaled tryptamines (5-MeO-DMT), this strategy would seem to be adaptable. For other serotonergic psychedelics such as LSD or mescaline, the length of the psychedelic effect may present challenges for use of this strategy. Notably, while the trial protocol permitted long-acting opioids, it’s unclear how many trial participants were actually taking them or if their results differed from others in the trial.

How are opioids used with ibogaine?

When ibogaine is used in a person that uses opioids, it is typically with the intention of managing opioid use disorder (OUD) rather than helping mood or having an analgesic effect in a person with chronic pain. Ibogaine is contraindicated to be used in conjunction with long-acting or extended-release formulations as well as the Medication Assisted Treatment (MAT) drugs methadone and buprenorphine. This is because ibogaine is known to sensitize the user to opioids back to pre-opioid use levels, thus opioid use while on ibogaine can be dangerous and increase risks for overdose. Another risk is arrhythmias and cardiotoxicity, which is worsened considerably by methadone. Therefore, ibogaine use should be attempted only in the opioid user that wants to stop using opioids completely and is on a short-acting opioid prior to ibogaine use.

Ketamine

Ketamine is more accurately classified as a dissociative anesthetic rather than a psychedelic. Given anesthetics have sedative properties, there could be additive risks of sedation or respiratory depression when ketamine or opioids are combined. This can become excessively dangerous with high doses, unmonitored environments, or use of other sedatives like GHB, alcohol, or benzodiazepines. Serotonergic psychedelics are likely lower risk psychedelics to use in combination with opioids when it comes to ketamine. Other pain medications such as OTC analgesics possess minimal risk in combination. There may be some theoretical interactions between drugs that interfere with GABA such as the gabapentinoids (gabapentin, pregabalin), although these interactions are not well documented if they are real.

Conclusions

OTC analgesics are low risk with many psychedelics and can be used to help with minor aches and pains that come up around the time of psychedelic use. Prescription agents to manage pain taken on a chronic basis are more complex and should be assessed in the context of user ‘set & setting’ to optimize potential for healing psychedelic experiences. Ketamine has some additional risk with sedative analgesics like opioids, although is combined in clinical practice for opioid-sparing effects. Ayahuasca and ibogaine are special cases in which scrutiny for drug interaction that has physical risks should be assessed, particularly with opioids.

 
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Drug interactions between stimulants & psychedelics*

by Benjamin Malcolm | SPIRIT PHARMACIST | 6 Jun 2019

Stimulants are many things to many people. For some they are about focus, productivity, and being ‘smart’…it seems that many are searching for an edge when it comes to task accomplishment, goal-oriented activity, or management of attention deficit disorders. For others, they have become disordered habits or even addictions and they are stuck in cycles of binging and crashing. Others still, use them to boost energy associated with depression or fatigue syndromes, manage weight loss or binge-eating, avoid narcoleptic episodes, and to ‘power through’ congestion and colds. As psychedelic use becomes a dinner table conversation in millions of households, more and more people are attracted to them for management of clinical conditions in larger doses or even boosting focus and productivity in microdoses.

But what are the risks of using stimulants with psychedelics, and can it be counterproductive?

Physical risks seem mostly related to additive stress on the cardiovascular system, while psychological risks are more theoretical, but do include potential for counterproductive effects. In this article, we’ll explore these questions with a focus on combinations of psychedelics with traditional prescription stimulants used by mouth.

What are stimulants anyway?

Psychostimulants (stimulants) have long histories of use and are commonly used for both recreational and therapeutic purposes. They have been used since time immemorial for increased stamina, wakefulness, or euphoric effects. Examples of plants with naturally occurring stimulants are coffee and tea (caffeine), Ma Huang (ephedrine), Khat (cathinone), and Coca (cocaine).

The most common therapeutic stimulants are various forms of amphetamine (Adderall; Dexedrine; Lisdexamfetamine; Desoxyn; several other brand products) and methylphenidate (Ritalin; Concerta; several other brand products). These stimulants will be referred to as ‘traditional stimulants’ throughout the rest of this article and serve as the focus of discussion when it comes to combining stimulants with psychedelics. Traditional stimulants provide a stimulating effect to the central and sympathetic nervous systems. They promote the release of neurotransmitters such as norepinephrine and dopamine which lead to wakefulness, increased energy, decreased fatigue, and euphoria. They also activate ‘fight or flight’ responses to increase blood pressure and heart rate as well as dilate airways.

Other stimulants include modafanil (Provigil) and Armodafanil (Nuvigil). These are utilized less than traditional stimulants, although are becoming popular for use as ‘neurohacking’ agents to boost cognitive performance in persons without attention deficit disorders. Stimulants can be used as decongestants (pseudoephedrine), anorectic weight loss aides (phentermine), or antidepressants (bupropion). In addition, supplements that make claims of being ‘metabolism boosting’ frequently contain either natural or synthetic stimulants.

Can psychedelics also be stimulants?

Yes they can, and some stimulants are indeed dually categorized as psychedelics and stimulants. For example, the phenylethylamine chemical backbone of MDMA and mescaline is shared with d-amphetamine and methamphetamine. There are myriad Novel Psychoactive Substances (NPS) derived from phenyethylamine such 2Cx, DOx, NBOMe compounds. Other NPS use a cathinone chemical backbone and are collectively referred to as ‘bath salts’. Substances like methylone or mephedrone are psychedelic cathinones reported to mimic effects of MDMA. Generally, phenylethylamine or cathinone psychedelics have predominately serotonergic activity along with norepinephrine and dopamine activity, whereas stimulants like dextroamphetamine (d-amphetamine) or methamphetamine have predominately norepinephrine and dopamine activity with relatively minor effects on serotonin. This general rule may not apply in all cases of NPS as each of these substances has a distinct pharmacologic profile that may alter risks in combination with other drugs including stimulants. For example, the stimulant para-methoxyamphetamine (PMA) features monoamine oxidase inhibition (MAOI) as part of its pharmacologic profile, which can increase the risk of serious toxicity and death. It is outside the scope of this article to discuss all NPS, and MDMA will serve as the focus of discussion of combinations of traditional and psychedelic stimulants due to having the most data available and being the farthest along in clinical development.

Table. Overview of Stimulant Structures:



How does stimulant use pattern and route of administration interface with intentions of psychedelic healing?

Stimulants tend to be habit forming, carry the potential risk of developing substance use disorders, and many are regulated as controlled or illicit substances. When stimulants are used in large quantities, increased frequency, or by a route of administration (ROA) such as insufflation (snorting), inhalation (smoking), or injection they cause immediate and intense effects that carry considerable cardiovascular and psychological risks in and of themselves. Common recreational stimulants used by these ROA include amphetamine, methamphetamine, and cocaine. Physical adverse effects include stroke, heart attacks, seizures, muscle breakdown, or kidney failure while psychologically, paranoia, psychotic symptoms, agitated and aggressive behavior, craving and dependence can occur. If you are seeking to use psychedelics for management of a stimulant use disorder then ibogaine has the best evidence for benefit, although ayahuasca and 5-MeO-DMT have also been touted as helpful. Comprehensive review of psychedelics for treatment of stimulant use disorders is outside the scope of this article. While cognitive liberty supports the psychonaut’s right to explore these ROA, it seems unlikely that these methods of stimulant use are aligned with intentions of using psychedelics to facilitate healing processes. Therefore, the duration of the article will explore potential risks and management strategies of combining traditional stimulants used by mouth for therapeutic purposes with psychedelics.

What physical risks are there when combining stimulants and psychedelics?

The main (acute or short-term) physical responses of combining stimulants with psychedelics are additive increases in blood pressures, heart rates, and thermodynamic responses (increased body temperatures). These could lead to risks of adverse events such as arrhythmias, heart attacks, stroke, kidney failure, or seizures. How severe these risks are likely depend on a number of factors including characteristics of the user, route of administration (ROA), dose, and particular combination used. When it comes to adverse effects as a result of stimulants our old friend Paracelsus is insightful:

“What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison” – Paracelsus

Persons that are elderly or have existing cardiovascular conditions such as high blood pressure, arrhythmias, or histories of heart attack and stroke would be at the greatest risk of physical adverse effects of psychedelic stimulants such as MDMA as well as combinations between stimulants and psychedelics. In phase II clinical trials, doses of MDMA (75-125 + booster 37.5-62.5mg) increased systolic blood pressure (SBP) by an average of 25 mmHg, diastolic blood pressure (DBP) by 12mmHg and heart rate (HR) by 28bpm. Therefore, these values may be helpful in guiding potential cardiovascular responses to MDMA. If blood pressures, heart rates, or other aspects of cardiovascular function are a concern, beyond avoiding use, antihypertensive drugs such as clonidine and carvedilol have been shown to attenuate cardiovascular responses to MDMA without interfering with subjective effects.

Is there a hierarchy to risk when it comes to combining stimulants and psychedelics?

As far as psychedelics commonly used with healing intentions, those that contain a MAOI such as ayahuasca are likely the highest risk followed by psychedelic stimulants like MDMA. Tryptamines appear to have lower physical risks in combination with stimulants, although can still elevate blood pressures and heart rates. We’ll explore various risks of these combinations now:

I. Stimulants + MAOI containing Psychedelics (Ayahuasca)

These combinations can carry risks of severe physical toxicities including hypertensive crisis and Serotonin Syndrome. The most dangerous drugs to take in combination with MAOIs are drugs that block serotonin reuptake as well as drugs that release serotonin. Neither methylphenidate nor amphetamine do this to a significant extent and slow introduction of stimulants to MAOI regimens have been used historically with expert oversight. However, risk of extreme hypertensive responses to the combination of stimulants and MAOIs has occurred and cases of harm have typically featured intracranial bleeding as result of very high blood pressures rather than Serotonin Syndrome. Risk of developing Serotonin Syndrome is higher when combining psychedelic stimulants that release serotonin such as MDMA opposed to traditional stimulants.

Bottom Line: Stimulants can be hazardous with MAOIs and discontinuation is the safest practice.

II. Stimulants + Phenylethylamine Psychedelics (MDMA)

Since phenylethylamine psychedelics such as MDMA and mescaline are themselves psychostimulants, there may risks of additive stimulant effects when combined with amphetamine or methylphenidate products.

One study investigated differences between placebo, methylphenidate, MDMA and the combination of methylphenidate and MDMA in healthy volunteers. They found that methylphenidate (60mg) did not enhance psychoactive effects of MDMA (125mg) or have additive effects on core temperature increases when used in combination. The hemodynamic response (combination of blood pressure and heart rate effects) was significantly higher when MDMA and methylphenidate were combined compared to each drug alone. They also found higher rates of subjectively reported adverse effects, however no severe adverse effects were observed. There is very little research on the effects of combining amphetamines with MDMA from a laboratory setting since most studies have aimed at comparing them to elucidate potential differences. However, similar to methylphenidate, there is a high degree of plausibility that there are additive effects on the cardiovascular system. MDMA and amphetamines are not uncommon to combine in recreational settings either via separate drug ingestions or due to impurities in ecstasy tablets. It is likely that impurities in ecstasy tablets or combination with other psychostimulants has contributed to situations in which toxic effects including death have been reported. For a number of reasons results from recreational literature are not likely very generalizable to persons taking therapeutic doses of traditional stimulants who wish to use psychedelics for healing. Nonetheless, the body of literature from recreational settings could be used as a harbinger of potential dangers when psychedelics and stimulants are combined in high doses or unsafe environments.

Bottom line: Given higher cardiovascular stress, increased reports of adverse effects, and lack of enhancement of psychedelic effects, it appears there is little to gain by combining stimulants with MDMA and potential for increased risks.

III. Stimulants + Tryptamine Psychedelics (Psilocybin, LSD)

Classic tryptamine psychedelics like psilocybin or LSD appear to be the least risky to combine since there is no mechanistic overlap in release of neurotransmitters or blockade of neurotransmitter reuptake. Tryptamine psychedelics do cause some amount of vasoconstriction and are associated with increased blood pressures or heart rates so some risk likely still exists. There is little (if any) research from clinical settings observing effects of combining stimulants with psychedelics. Some tryptamines, such as 5-MeO-DMT, lack basic studies characterizing cardiovascular responses to administration and are difficult to predict risk with for this reason. Recreationally, psychedelic psychostimulants like MDMA are often combined with psilocybin mushrooms or LSD and referred to as a ‘hippy flip’ or ‘candy flip’. There is little literature supporting combinations drastically increase physical risks, although do lead to intensified psychological experiences, and should be approached with caution.

Bottom Line: Stimulant discontinuation should be considered based upon intentions of use and individual risk assessment.

Are there psychological risks of combining stimulants with psychedelics?

There are some interesting differences found in psychological tests and rating scales between traditional stimulants and psychedelics as well as pharmacologic observations that may carry implications for healing effects. The emphasis is on may here due to the largely theoretical nature of this discussion and the reader is encouraged to approach the section with healthy skepticism.

I. Focus, psychosis, and surrender

Traditional stimulants boost dopamine and norepinephrine levels, which has been associated with the therapeutic effects of increased focus, concentration, motivation, and energy. There is often much emphasis placed on allowing non-linear modes of thinking, non-directive therapeutic approaches, periods of silence, and ‘surrendering’ to the effects psychedelics when discussing optimal navigation of psychedelic states in psychedelic assisted psychotherapy. This may lead one to wonder if drugs that enhance aspects of logical or rational cognitive abilities would affect the healing mental processes that are active under the influence of psychedelics. It is unclear if a drug that increases focus could modulate an individual’s ability to ‘surrender’ or interfere with non-linear thinking.

In addition, traditional stimulants are often used as a pharmacologic model of psychosis due to psychotic symptoms caused by excessive dopamine signaling. Among neuroscientists, psychedelics have also held long-time interest as potential pharmacologic probes in models of psychosis. Originally, psychedelics were termed ‘psychotomimetic’ due to the observation that the user appeared to be in a psychotic state while under their influence. Emotional discomfort, panic, paranoia, and delusional states often occur transiently with psychedelics and have been reported in clinical trials. It is unknown if stimulant and psychedelic combinations may increase risk of transient psychotic symptoms like paranoia at low-moderate doses in controlled settings.

II. Facial recognition

Psychedelic stimulants such as MDMA have been found to decrease the ability of an individual to accurately identify faces displaying negative emotions leading to positive emotion misclassification. Conversely, the traditional stimulant methylphenidate increases recognition of faces displaying negative emotion and misclassification of faces displaying positive emotion. The effects of MDMA on facial recognition is postulated to be a favorable component of the drug’s pharmacologic profile as it may be related to its pro-social effects or therapeutic effects in PTSD or social anxiety in autistic adults. It is unknown how these seemingly opposed effects on facial recognition tests may effect therapeutic uses of psychedelics.

III. Stimulants, psychedelics and the ego

The ego can be defined as a person’s sense of ‘who they think they are’ and is thought to correlate with the portion of the mind that is self-referential and constructive of a sense of personal identity. In contemporary neuroscience, this is often mapped to a set of functionally interconnected neural circuits collectively termed the Default Mode Network (DMN). The effects of several tryptamine psychedelics such as ayahuasca, LSD, and psilocybin have demonstrated that they globally diminish DMN activity and that this effect is correlated with a subjective sense of ‘ego-dissolution’ and spiritual or mystical experience. In turn, mystical experiences have been linked to improvements in mindfulness and longer term psychosocial functioning. On the flip side, stimulants are known to increase self-confidence or a sense of superiority and have been classified as ‘ego-inflating’ drugs. A two factor scale termed the Ego Dissolution Inventory (EDI) was designed to discriminate between drugs with ‘ego-dissolving’ vs. ‘ego-inflating’ characteristics. When tested in a large online sample it was found that psychedelics are strongly correlated with ego-dissolution while cocaine was strongly correlated with ego-inflation. These observations may carry implications for interactions between psychedelics and stimulants. If the intention is use of a tryptamine psychedelic to create a state of consciousness in which the ego is dissolved, then it may not be favorable to combine them with stimulant drugs with ego-inflating properties. However, MDMA has demonstrated therapeutic properties in several phase II trials and has pharmacologic properties of both stimulants and psychedelics. It is unknown if the overall effects of MDMA are ego-dissolving or ego-inflating. The fact that MDMA can offer healing and exist as both a stimulant and a psychedelic may render the perspective that ego-dissolving and ego-inflating drugs are incompatible in healing processes as reductionist or inaccurate.

Risk mitigation

Use of concurrent stimulants have not been permitted in studies of MDMA- or psilocybin-assisted psychotherapies to date. Therefore, research has set a precedent of discontinuing stimulants prior to therapeutic psychedelic use. This is likely done for two reasons: The first is fear of introducing risks discussed above and the second is to keep the experiment pure and prevent confounding their results with other drugs. It appears that psychedelics largely retain their effects when combined with stimulants and cross-tolerance has not been observed in laboratory settings. Thus it is conceivable that stimulants and psychedelics may not be considered absolute contraindications if psychedelic-assisted psychotherapy became Food and Drug Administration (FDA) approved (especially with psilocybin). That being said, the most reassuring method of reducing risk and optimizing potential benefit is discontinuation of stimulants.

Stimulants have withdrawal syndromes characterized by low mood, irritability, fatigue, and lowered motivation. Typically this last 7-14 days, although can be persistent beyond this time frame. Many persons taking stimulants for therapeutic purposes do not take them on a daily basis. For adults with attention deficit disorders, it is common to take a stimulant during the workweek and take a ‘drug holiday’ each weekend. For persons taking relatively low doses of stimulants whom do not report severe withdrawal syndromes or those accustomed to taking drug holidays, it is relatively simple to discontinue stimulants. For persons accustomed to everyday use, taking higher doses, or those that experience severe discontinuation syndromes, then tapering the dose of stimulant would reduce discontinuation symptoms and risk of clinical decompensation. It is recommended to not discontinue psychotropics without support and oversight from your providing prescriber. Recruitment of additional support systems such as friends, family, community, a therapist, or a psychedelic integration coach is desirable.

Stimulants are rapidly eliminated from the body and it is predicted that methylphenidate would be completely eliminated after 24-48 hours (half-life ~2-6 hours), while amphetamine products completely eliminated after 48-72 hours (half-life ~12 hours). Depending on intentions of psychedelic use and the individual’s relationship to stimulants, consideration of longer discontinuation times prior to use may be reasonable. When prominent withdrawal effects are present, it may be best to wait until the withdrawal symptoms have run their course before engaging with psychedelics. If desired and aligned with intentions of psychedelic use, it is predicted to be safe to resume stimulants 24 hours after using a psychedelic without a MAOI and 48 hours after psychedelics containing a MAOI (ayahuasca).

Summary and conclusions

Combinations of psychedelics and stimulants are somewhat less clear cut than drugs that directly interfere with psychedelic effects like antidepressants. Research in psychedelic-assisted psychotherapy has set a precedent for stimulant discontinuation prior to psychedelic use, while stimulant and psychedelic combinations are common in recreational settings. There is mechanistic overlap between some psychedelics and stimulants, although differences are also apparent. Stimulant management with psychedelic use is likely personal and multifaceted. The users’ baseline cardiovascular status, particular drug combination planned, doses of drugs, and intentions for psychedelic use are important principles in guiding decision making when it comes to navigating psychedelics and stimulants.

*From the article here :
 
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“What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison” – Paracelsus

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Antidepressants and Psychedelics: What do we know, and what are the risks?​


by Camile Bahi | Mind Foudation | 11 Sep 2020

Most recent clinical trials with psychedelics either asked participants to stop taking their antidepressant medications before enrolling, or they rejected patients that were taking antidepressants. Similarly, some psychedelic retreat centers only allow participants who are not currently taking antidepressants.

As psychedelics have shown initial promise for hard-to-treat depression, an often-raised concern relates to the possible risks of the interaction between antidepressant drugs and psychedelics. This article aims to investigate this issue and provide some preliminary answers.

Classical psychedelics are defined by their ability to act as serotonin receptor agonists, particularly at the Serotonin 2A receptor (5HT2AR). Accordingly, many of the subjective and biological effects of classical psychedelics are blocked after administering 5HT2AR antagonists such as ketanserin. Classical psychedelics have been shown to be relatively safe in the context of clinical trials, with notable side effects being mild headaches, small elevations in blood pressure, and acute anxiety, none of which commonly require medical intervention. Although the exact mechanisms of action and the pharmacokinetics of these molecules are not completely understood, two particular issues have been raised when it comes to their interaction with antidepressant drugs: the so-called serotonin syndrome and a decrease in subjective psychedelic effects.

Serotonin Syndrome: Antidepressants and psychedelics

Serotonin syndrome is a potentially lethal adverse drug reaction that is most likely to occur when two compounds able to raise serotonin neurotransmission are taken simultaneously. However, it is also known to occur after only one such compound. Serotonin is produced from the amino acid L-tryptophan and its effects are regulated by re-uptake mechanisms, feedback loops, and enzymes such as monoamine oxidase. Serotonin acts on the nervous system both at the central and at the peripheral level. In the central nervous system, it plays a role in awareness, behavior, muscle tone, body temperature, and pain. In the periphery, it regulates vascular tone, nociception (pain perception), and gastric activity. The effects of serotonin are mediated through 7 receptors types (from 5-HT1 to 5-HT7) and at least 14 subtypes.

Serotonin syndrome has been reported in all age groups and is estimated to occur in approximately 15% of persons who overdose on SSRIs. Nevertheless, an accurate incidence rate of this syndrome is difficult to obtain because its symptoms lack specificity, and because of the lack of awareness concerning this condition among physicians. A survey found that 85% of physicians were unaware of the existence of this toxidrome.

The severity of serotonin syndrome can vary from mild to life-threatening. Its symptoms are often described as a clinical triad: neuromuscular abnormalities (such as tremor or muscle hypertonicity leading to hyperthermia), autonomic nervous system hyperactivity (leading to increased heart rate and diarrhea), and changes in mental state (such as agitation or delirium; see figure 1 for an overview).



Figure 1: Spectrum of clinical symptoms: Manifestations of the serotonin syndrome range from mild to life-threatening. The vertical arrows suggest the approximate point at which clinical findings initially appear in the spectrum of the disease, though not all characteristics always present themselves in a single patient with serotonin syndrome. Severe signs may mask other clinical findings. For example, muscular hypertonicity can overwhelm tremor and hyperreflexia.
The precise pathophysiology of serotonin syndrome is not completely understood, but it appears to result from an excess in serotonin neurotransmission. It is not linked to a single serotonin receptor, even though it is suggested that 5-HT2A receptors substantially contribute to the condition. Other receptors, such as 5-HT1A, appear to also contribute to it when serotonin concentrations reach a point where all other receptor subtypes are saturated (see figure 2 for a visualization). Other neurotransmitters, such as norepinephrine, may also play an important role in this syndrome: for example, an increase in CNS norepinephrine concentration during serotonin syndrome correlates with more severe symptoms. Dopamine could also be involved, since an increase in dopamine neurotransmission can indirectly trigger serotonin release.


Figure 2: ^^Diamond = drug-blocking 5-HT uptake; shaded circles = 5-HT; star = direct acting 5-HT agonist.^^
Mechanisms of Serotonin Syndrome :
1) Increased doses of L-tryptophan will proportionally increase 5-hydroxytryptamine (5-HT or serotonin) formation.
2) Amphetamines and other drugs increase the release of stored serotonin.
3) Inhibition of serotonin metabolism by monoamine oxidase (MAO) inhibitors will increase presynaptic 5-HT concentration.
4) Impairment of 5-HT transport into the presynaptic nerve by uptake blockers increase synaptic 5-HT concentration.
5) Direct serotonin agonists can stimulate postsynaptic 5-HT receptors.
6) Lithium increases postsynaptic receptor responses.

In most countries, prescribing more than one serotonin medication at once is contraindicated, since this can lead to serotonin syndrome. As detailed in Table 1 below, every medication that increases serotonin neurotransmission can be involved in its pathogenesis. Most cases involve SSRI or monoamine oxidase inhibitor (MAOI) drugs, taken simultaneously with at least one other medication raising serotonin levels. Combining drugs that differentially increase serotonin neurotransmission is more likely to induce severe serotonin syndrome.


Table 1: Drugs Associated with Serotonin Syndrome.

There is no empirical data on the interaction between psychedelics and antidepressants, and whether this raises the risk of serotonin syndrome. Nevertheless, it is well-known that psychedelics have 5-HT2AR agonist properties, therefore increasing 5-HT2AR neurotransmission. Thus, from a pharmacological point of view, it seems likely that their co-administration with serotonergic antidepressants could induce serotonin syndrome. Accordingly, it could be dangerous to mix psychedelics with any type of medication that increases serotonergic neurotransmission.

Furthermore, it is important to note that several psychedelics, such as LSD and 5-Meo-DMT, are metabolized by CYP2D a liver enzyme that is involved in metabolizing many substances. At the same time, SSRIs are both a substrate and an inhibitor of this enzyme. This means that CYP2D is less available for metabolizing both psychedelics and SSRIs, resulting in an increase in blood concentrations of serotonergic substances, which is associated with the induction of serotonin syndrome.

For this reason, it is recommended to taper antidepressant medication before engaging in any psychedelic therapy or usage. Moreover, since administration of serotonin agents within five weeks after the discontinuation of SSRIs has been shown to induce serotonin syndrome, it appears to be safer to wait for at least five weeks before using any psychedelic compound.

Antidepressant drugs blunting subjective psychedelic effects

In addition to the risk of serotonin syndrome, the subjective effects of the psychedelic experience may be altered if psychedelics are combined with antidepressants. Anecdotal evidence suggests that the acute use of SSRIs, as well as chronic use of tricyclic antidepressants, can alter the subjective effects of psychedelics. Regarding tricyclic antidepressants, this observation could be related to postsynaptic receptor sensitization and increased dopamine levels, which indirectly lead to an increase in serotonin neurotransmission.

Conversely, chronic administration of SSRIs or MAOIs have been shown to decrease the subjective effects of psychedelics. Concerning SSRIs, a possible reason for this could be that the chronic administration of SSRIs causes downregulation of 5-HT2AR receptors. This, in turn, may make someone less sensitive to substances affecting these receptors, such as psychedelics. Therefore, this decrease in subjective effects may result from 5-HT2AR downregulation. Concerning MAOIs, chronic administration has been shown to trigger serotonin receptor desensitization, which could explain the observed decrease in subjective psychedelic effects.

The precise mechanisms underlying the modulation of the psychedelic experience by antidepressants are still unclear, and further research should be conducted in order to gain a better understanding. Moreover, the risk of serotonin syndrome cannot be ignored due to the observation of blunted subjective effects of psychedelics following 5-HT2AR down-regulation. Specifically, it might be the case that serotonin syndrome depends on the rate of occupied 5-HT receptors, whereby a higher rate of occupied receptors could be reached more easily when the global number of receptors is lowered. Moreover, several inter-individual variations, such as genetic variations in the enzymes responsible for drug metabolism, could also play a role in the occurrence of serotonin syndrome.

Some concluding thoughts

It is impossible to state with certainty what the relationship is between serotonin syndrome and the pharmacology of psychedelics. Current knowledge is insufficient for formulating an accurate assessment of the risk, or a model of the modulation of both subjective and physiological effects arising from the combination of antidepressants and psychedelic substances.

There has not been much progress in elucidating the pathophysiology of serotonin syndrome in recent years. However, since we are gaining a clearer view of the pharmacology of psychedelics, we might develop more precise recommendations for clinical work in the future.

Nevertheless, a close look at the effects of common antidepressants and psychedelic drugs on serotonin neurotransmission suggests that this combination is risky from a pharmacological point of view, and that it would be very unlikely to have clinically beneficial effects. Consequently, caution is advised when considering taking a psychedelic while on antidepressant medication.

 
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Safely and Successfully Stopping Antidepressants*

by Benjamin Malcolm | Spirit Pharmacist | 6 Jan 2021

The decision to stop antidepressants is individual and should involve and be supervised by the prescribing provider whenever possible. There are several factors that can help make the decision or weigh into the decision if it is a good time to taper. Some factors include how well the medication is working or effectiveness, how well tolerated the medication is (side effects), symptom history, sensitivity to withdrawal, life-timing and ongoing stressors, personal growth and development, as well as therapeutic support and planning.

A growing problem: Long-term antidepressant use

Antidepressants were designed and originally studied for the treatment of major depressive disorder, which is characterized by episodes of depression. While some persons do feel depressive symptoms chronically and may benefit from continuous therapy, most persons experience discrete episodes. Therefore, antidepressants were never designed to be used as chronic maintenance medications. Rather, they were designed to be used over the course of an episode, which typically lasts 9-12 months.
Since the approval of the first selective serotonin reuptake inhibitors (SSRI) Prozac in 1988 there has been a steady increase in the number of antidepressant prescriptions. At this point around 13% of the US adult population takes antidepressant medication, with whites, females, and persons over 60 seeing the most dramatic rises in use. It is mostly long-term use prescribed by general practitioners that account for the increasing number of antidepressant users. Unfortunately, many prescribing providers are unprepared to help their patients discontinue antidepressants. In the US, around 2/3 antidepressant users have been taking the medication longer than 2 years and it’s estimated that 30-50% of long-term users have no evidenced based indication to continue them.

Roadblocks to stopping antidepressants

There are many potential obstacles to stopping antidepressants, although a few themes emerge when browsing the literature. One is confidence and knowledge in ability to safely discontinue antidepressants. Patients often look to their providers for this information, however treatment-guidelines as well as manufacturer prescribing information lack evidence-based recommendations on how to discontinue antidepressants. Subsequently and unfortunately, it’s an area that providers often do not feel confident in themselves.

An interrelated theme are fears of antidepressant withdrawal syndromes. Persons may at time forget to take their antidepressant with them on vacation or attempt tapering or discontinuation of antidepressants themselves and run into bothersome and sometimes destabilizing withdrawal symptoms. Antidepressants work over a period of weeks to months to improve mood and likely induce neuro-adaptation events that leave the user with a physical (and at times psychological) dependence on the medication.

Another common fear is return of original illness. This occurs commonly and may be expected given antidepressants rarely treat the etiology of mental illness. Return of symptoms of the original illness occurs in many persons that stop antidepressants within a year, thus requires close attention and an alternative therapeutic plan is reasonable to be developed ahead of time. In this vein, persons are less likely to discontinue antidepressants when they’re working well, however treatment-refractory depression (defined as failing therapy with at least 2 antidepressants) is prevalent at around 30%.

Essentially, users find themselves ‘trapped’ on antidepressants due to mediocre efficacy, presence of significant withdrawal, and lack of knowledge as to how to taper and discontinue them.

Antidepressant withdrawal reactions

Much can happen in the time immediately after stopping or decreasing the dose of an antidepressant, creating confusion as to what the correct course of action is. Antidepressant Discontinuation Syndrome (ADS) has been defined by symptoms such as fatigue, insomnia, nausea, feeling off-balance or dizzy, sensory disturbances such as feeling abnormal sensations or ‘brain zaps’, as well as anxiety and irritability. Beyond symptoms of ADS which may be distinct and recognizable compared to symptoms of original illness, persons can also experience ‘rebound symptoms.’ Rebound symptoms are similar to those of original illness, however they are experienced almost immediately upon dose decrease and occur with greater intensity than those of original illness. Additionally, rebound symptoms resolve as the antidepressant withdrawal reaction completes itself whereas return of original symptoms may arise more slowly and after a longer time period from stopping or decreasing the dose of antidepressants. The diagram below depicts temporal differences in rebound symptoms vs. return of original symptoms.



Providers and persons taking antidepressants may take a dose step down, experience lower moods or increased anxiety almost immediately, and falsely conclude there was a return of original illness and reinstate the antidepressant. When symptoms rapidly resolve after reinstating or increasing the dose of an antidepressant it is a helpful sign in understanding that the user was having trouble related to withdrawal of medication rather than exacerbation mental illness.

Timeline and severity of antidepressant withdrawal reactions

There are considerable amounts of variability in the types of reactions persons experience when lowering their dose of antidepressant. Persons using longer than the minimum 6 weeks required to understand if the antidepressant will have a therapeutic effect are at risk for antidepressant withdrawal. Persons taking higher doses, agents with shorter-half lives (paroxetine, venlafaxine), or use of an antidepressant for a condition such as panic disorder can increase risks of withdrawal syndromes. It is reasonable to believe withdrawal symptoms emerge as the antidepressant leaves the users system. For most SSRI and related serotonin reuptake blocking antidepressants (SNRIs) onset of withdrawal occurs within 2-5 days of a dose decrease or stopping use. Withdrawal symptoms typically peak within 5-14 days and gradually resolve over 2-3 weeks in most users. Depending on the sensitivity of the individual to withdrawal and the size of the dose decrease severe symptoms (e.g. suicidality) or reactions that last longer are possible.


Rate of antidepressant taper

Current or ‘normal’ recommendations for antidepressant tapering in persons with major depression suggest ‘tapering slowly over 2-4 weeks.’ This rate of taper is too fast for most antidepressant users resulting in intolerable withdrawal syndromes and reinstatement of antidepressant use. Ideally, the rate of taper would be slow enough that the antidepressant user does not notice that they are tapering or withdrawal symptoms are limited to being mild and not bothersome. For most persons tapering over a period of 2-3 months is reasonable, although for some 4-6 months may be necessary. Antidepressant tapers are traditionally accomplished with linear step-down dosing of the antidepressant (e.g. a 25% decrease in dose every 3 weeks). Persons may find that they need smaller dose decreases the closer they get to being completely off the medication or that subsequent step downs are more difficult than initial ones. Alternative and emerging tapering strategies involve tiny decreases of the antidepressant on an almost daily basis (microtapering) or decreasing rapidly initially and slowing down as the taper progresses (hyperbolic dose reduction). There is no data to clarify if one method works better than another.

One difficulty that persons may face is finding step-down doses of their antidepressant small enough that the dose reduction doesn’t result in moderate-severe withdrawal syndromes. Antidepressants in immediate-release tablet forms can be cut using pill splitters to create smaller doses. Antidepressants in capsules or extended-release tablets cannot but cut, crushed, or chewed because it will destroy the extended-release mechanism and result in unwanted spikes and crashes and blood levels of antidepressant during the taper phase. Extended-release capsules can often be opened, contents weighed, and an amount discarded to create a smaller dose. The user should swallow extended-release beads whole in a spoonful of applesauce. Obviously, this type of solution is imprecise, tedious, and involves tampering with the medication thus is far from ideal and not recommended by most sources due to these factors. Some antidepressants are available in liquid formulations which can be used to create customized doses. One helpful solution are ‘tapering strips’ which involve custom compounded blister packs of antidepressants that have smaller and smaller doses as the taper progresses. Tapering strips can be customized depending on sensitivity to withdrawal and desired rate of step-down. They can be ordered by prescribers and shipped worldwide from https://www.taperingstrip.com/prescribing-and-ordering/

Monitoring the taper

Due to the variability in individual responses to tapering antidepressants as well as confusion between rebound symptoms or original illness it clarifies the pattern of withdrawal and planning subsequent step-down doses to monitor the taper closely. Monitoring parameters may include depression (mood), anxiety, sleep, as well as symptoms specific to antidepressant discontinuation syndrome. It is reasonable to record other interventions used or a short journal entry about the days events or other stressors that are influencing the picture. By doing this daily one can then plot their antidepressant withdrawal reaction and see it as a predictable pattern. By knowing the pattern, subsequent steps are easier as alternative interventions and support can be planned for times predicted to be rough.

To help with antidepressant tapers I created an Antidepressant Monitoring and Support Kit. The Antidepressant Monitoring and Support Kit allows persons taking antidepressant to clearly track themselves over the course of a month and plot their individual withdrawal reaction. They can then share the results with their provider to plan the next step of their taper.

Managing original illness: Emerging treatments with psychedelics

Antidepressants treat symptoms of depression as well as other psychiatric conditions which can increase a user’s functionality and significantly improve their quality of life. However, antidepressants are not thought to treat the underlying etiology and it is realistic of users stopping antidepressants to expect that they will need to grapple with symptoms of their illness once more. For some, antidepressants were effective for some time although waned in benefit over time and they are already managing illness that could be compounded by withdrawal. Identifying alternative interventions and gathering resources to treat symptoms of illness prior to tapering is a sage choice.

One emerging strategy for management of depression, anxiety, PTSD and other disorders that antidepressants are currently used for is psychedelic-assisted psychotherapy. Psychedelic therapies are intermittent and do not involve regular use. They are conducted in supervised settings and involve extensive therapy outside of psychedelic use. There is no data to support that psychedelics are helpful with antidepressant withdrawal syndromes, however there is increasingly supportive high-quality data suggesting psychedelic therapies to have high rates of success where antidepressants have previously failed. Therefore, particularly if you have tried several antidepressants without helpful effects or know you will need to treat your original illness it may be prudent to explore their healing potentials. Learn more about how antidepressants interface with psychedelics in my guide to antidepressant and psychedelic combinations.

Summing up

Antidepressant withdrawal reactions and tapering can be complex, and many persons find it much more challenging than they had expected. Learning about withdrawal and how to manage it as well as planning, monitoring, and supporting antidepressant tapers are key ingredients for success.

Additional resources and help

If you found this article to be of help, I’d highly recommend my courses or services. I’m passionate about helping persons successfully and safely taper antidepressants as well as psychedelic therapies and have much more to offer as far as help and resources!

I also offer individualized consultations regarding use of psychotropic medications and psychedelics. I provide professional risk evaluations and education sessions in which antidepressant tapering and psychedelic therapies can be evaluated and discussed.


*From the article here :
 
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mr peabody

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Lithium and Psychedelics

by Benjamin Malcolm | Spirit Pharmacist | 23 Dec 2020

Lithium is unique as a ‘drug’ because it is a naturally occurring chemical element on the periodic table rather than a small organic molecule. Lithium has a similar electronic configuration as sodium and both metals carry a positive charge. Lithium is used for depression, mania, and prevention of mood episodes associated with bipolar disorders. It can also be helpful as an augmentation agent for treatment-refractory depression.

It is both one of the first treatments to be recognized as having significant psychotropic potential in persons with bipolar disorder and to this day seems to be the ‘best’ treatment for management and prevention of mania. It is also known to have ‘anti-suicidal’ properties, which is unique among treatments for bipolar disorder (with the possible exception of ketamine).

At therapeutic doses lithium has a narrow therapeutic index meaning that therapeutic doses and toxic dose ranges are close together. Lithium toxicity can be severe and life threatening acutely. Moreover, lithium can result in other toxicities from long-term use. For this reason, periodic monitoring of lithium levels in blood is typical, along with monitoring other factors that effect lithium levels such as adherence, kidney function, fluid and water balance, concurrent medications, drugs, or supplements, and age.

Lithium Salts

Lithium in its elemental or metal form is highly reactive, so it exists and is taken in various salt formulations. For example, lithium carbonate and lithium citrate are available by prescription for the treatment of bipolar disorder, whereas low dose lithium orotate is available over the counter as a supplement used for various mood or neurologic disorders. The different salt formulations each have different molecular weights, so 100mg of lithium orortate does not contain the same amount of elemental lithium as 100mg of lithium carbonate. Below are relative conversion ratios between various salt formulations of lithium and the amount of elemental lithium they contain.
  • Lithium Orotate = 3.83mg elemental lithium per 100mg salt
  • Lithium Carbonate= 18.80mg elemental lithium per 100mg salt
  • Lithium Citrate = 9.91mg elemental lithium per 100mg salt

Put it in the water?

Due to lithium being naturally occurring it can be found in some drinking water and our diets. Interestingly, this may confer a population level benefit as the suicide rates are lower in populations that drink water containing lithium. The average amount of lithium in drinking water is ~140 ug/L (range 0-200 ug/L), which would equate to ~0.3-5mg if drinking 2-4L (1/2-1 gallon) of water daily.

Supplementation with Lithium Orotate

Amounts of element lithium when used as a supplement (10-20mg/day of the 3.83 mg lithium/100 mg orotate salt) is much lower than standard clinical doses of lithium carbonate or citrate used in bipolar disorders. Using a conversion ratio, it is calculated there would be 0.76mg of lithium in 20mg of the orotate salt. Therefore, a supplement dose of lithium orotate is approximately 1.5-3x above drinking water, yet 100-300x less than if you were taking lithium for bipolar disorder.

Salt Balance and Lithium

The kidney filters sodium and excretes it in urine, although is also capable of re-absorption to balance body water and sodium. Lithium is excreted almost entirely by the kidney and is handled similarly to sodium at reabsorption sites.

Practically, this means that stability in sodium and water balance is important to stability of levels in lithium therapy. Too little salt and dehydration can increase lithium levels to toxic ranges, too much salt and overhydration can decrease lithium levels and reduce efficacy of therapy. Therefore, persons using and prescribing lithium need be mindful of other medications, conditions, and illnesses that influence or impair salt and water balance. Diuretics (hydrochlorothiazide, chlorthalidone), some blood pressure medications (ACEI or ARB), and NSAIDS (e.g. ibuprofen) are most notoriously known to increase lithium levels. It’s common counseling to keep salt and fluid intake consistent and avoid excessively hot environments or extreme exercise while using lithium.

To this end, MDMA is known to be able to cause low body sodium or hyponatremia via release of arginine vasopressin (AVP or anti-diuretic hormone), which impairs the kidney’s ability to get rid of free water. Hot environments for ingestion and hyperthermic responses to MDMA may lead to dehydration or excessive fluid intake, sustained levels of high physical activity, and salt loss via sweating. Low body sodium due to excess AVP secretion (SIADH) could result in lower lithium levels due to dilutional effects associated with increased total body water or decreased reabsorption by the kidney’s proximal convoluted tubule (increased clearance of lithium and salt-wasting). Interestingly, lithium impairs the ability of vasopressin to act (thus can cause nephrogenic diabetes insipidus with long term use) and appears protective against hospitalization for SIADH in persons taking other psychotropic medications linked to hyponatremia. Overall the picture is complex, yet can be reasoned that psychedelics like MDMA or behaviors associated with use may have significant effects on fluid balance or electrolytes that could impact efficacy or safety of lithium therapy.

Other aspects of psychedelic use may also shift fluid or electrolyte balances which could impact lithium therapy. For example, dietas associated with ayahuasca use could drastically reduce dietary sodium intake and result in increased lithium levels. Ayahuasca frequently leads to vomiting and/or diarrhea which could also impact fluid and electrolyte balance.

Mechanism of Lithium & Serotonergic Potentiation

Lithium has a complex mechanism of action and appears to modulate monovalent cation binding sites (e.g. sodium) as well as second messenger cascades intracellularly. It appears to effect monoamine neurocircuitry such as those associated norepinephrine, dopamine, acetylcholine, and serotonin. Due to reports of serotonin toxicity occurring with lithium in combination with other drugs with serotonergic mechanisms it appears to increase or enhance serotonin neurotransmission. However, lithium is commonly combined with other serotonergic reuptake blocking antidepressants (SSRIs, SNRIs) or atypical antipsychotics (5HT2A receptor blocking agents) in clinical practice. It has been argued that cases of toxicity reported with SSRI/SNRI antidepressants and lithium, usually have other explanatory factors (e.g. elderly age, illnesses with fluid or electrolyte imbalances), supratherapeutic doses, or could be attributed to the effects of either drug alone. Screening, close monitoring, or excluding those positive for such factors may reduce risks associated with combinations of drugs involving lithium.

Psychedelic Interactions with Lithium

Serotonergic Psychedelics (MDMA, LSD, psilocybin, DMT, mescaline)

There is scant data to inform how psychedelics interact with lithium. If lithium potentiates serotonin and other monoamine neurotransmission, it is logical to think psychedelic experiences and risks of their adverse effects could be potentiated also.

One small study of 10 people and subjective reports with LSD reported potentiated experiences [9]. Anecdotes found on Erowid highlight possible adverse effects, with several cases of seizures documented with LSD and lithium in combination. Other anecdotes report similar phenomenon with MDMA or psilocybin - either potentiated experiences or seizures. There is no information on doses of lithium taken in these sources, but assuming they were taking clinical doses (600mg/day or more) seems reasonable as the descriptions are cases in which the persons were diagnosed with bipolar disorder or another refractory mood condition.

Ayahuasca (MAOIs)

Clinically, lithium has been combined with monoamine oxidase inhibitors for refractory depression on occasion without precipitating serotonin syndrome, although given potentiation of serotonin neurotransmission and other reports of serotonin toxicities involving lithium, it is a moderate-high risk combination.

Ibogaine

Lithium is known to lead to changes in cardiac conduction that have led to arrhythmias and electrocardiogram (EKG) monitoring is recommended with lithium therapy. Medications affecting the cardiac conduction may increase risks of lithium therapy (e.g. amiodarone). Bradycardias (slow heart rates) and arrhythmias are adverse effects of ibogaine, which could be increased with concurrent lithium use.

Ketamine

Lithium has been combined with ketamine during clinical trials of persons using ketamine to treat bipolar depression and appears safe in this context. Lithium does not need to be stopped or held for persons to undergo ketamine assisted therapies. Current data supports lithium to be the safest and most effective psychedelic for persons requiring therapy with lithium.

What about Bipolar Disorder?

One major risk that is introduced by stopping or holding lithium to work with serotonergic psychedelics are risks associated with loss of lithium’s therapeutic efficacy resulting in mania or mood decompensation. Especially if lithium were stopped abruptly, discontinuation syndromes or extreme symptoms could emerge. Additionally, serotonergic psychedelics are considered relatively (bipolar II) or absolutely (bipolar I) contraindicated with bipolar disorders due to cases of precipitating mania. It may be overly activating to discontinue mood stabilizers and use activating substances like psychedelics in their absence for persons predisposed to mania.
Unless encouraging data emerges that can speak to efficacy and safety, it is best to avoid psychedelic use in persons with significant history of mania.
This said, it is difficult to say exactly how severe the risks of using psychedelics are in persons with bipolar disorder. For example, use of serotonin blocking antidepressants or stimulants are also relative contraindications in bipolar disorder (at least without conjunctive mood stabilizers) due to ability to precipitate mania, yet are not uncommon prescriptions for persons suffering from a bipolar condition. Heavy alcohol, cannabis, or caffeine use is also associated with mood decompensation in bipolar disorder.

Whether serotonergic psychedelics have higher risks of exacerbating mania than antidepressants, stimulants, or other substances is unknown. Overall psychedelics result in liberation of psychic material, perceptual distortion, and reduced executive function. Moreover, commonly reported aspects of psychedelic use – expansive feelings and emotional ranges, a sense of embodying God or an inflated sense of Self, loosening of thought and belief structures, fantastical experience, or anxious ego dissolutive effects seem to have overlap with aspects of manic states. Many atypical antipsychotics have anti-manic effects and have pharmacologically opposite effects to psychedelics at 5HT2A receptors.

In challenge to conventional psychiatric wisdom a case was reported in which a young female with history of bipolar I disorder with psychotic features overdosed on LSD (~1200μg), had a (pseudo) ‘seizure’, awoke in the hospital the next morning and proclaimed “It’s [bipolar illness] over.” She experienced stabilization of mood without further episodes until post-partum depression occurred 13 years later [20]. I report the case with high levels of interest and desire to not simply cherry-pick cases of precipitating mania without presenting the converse situation. This said, please don’t read this to mean that overdose of psychedelics is likely a curative treatment for bipolar disorder.

More data is required to understand or quantify risks and benefits of psychedelic use generally, while even less is available for persons with bipolar disorder. Unless encouraging data emerges that can speak to efficacy and safety it is best to avoid serotonergic psychedelic use in persons with significant history of mania. Depressive states of bipolar disorders in therapeutic settings with close monitoring and post-use support may turn out to carry significant benefits with lower risks than use in presence of mania.

Elimination and Washout of Lithium

Lithium has a half-life of ~24 hours, therefore a period of 5 days would be predicted to be sufficient time to eliminate it from the body’s system. There would be little predictable risk of adverse drug reactions due to combination with serotonergic psychedelics with this approach. Lithium could be re-started 24-48 hours after serotonergic psychedelic use (LSD, MDMA, psilocybin, mescaline) without risk of adverse reactions due to drug interaction.

It is more appropriate to taper and discontinue lithium and observe a period of relative mood stability off of the medication before attempting work with psychedelic therapies opposed to abrupt discontinuation, especially when a significant history of mania or suicidality is present.

Conclusion

Lithium is a complex medication and may be able to potentiate effects of serotonergic psychedelics, creating risks of intensified psychological experiences, seizures, or acute toxicity. There are also considerable risks in stopping or discontinuing lithium in persons with history of bipolar disorders, mania, or suicidality. Currently, persons using lithium for bipolar disorder are not likely to be appropriate candidates for psychedelic-assisted psychotherapy with serotonergic agents. Lithium has been used with ketamine in clinical trials for bipolar depression with acceptable safety and good effects.

 

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Psychedelic healing & benzodiazepines: Are chill pills cool to combine?

by Benjamin Malcolm | SPIRIT PHARMACIST | 8 Jul 2019

Benzodiazepines (“Benzos”) are commonly prescribed drugs for anxiety disorders and psychedelics are being studied to treat anxiety amongst other psychiatric conditions. Due to psychedelic-assisted psychotherapies (PAP) being poised to enter the clinician’s armamentarium in the near future, it stands to reason that the question of how to manage benzodiazepines in the context of psychedelic therapies will be relevant clinically. Outside clinical settings, benzodiazepines and psychedelics are already being used and combined in a variety of contexts, thus from a harm reduction perspective it’s already relevant to understand more about how these two classes of drug interact. In this article, we’ll explore how benzodiazepines interface with psychedelic healing as well as potential strategies to minimize risks and maximize benefits.

Benzo background

What are benzodiazepines?

Benzodiazepines are a group of substances that facilitate GABA neurotransmission. GABA is the major inhibitory neurotransmitter in the brain, thus benzodiazepines have a globally calming effect on brain function. Examples of benzodiazepines include diazepam (Valium), lorazepam (Ativan), alprazolam (Xanax), clonazepam (Klonopin), oxazepam (Serax), temazepam (Restoril) as well as several others. Benzodiazepines are regulated as controlled substances in the United States due to their euphoric and sedative effects as well as their potential for dependence, tolerance, and development of benzodiazepine use disorders (addiction).

How are benzodiazepines used?

The calming properties of benzodiazepines on the brain are leveraged in both acute (emergency) and non-acute clinical situations. For example, benzodiazepines have been used to manage seizures, provide sedation for patients undergoing surgery or in Intensive Care Units, and provide calming effects for persons that are agitated and combative. In non-emergent clinical settings they are prescribed for the management of anxiety disorders and are either taken on an ‘as needed’ or ‘scheduled’ basis. Clinical guidelines for anxiety disorders recommend short courses of use to manage severe symptoms and recommend against the long term use of benzodiazepines due to risks associated with withdrawal and addiction as well as short and long term side effect burdens. Clinical guidelines for PTSD recommend against the use of benzodiazepines due to harm generally outweighing benefits. Nevertheless, due to their fast onset of action and propensity for habituation, it is common to encounter persons that have been using benzodiazepines daily for long periods of time.

In non-clinical contexts benzodiazepines are often used for their sedative and euphoric effects. Benzodiazepines, especially when combined with other sedatives like alcohol, are notorious for being able to produce anterograde amnesia (blackout), and have gained a reputation as date rape agents. For example, the benzodiazepine flunitrazepam is commonly known as a ‘roofie.’ They have also been implicated as contributing to rising overdose deaths, especially in combination with other sedatives like opioids. Due their cross-tolerance and longer lasting effects on GABA neurotransmission compared to alcohol, they are also used in alcohol detoxification protocols.

Benzodiazepine interactions with psychedelics

Generally, benzodiazepines will diminish effects of psychedelics and are have been known to be ‘trip killers’ in the psychedelic community. Psychedelics have been conceptualized as non-specific amplifiers of emotion while benzodiazepines have dampening effects on emotion, creating a theoretical rationale for counterproductive therapeutic effects. Additionally, chronic benzodiazepine use has been associated with reduced efficacy of cognitive behavioral therapy and reduced gains of exposure therapy in persons with PTSD. Benzodiazepines have cognitive dulling effects that may increase the difficulty of participation in the therapeutic process or prevent them from remembering covered materials. It may therefore be reasonable to think that benzodiazepines could hinder PAP either by pharmacologic interaction or interference with psychotherapy elements of the intervention.

Beyond taking the edge off of subjective effects of psychedelics, benzodiazepines are not dangerous to combine with psychedelics. It is not uncommon in recreational environments for users of psychedelic amphetamines such as MDMA to use a benzo during the comedown phase of the experience to decrease anxiety or facilitate sleep or to ‘abort’ bad trips with LSD. Benzodiazepines have also been administered in emergent situations involving psychedelics to reduce combative behaviors or abort seizures. Guidelines for psychedelic clinical research recommend the use of benzodiazepines in the last resort situation in which acute psychological distress is insufficiently managed by non-drug supportive means.

In contemporary clinical trials of MDMA- and psilocybin-AP, the use of benzodiazepines have been disallowed prior to a psychedelic session. One protocol for MDMA-AP (pages 58-60) in persons with PTSD required taper and discontinuation for 5 half-lives plus an additional week to demonstrate stability for benzodiazepines. Another randomized study of psilocybin-AP (see supplementary materials) for depression and anxiety in persons with cancer excluded persons using benzodiazepines on a daily basis and required those using on an intermittent (PRN or ‘as needed’) basis to refrain from use at least 5 half-lives prior to the psychedelic session. Although not permitted prior to PAP sessions, benzodiazepines have been included in protocols of psychedelic clinical trials as rescue medications in the case of an emergent situation as well as severe anxiety or insomnia in the week after psychedelic use. They were utilized to manage anxiety in the week after (usually not day of) MDMA-AP in 24 of 51 sessions in one study. In another study of MDMA-AP they were utilized less, although persons exposed to them (and had to taper off) prior to study enrollment appeared more likely to need them after MDMA use. In clinical guidelines for the use of ibogaine constructed by the Global Ibogaine Therapy Alliance (GITA), it is recommended to not discontinue the use of daily benzodiazepines in persons undergoing ibogaine therapy for opioid detoxification due to potential risks of discontinuation and withdrawal seizures complicating the opioid detoxification.

There are three conclusions that can be drawn from all this:
  1. Psychedelics and benzodiazepines are not dangerous to combine, although taper and discontinuation of chronic benzo use may optimize therapeutic potential of experience(s)
  2. Due to the serious potential risks of withdrawal with benzodiazepines, the risks of discontinuation in chronic users may outweigh benefits of a psychedelic experience in certain situations
  3. Intermittent and sparing use of benzodiazepines in the week after PAP sessions may be helpful in managing anxiety or insomnia, especially in persons with previous benzodiazepine exposure
Benzodiazepine withdrawal

Let’s dive into withdrawal and some of the properties of benzodiazepines next as they will help determine what reasonable and safe management strategies may be.

What are risks of benzo withdrawal?

Benzodiazepines are known to be habit forming and addictive drugs with tolerance and dependence occurring after 3 weeks of consistent use. Due to the calming GABAergic properties of benzodiazepines, they create states of heightened excitatory activity when they are withdrawn, which can lead to things like insomnia, anxiety, panic attacks, hypersensitivity to sensory stimuli, and in severe cases seizures or psychosis. While it is common for psychotropic drugs to have withdrawal or discontinuation syndromes, the withdrawal syndrome for persons taking benzodiazepines can be overwhelming and medically dangerous. It is due to the life-threatening nature of seizures that discontinuation of benzodiazepines should not be done abruptly. It also makes benzodiazepine withdrawal somewhat unique, because while withdrawing from heroin is extremely uncomfortable, there are typically no life threatening complications that occur. Therefore, abrupt discontinuation of daily long term users is dangerous and should be avoided. Other common substance withdrawals that can be complicated by seizures includes alcohol.

What factors increase risk of severe benzodiazepine discontinuation syndromes?

There are a few factors that help guide potential for severe withdrawal:
  • Dose
    • Higher doses are higher risk
  • Frequency of use
    • Daily use higher risk than intermittent or ‘as needed’ use
  • Chronicity of use
    • >8 weeks of consistent use typically requires taper
    • The longer the period of use, the slower the taper should be
In essence, the bigger the dose over the longer period of time, the more difficulty and risk in discontinuation. Age may also play a role as persons aged over 60 years are usually more sensitive to withdrawal. The primary factors that determine potential for severe withdrawal listed above also help to inform tapering schedules, with longer tapers for long time daily users.

By taking these factors in combination we can come up with 3 profiles of different benzodiazepine users:



When does withdrawal begin and how long does it last?

The half-life of the benzo in question plays a role in how soon the withdrawal symptoms begin, how long they last, and (to a lesser extent) severity of discontinuation syndromes. For example, with shorter acting benzodiazepines like alprazolam (Xanax), the withdrawal syndrome can begin within 24 hours, while with longer acting benzodiazepines like diazepam (Valium), the withdrawal syndrome may not occur for 3-5 days after last use. It is in the first few days after withdrawal begins that risk of seizures are highest.

Below is a table listing commonly encountered benzodiazepines, doses, and whether they’re considered short, intermediate or long acting.



Withdrawal symptoms generally persist for a week to a month and peak around 14 days after last use. During this time, symptoms of illness often return and are experienced to a more severe degree than their baseline symptoms prior to benzodiazepine use and is called “rebound anxiety” or “rebound insomnia”. In addition, many persons may experience a protracted and persistent phase of withdrawal after the initial withdrawal syndrome that can last up to a year, however symptoms of illness typically improve in this timeframe.

Where can I find more information on withdrawal effects and safe tapering schedules?

Luckily, there are several very good resources dealing with taper, withdrawal, and discontinuation online. Be sure to check out:
Management strategies

Hopefully it’s fairly clear by now that tapering benzodiazepines and discontinuing them prior to PAP is ideal, although this is perhaps unrealistic in all cases. Let’s explore the idea of skipping a dose on the day of the psychedelic session as an alternative strategy.

Can you just hold the dose of benzo for the day?

Using the pharmacokinetics (time to withdrawal onset) of the benzodiazepines and the use pattern of the individual, it is not entirely unreasonable to envision cases in which users of intermediate to long-acting benzodiazepines could simply hold a dose the day of a psychedelic session without introducing risks of experiencing severe withdrawal. The pros of this approach is that it reduces risks associated with the long and protracted withdrawal or rebound anxiety and insomnia while still allowing potential for a reasonably potent experience. The cons are that some benzodiazepine will still be in the users’ system and effects of psychedelic therapies could be reduced or that partial withdrawal states could increase risks of psychological difficulty or adverse events during psychedelic sessions. Holding the dose the day of a psychedelic session is likely a poor strategy for a user taking a short acting benzodiazepine and accustomed to using it daily or multiple times daily (e.g. use of alprazolam twice daily), particularly when psychedelics that have potential to increase seizure risk are planned for use (e.g. MDMA). Converting users of short-acting benzodiazepines to long-acting benzodiazepines can be a useful strategy to prepare for tapering or make holding the dose a more reasonable approach.

To taper or hold for the day?

There’s a speculative and philosophical debate around the ‘correct’ approach to psychedelic healing when there are concurrent psychotropics that act to repress emotion the user is taking. It seems many would feel that ‘if you want to heal your wounds, you must first remove all the bandages’ and favor an approach of tapering off a benzodiazepine (or really any and all psychotropics) prior to engaging with psychedelics for therapeutic purposes or with healing intentions. Others may see psychedelics as tools to help in the process of taking off bandages and healing wounds due to the potentially overwhelming challenges of an unsupported tapering process and additional supports offered in PAP interventions. The best approach is unknown, although suspect it is likely something best individualized.

Clinical research in psychedelics has set a precedent of tapering off benzodiazepines prior to PAP sessions. It is likely that persons that would otherwise be candidates for trial participation were excluded due to inability to discontinue benzodiazepines given the timelines involved for safe tapering. It is also likely that if a psychedelic therapy is approved for use that clinician’s will want to treat persons that use benzodiazepines. This may be especially true given psychedelics are being studied for treatment refractory conditions for which psychotropic polypharmacy is common. It seems that if PAP is approved, daily benzodiazepine use perhaps should not always be an automatic disqualification for psychedelic use.

For many users, the fear of coping without benzodiazepines or tolerating the rebound of painful feelings can be overwhelming and a supportive structure that provides safe places for discussion is essential. In many ways the support and space a person needs for a successful taper process mirror the supports provided in PAP interventions. Due to the ability of psychedelics to catalyze change, stimulate active coping mechanisms, increase confidence in self-mastery, reduce problematic substance use, and simultaneously improve symptoms of mood and anxiety disorders, it’s plausible that psychedelics could be leveraged to improve success rates in the discontinuation and stabilization of persons with mental illness without concurrent psychotropics.

It’s conceivable that a daily benzodiazepine user begins a taper process and uses the structure of PAP to wean off and manage feelings associated with withdrawal, especially in the scenario that an individual is on several psychotropics (e.g. antidepressants and benzodiazepines) that would optimally (or necessarily) be tapered and discontinued. It may be preferable to use a step-wise approach and a series of psychedelic sessions to help manage and support intentions for discontinuation of several medications. Benzodiazepines are recommended to be continued when using ibogaine for opioid detoxification due to seizure risks and inability of ibogaine to reduce benzo withdrawal symptoms. These hypothetical scenarios and real world examples provide much food for thought when it comes to how benzodiazepines interface with psychedelic healing both contemporarily and in the future. Depending on user intention and goals related to medication use, requirement of taper prior to PAP may not be preferable or produce the best results in every situation.

Conclusions

Benzodiazepines diminish effects of psychedelics and may interfere with therapeutic processes. Tapering and discontinuation of benzodiazepines prior to PAP seems ideal, but can be overwhelming or dangerous if done abruptly or in unsupported environments. In selective situations it may be permissible to continue benzodiazepine use with psychedelic interventions or use benzodiazepines to manage psychological aftermath of difficult experiences. Given the challenges and dangers in tapering and discontinuing benzodiazepine use, an individualized strategy is optimal when approaching psychedelics with intentions for healing in benzodiazepine users.

 

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On psychotropics and psychedelics: To taper or not to taper?

Spirit Pharmacist | 28 Feb 2020

As psychedelics gain popularity for healing of mental illness, larger numbers of persons taking medications to treat mental health conditions (psychotropics) are gravitated towards their use. A common conundrum in psychedelic healing practices is the optimal management strategy when the participant is taking psychotropic medication. In this article we’ll walk through some of the benefits and risks of tapering psychotropic medications in preparation for psychedelic use as well as outline an approach that the end user can take in order to make informed decisions with their treating provider(s).

Psychotropics and psychedelics: Strange bedfellows or healing allies?

Existing medications to treat mental health conditions (psychiatric pharmaceuticals or psychotropics) can be effective in reducing symptoms of illness, leading to improvements in how a person feels as well as their functionality. The benefits of psychotropics include an enhanced tolerance to stress, although this may be accomplished via a narrowing of their emotional range, leading to side effects such as feeling “numb, like a zombie”. Psychotropics typically do not ‘cure’ mental health conditions, can produce physical dependence and withdrawal syndromes when taken for extensive periods, may have bothersome side effects, and may not produce robust benefits in some.

The term psychedelic means ‘mind-manifesting’ or ‘soul-manifesting’ and psychedelics have been thought of as amplifiers of consciousness, meaning they increase the intensity of thoughts or feelings. Current research suggests that moderate to large doses of psychedelics (macrodoses) in combination with psychotherapy can help to surface emotional content, which can then be processed therapeutically. In studies, this has led to persistent improvement in symptoms and functioning that are sustained over periods of weeks –months and occasionally years, sometimes with as little as one psychedelic session. Taking psychedelics in small ‘subperceptual’ doses has become popular and may work in a similar fashion yet more subtly over a longer period. For example, in a study that followed persons that microdosed for 6 weeks they found decreases in depression and stress, yet increased neuroticism, implying that although they felt better, they were also more sensitive to emotion.

Therefore, it appears that existing psychotropics and psychedelics may affect mental states in divergent ways: traditional psychotropics help a person tolerate a difficult situation or ‘weather the storm’ while psychedelics help a person with emotional processing or to ‘shake the snow globe’. These two mechanisms have been discussed as enhancement of ‘passive’ and ‘active’ coping mechanisms, respectively. There may be possible benefits to combining them due to simultaneous activation of different sets of coping mechanisms. Conversely, these mechanisms may be counterproductive, either in intensity or quality of subjective experience or in their impact on mental healing processes.

I’ve written extensively about the existing data in other blogs related to antidepressants & related serotonergics, benzodiazepines, stimulants, analgesics, and antipsychotics.

In summary, there is some validity to the idea and small amounts of data suggesting that psychotropics may diminish or interfere with psychological aspects of psychedelic experiences, which could lead to counterproductive effects. However, there is a general lack of data confirming how much they interfere and whether this is worth the risks associated with taper, discontinuation, and washout of psychotropic medications.

Psychedelic – psychotropic interactions

There are many possible ways that various psychotropics may interact with psychedelics. For example, some interactions may involve competition or blockage in metabolic pathways leading to boosted concentrations of psychedelics or psychotropics (pharmacokinetic). Others may involve synergistic or counterproductive effects in neuronal tissues of the brain (pharmacodynamic). For the purposes of this article it may be useful to dichotomize drug interactions into those that present some risk of physical danger vs. those that are likely limited to psychological risks. This is a helpful distinction because physical dangers are much more tangible as far as having known and predictable negative outcomes, whereas psychological dangers are mostly theoretical at this point and may be risks the participant is willing to take.

The physical and psychological risks of combining major classes of psychotropics with commonly used psychedelics are summarized and this table

Set, setting, and psychotropics

‘Set and Setting’ is an often discussed topic when designing optimal psychedelic experiences. The term ‘Setting’ refers to the physical environment and surroundings for the experience itself. The term ‘Set’ refers to mindset and encompasses the mental state of the user coming into their experience including things like expectations or intentions of use. It is generally thought that psychedelics are best experienced at times a person is feeling calm and relatively well overall, although this is not always the case in studies in of persons being treated for mental illness.

The presence or absence of psychotropics can directly affect the ‘Set’ of the psychedelic user. For example, use of a benzodiazepine in close proximity to a psychedelic experience may diminish the intensity of the psychedelic experience and interfere with therapeutic processing of emotional content. On the flip side, discontinuing use of a benzodiazepine you were physically dependent on may lead to worsening insomnia or anxiety. If insomnia or anxiety is so severe the user cannot rest well for several days in a row, then the ‘Set’ of the user may become so poor that the psychedelic experience is negatively impacted.

Different persons have very different responses to stopping medications or changing doses. For some, tapering, discontinuing, and washing out is not a difficult process and does not lead to significant worsening of symptoms. Others may be very sensitive to withdrawal effects and dose changes or experience large increases in symptom severity or even suicidality when medications are tapered or discontinued. Therefore, in the absence of risks of physical toxicity, the decision to taper, discontinue, and washout mental health medications prior to psychedelic use is a risk vs. benefit decision that is unique to the individual and best made by the user in conjunction with their treating provider(s). This perspective and approach to interactions between psychedelics and psychotropics is generally aligned with principles of cognitive liberty, which supports the autonomy of an individual to determine their own mental state and consciousness as a fundamental right.

To taper or not to taper: That is the question

In the presence of known and significant physical risks, the decision to taper, discontinue, and washout psychotropic medications for an appropriate amount of time is not difficult. Psychedelics with a high propensity for physical risks in combination with psychotropics primarily include ayahuasca and ibogaine, although other combinations with phenethylamines or ketamine can also have significant physical risks. Classic tryptamine psychedelics (LSD, psilocybin, DMT) typically are the lowest risk in combination with psychotropics.

In the absence of significant physical risks, the decision to taper, discontinue, and washout psychotropic medications is rather grey and may be made based upon gauging possible risks and benefits of each strategy. The primary benefit of continuing to use a psychotropic medication when approaching psychedelics is avoidance of taper, discontinuation, and wash-out. This process is inherently very challenging for some because they are still experiencing symptoms of illness even on their medications and tapering and discontinuing medication can lead to withdrawal and further exacerbation of underlying symptoms. Especially when the user is sensitive to effects of withdrawal or experience extreme symptoms (e.g. suicidality) when tapering or without medication, it could be of benefit or safer to continue mental health medications. On the flip side, some data reports muting, blunting, or diminished acute psychedelic effects when psychedelics are combined with psychotropics. Others report heightened sensitivity to medications or side effects after use of psychedelics, although neither of these effects are well characterized or proven.

Therefore, while it may be ideal for acute subjective effects to taper, discontinue, and wash-out psychotropic medications prior to psychedelic use, this must be weighed against the potential risks associated with withdrawal of medication or symptoms of untreated mental illness returning. Similarly, it may be ideal to allow the post-use effects of psychedelics to continue unfolding without re-introducing medication, although must be balanced against severity of symptoms experienced post-use.

Taper vs. hold

Many medications for mental health should typically not be stopped abruptly unless emergency circumstances warrant it. Using a psychedelic is not an emergency circumstance. However, there may be certain medications that a person is reliant on that are not currently options or good options to proceed with a taper and washout. For example, sleep aids or benzodiazepines are often prescribed in conjunction with antidepressants to help with sleep or anxiety. If an individual is already tapering an antidepressant, it may be unrealistic or intolerable to attempt tapering more than one medication simultaneously. It’s also a general rule of thumb in psychiatry for daily benzodiazepine users to not attempt taper unless things are going really well. This is because persons taking higher doses of benzodiazepines daily can become suicidal or have a seizure if you taper too fast or stop too suddenly, amongst myriad other intense and unpleasant withdrawal effects. Hence it may be conceivable for some users or situations that continuation of a psychotropic with a strategy of holding one to a few doses (or maybe simply reducing the dose for a few doses) around the time of the session to minimize blood concentrations may be more reasonable than taper, discontinuation, and washout. Medications in which this strategy may be particularly reasonable include GABAergics such as benzodiazepines, Z-hypnotics (zolpidem, eszopiclone, zaleplon), gabapentin, and pregabalin. Trazodone is another commonly used sleep aid that is optimal to wash out, yet may not be feasible to for some due to reliance on it for adequate sleep.

I’ve written more extensively about benzodiazepines, antidepressants as well as trazodone, and gabapentinoids in the linked articles.

How should I decide what to do?

The decision to taper, discontinue, and wash out psychotropic medications is personal. There are many potential factors to consider when making the decision and an inventory or self-reflection upon these factors in conjunction with your treating provider(s) can aid in making the best decision for you. Some questions you may want to consider:

  • What are the benefits and side effects of my existing medication(s)?
  • What are my goals regarding use of medication(s)?
  • What is the compatibility between my current medication(s) and planned psychedelic?
  • Do I have experience tapering and washing out my medication(s)?
  • Am I sensitive to withdrawal or experience extreme symptoms when not taking medication(s)?
  • Is my provider(s) supportive of a plan to taper me off? Will they help me with step-down doses or managing withdrawal?
  • What is my support network and is it strong enough to get me through a taper and washout?
  • Is it a good time in my life overall to attempt a taper and use psychedelics?
  • Am I ok with a potentially less intense subjective experience or is it an intention to have the most potent experience possible?
If you’d like to walk through these questions in a professional consultation I’m happy to help with this.

I want to taper, discontinue, and wash out

Stopping abruptly or tapering too quickly puts the user at risk for severe withdrawal symptoms that could precipitate acute crisis situations such as suicidality. The rate of taper should be individualized as some are much more sensitive to withdrawal than others. The goal rate of taper should be so slow that user feels minimal withdrawal effects. If you’re finding that you ‘need something else’ to substitute or ‘get you through’ the taper process, you’re encouraged to slow down the rate of taper as it’s a sign you are experiencing significant withdrawal effects. If you’ve completed the taper process and been off your medication more than two weeks and noticing your mood, anxiety, or sleep is worsening, then it’s more likely a return of illness symptoms than withdrawal of medication.

In the circumstance you’re taking more than one medication that may interfere with the mechanism of psychedelics, it may not be reasonable to taper off of more than one medication at a time. This is because managing multiple withdrawal syndromes may be overwhelming and destabilizing or increase risk of rapid return of severe symptoms.

While rates of taper should be individualized, further discussion of drug interactions, medication tapers, and discontinuation times for various medication classes may be found in other blog articles I’ve authored on antidepressants, benzodiazepines, stimulants, analgesics, and antipsychotics.

Given anticipated withdrawal syndromes or return of original symptoms of illness, it’s reasonable to anticipate that tapering medications may be a challenging period, perhaps even more challenging than the psychedelic journey and subsequent healing process. Attempting to view the emotional or physical difficulties that arise in medication taper processes as ‘practice’ for the possibly intense emotional effects of psychedelic experiences can be a useful psychological strategy. Arranging extra support for the process from your provider(s) and/or connecting with psychedelic support networks ahead of starting the taper process is another helpful strategy to ensure the taper is manageable.

Conclusions

In the absence of physical risks and/or clear data to guide management strategies of psychedelics and psychotropics, the decision to taper, discontinue, and wash out medications is best individualized. This approach supports the autonomy of the individual and respects individual differences in ability to taper medications in preparation for psychedelic use. Clarification of goals and intentions surrounding use of existing medications is a helpful practice in arriving at an informed and optimal decision for psychedelic users. Anticipating medication tapers may be challenging and arranging additional support for the process is a good strategy to increase success rates and improve safety.

 

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Coping with Antidepressants and Psychedelics

by Benjamin Malcolm | Spirit Pharmacist | 11 Jan 2021

Both traditional antidepressants and psychedelics work primarily on serotonin neurotransmission and have been found helpful in treating or managing mental illnesses such as depression, although they appear to leverage different sets of coping mechanisms. This finding could have major implications into our understanding of when or how we would want to use them:

Traditional serotonin blocking antidepressants (e.g. SSRIs, SNRIs) are known to produce longer term neuroadaptive changes to the brain over weeks to months resulting in an enhanced tolerance to difficult conditions. This has been termed ‘passive coping’ because it allows the user to deal with their life more effectively. This explanation aligns well with what persons tell me about antidepressants: When the effects are helping, they mention “I stopped having emotional outbursts or daily crying spells” or “I just wasn’t bothered by the little things as much.” When the effects are unfavorable, they mention “I felt numbed out, like I couldn’t experience my full range of feelings.” The commonality between the stories is that emotional sensitivity was decreased. My analogy for this type of coping is ‘Weathering the Storm.’

Psychedelics can produce almost immediate shifts in mood and are being discovered as ‘psychoplastogens’ or agents that increase the ability for the brain to re-mold itself. Used therapeutically, these effects may result in the modulation of negative core beliefs or effective processing of emotional traumas that drives psychopathology. When things work well the effects can catalyze processes of positive self-transformation. Persons may mention a peak psychedelic experience feeling like “a factory reset for my brain” or that “I was rewired”. This tends to lead to processes of identity restructuring in the time afterwards. When things go sideways the user may feel that trauma was activated without resolution, leaving the user in a hypersensitive and challenging emotional state. The commonality is that emotional sensitivity was increased. My analogy for this type of coping is “Transformation and Change” (metamorphosis).

Keep in mind we are talking about serotonin; one of the most ancient, enigmatic, and complex of neurotransmitter systems.  Any discussion we have at this stage is reductionist. For example, the paper this information was taken from focuses on comparing actions of drugs at 5HT1A vs 5HT2A receptors, yet there are a dozen other types of serotonin receptors cut out of the picture [1]. Healthy to take with a pinch of salt 😊


Keep in mind we are talking about serotonin; one of the most ancient, enigmatic, and complex of neurotransmitter systems. Any discussion we have at this stage is reductionist. For example, the paper this information was taken from focuses on comparing actions of drugs at 5HT1A vs 5HT2A receptors, yet there are a dozen other types of serotonin receptors cut out of the picture. Healthy to take with a pinch of salt. 😊

Use of psychedelics to catalyze transformation and change is not new. For example, traditional cultures have utilized psychedelics during rites of passage. Placed within our model of psychedelics as agents of adaptive change, use during times of life that naturally demand a high degree of adaptation may be advantageous. Another example of psychedelic use to aid in situational transition or change are those using psychedelics for existential anxiety associated with life-threatening illness.

Psychedelics are being explored for treatment of alcohol use disorder and quitting cigarettes, which ultimately involve habitual change and reduction of behaviors negative for health. Depression and anxiety are thought of as bio-psycho-social-spiritual illnesses due to the complex interaction between persons and their environment giving rise to symptoms of illness. It is often the situational circumstances (psychosocial stressors) of one’s life that precipitates or makes illness worse. Life presents challenging circumstances and most suffer to different degrees at certain junctures: The coping mechanisms employed during times of hardship range anywhere from healthful and promoting problem solving to toxic and promoting our demise.

The neuroscientific elucidation of psychedelics as agents that foster adaptive coping has the potential for application across a diverse variety of illnesses and life situations. Psychedelics are far from panaceas or magic bullets for ‘bad habits’ and do not automatically cause any shift in behavior, situation, or psychological perspective. There is much to be said for motivation and readiness for change that is prerequisite for sustained positive change. However, effects of psychedelics could increase the probability of positive change occurring or help clarify ambivalence that creates resistance to change. Supportive psychotherapy or psychedelic integration coaching can also increase the chances of sustained positive change.

Over the past 30 years we’ve been able to observe the effects of SSRI antidepressants in clinically depressed, anxious, or traumatized populations. Overall, we’ve observed modest benefits (small effect size) and increasing chronic use without reductions in persons experiencing the mental illnesses the medications are designed to treat. There are many times when increasing emotional sensitivity may not be desirable due to toxic life circumstances, however is it an optimal strategy to ‘weather the storm’ one’s entire life? This is not supposed to demonize antidepressants, argue positive transformations cannot be made with antidepressant use, or suggest they’re numbing agents that retard personal growth. On the contrary, my hope is that we learn to apply agents that enhance the right coping mechanisms at the right times to achieve the goals and fulfill the intentions of the user.

 
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Trazodone and psychedelics

SRIRIT PHARMACIST | October 02, 2020

Trazodone (Desyrel) is a psychotropic medication that functions as a sleep aid or hypnotic at lower doses and as an antidepressant at higher doses. It is classified as a serotonin antagonist and reuptake inhibitor (SARI), which is an atypical class of antidepressants to which the drug nefazodone (Serzone) also belongs.

How is Trazodone used?

By far the most common use of trazodone today is for sleep as the drug tends to cause so much drowsiness that it is hard to tolerate daytime use as an antidepressant.

Additionally, relative to other sleep aids (e.g. zolpidem or Ambien, eszopiclone or Lunesta; temazepam or Restoril) trazodone is not regulated as a controlled substance or thought to be addictive, which tends to boost popularity with prescribers due to improved relative safety.

How is Trazodone dosed?

The pharmacology of trazodone is dose dependent. At lower doses (up to ~150mg/day) it functions to block histamine, alpha-1 adrenergic and serotonin 2A (5HT2A) receptors, whereas at doses >150mg the drug blocks the serotonin reuptake pump significantly (like a SSRI). Therefore, as a sleep aid trazodone is typically used in doses of 25-100mg at bedtime, whereas antidepressant dosing is 150-200mg three times per day.

How might Trazodone interact with psychedelics that do not contain MAOIs?

Whether trazodone is used as a sleep aid or used as an antidepressant, it may be able to reduce or blunt the effects of serotonergic psychedelic substances that do not contain monoamine oxidase inhibitors (MAOIs). Antidepressants that block serotonin reuptake are known to reduce the subjective effects of MDMA and reported to diminish subjective effects of psilocybin or LSD in some users. Similarly, antipsychotics that block 5HT2A receptors are also known to diminish the effects of psychedelic substances. Given trazodone blocks 5HT2A receptors at lower doses and the serotonin reuptake pump at higher doses, it seems there is some rationale to think trazodone may interfere with psychedelic mechanisms of action no matter what dose is taken.

How might Trazodone interact with Ayahuasca?

Due to the monoamine oxidase inhibitors (MAOIs) in the ayahuasca vine and serotonin reuptake pump inhibition by trazodone, there is potential for dangerous drug interactions between trazodone and ayahuasca, particularly at high doses of trazodone (>100mg). Relative to SSRIs which are potent and selective for the serotonin reuptake pump, trazodone is a ‘weaker’ drug in this regard and may have relatively less risk of life-threatening serotonin toxicity, although is still predicted to have considerable risk in combination. Small amounts of data suggest that low doses of trazodone (50-75mg) can be combined with MAOIs. Moreover, the 5HT2A blocking effects of trazodone may diminish psychedelic effects of DMT. Compared to other psychedelics that do not contain an MAOI, there are additional physical risks associated with use of ayahuasca with trazodone.

How long does it take to wash Trazodone out of my system?


Typically, it takes 5 half-lives of a drug to wash it out or eliminate the drug from of the system. In the case of trazodone, it has an active metabolite (m-CPP) that could also be prudent to consider in washing out the medication. The half-life of trazodone and m-CPP are relatively short and both could collectively be washed out of a user’s system in approximately 4-5 days; the parent drug trazodone is likely eliminated in most after 2-3 days.

What about sleep?

Sleep quality as well as symptoms of mood, pain, and anxiety are highly interrelated. Abstaining from trazodone for daily users of a sleep aid can create a string of nights in which insomnia is worsened, sleep is poor, and emotional effects and functional deficits linked to sleep-deprivation accumulate. Stopping sleep aids abruptly can also lead to ‘rebound insomnia’ or insomnia that is worse than the baseline condition prior to starting drug therapy. This could plausibly lead to emotional crisis or affect an individual so severely that it is difficult to fully participate in therapeutic work. Therefore, until more definitive data is available to guide an optimal strategy, it is reasonable to balance the risk for diminished subjective effects with non-MAOI containing psychedelics against what the individual can tolerate regarding possible reductions in the amount or quality of sleep.

For non-daily users of trazodone as a sleep aid it is reasonable to accomplish a period of drug-free days prior to using a psychedelic substance. For daily users of trazodone an individualized decision that balances need for medication and sleep with potential for diminished effects can be made with the prescribing provider.

How can I taper Trazodone?


You should always involve your medical provider in decisions to start, stop and change medication, therefore the first step would be a conversation about the desire to stop or reduce your dose of trazodone. Trazodone is available in a number of strengths and comes as immediate release tablets, this makes finding appropriate step-down doses easier as it is permissible to cut tablets into smaller pieces to customize smaller doses. Depending on how long you’ve been taking it, what dose you’re on, and how sensitive you are to sleep problems in response to dose reductions are factors that can help decide a rate of taper. Monitoring the number of sleep hours, quality of sleep, and emotional state of the individual tapering are helpful methods for recognizing when the taper rate may be too aggressive.

As people taper sleep aids they have been taking on a consistent basis they will often run into withdrawal symptoms, however, some may also experience ‘nocebo’ effects or feeling worse due to knowledge something that you believed was beneficial is missing. The desire to substitute another sleep aid may be a marker that the taper rate is too aggressive as the individual is looking for something to fill the sleep void. If a substitute sleep aid or supplement is used, it is ideal to keep use temporary or reserve use for times it’s ‘needed’ opposed to routinely adding something simply because a taper is underway.

If tapering trazodone results in users ‘leaning’ on maladaptive coping skills (e.g. increasing alcohol intake, increasing use of pain pills or other sedatives etc.) to get extra sleep, it may be reasonable to instead focus on resolving problems with maladaptive coping prior to attempting a taper. Instead, the user may need to focus on other aspects of sleep hygiene or stress reduction, creating a bedtime ritual to help counteract reduction in their use of trazodone.

High Notes


Trazodone has potential to counteract psychedelic effects of non-MAOI containing psychedelics. It may present risk of dangerous serotonin toxicity with MAOI-containing psychedelics like ayahuasca, particularly at higher doses. It has a relatively short half-life and can be eliminated from a users’ system in a period of days, although potential negative effects of cumulative sleep-deprivation or rebound insomnia should be considered when a user is considering tapering or stopping trazodone in preparation for psychedelic use.

 
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