Focus on Surrendering? Drug Interactions between Stimulants & Psychedelics

amphetamine drug interaction mdma psychedelics stimulants Apr 26, 2021

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? 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 [1]. 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 [2]. 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 [3]. 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 [4, 5]. 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 [6]. 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 [7, 8].

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 [9]. 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 [10]. 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 [11, 12].

One study investigated differences between placebo, methylphenidate, MDMA and the combination of methylphenidate and MDMA in healthy volunteers [13]. 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 [3]. 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 [14]. 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 [15]. 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 [16]. 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 [17]. 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 [15]. 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 [13, 18, 19]. 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 [20-23]. 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 [24]. 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 [6, 25, 26]. 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.

Harm Reduction with Psychedelics and Stimulants

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 [12, 27]. 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 & 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.

 

This article is for informational purposes only. It is recommended that you do not use illicit substances or perform any other unlawful act.

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