Addiction Pharmacology, Psychedelics, and Therapeutic Use To Support Recovery

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Chapter Aims

• Describe the addiction potential of psychedelics and chemical theories of addiction
• Outline mechanisms of psychedelics that could contribute to therapeutic benefits
• Compare the pharmacologic profiles and addiction risks of various psychedelics
• Summarize clinical research involving psychedelic and substance use disorders
• Discuss contraindications and other clinical considerations of using psychedelics safely

Addiction Risks of Psychedelics

“Psychedelic”—meaning mind- or soul-manifesting—is an umbrella term including several classes of drugs, each with different neuropharmacological profiles. Their differences are an important place to begin a conversation about their potential for addiction or as addiction treatments. Their varying mechanisms lead to different subjective effects and can also give rise to both anti addictive or reinforcing (pro addictive) effects.

Most of the time when people say “psychedelics,” they're talking about classic psychedelics or the classic hallucinogens—psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and mescaline. The classic hallucinogens display a mostly non addictive or anti addictive pharmacology and tend to act by binding and stimulating serotonin receptors. The low addictive potential of classic hallucinogens likely extends to other traditional preparations involving the classics. For example, ayahuasca contains DMT along with monoamine oxidase inhibitors (MAOIs). Further, many nonclassic, naturally occurring psychedelics such as ibogaine from the iboga root appear to have powerful anti addictive properties and the unique ability to rapidly detoxify people from opiates [1-6]. The pharmacologic truth of classic hallucinogens and ibogaine is in stark contrast to their regulation in society as illicit or Schedule I controlled substances. There should be evidence to support high potential for abuse” and “no therapeutic value or an inability to be used safely even with medical supervision” to support regulation as an illicit substance. These claims about classic psychedelics are demonstrably false.

There is a whole host of novel designer serotonergic psychedelics, some with tryptamine (psilocybin-like) and some with phenethylamine (mescaline-like) backbones [7]. The prototype phenethylamine is 3,4-methylenedioxymethamphetamine (MDMA). These types of psychedelics are derived from amphetamine or cathinone (stimulant chemical structures) and are typically capable of releasing neurotransmitters like serotonin, norepinephrine, and dopamine. Some can release more dopamine and have shorter durations of action than MDMA (e.g. 4-MMC or mephedrone) which increases addictive properties [8, 9]. Additionally, there are classes of substances that could be categorized as psychedelics, such as dissociative substances like ketamine, or cannabinoids like THC that have reinforcing properties.

Chemical Hooks and Maladaptive Learning in Addiction

Our chemical models of addiction focus on substances that are pleasurable and reinforcing, which almost universally means the substance can directly or indirectly increase dopamine neurotransmission in the nucleus accumbens (NA). Several types of substances with variable mechanisms can lead to this, including alcohol, benzodiazepines, barbiturates (GABA-A), opioids (μ), THC (CB1), amphetamines (dopamine release), caffeine (adenosine), cocaine (blockade of dopamine reuptake), S-ketamine (μ opioid), and nicotine (α4β2). Other addictive or pleasurable activities (e.g. sex, pornography, gambling, online shopping, social media, sugar) are commonly capable of increasing dopamine in the NA.

Typically, an addictive substance has an initial  pleasurable or beneficial effect (e.g., feeling high, relief from pain, or social, cognitive, or emotional improvement). Often, over time and with repeated use, the individual may not find as much of a pleasurable effect–it might become something they need in order to function or feel normal. However, at least initially, the substance is pleasurable and it's reinforcing, which we believe is mediated primarily by the neurotransmitter dopamine. In essence, dopamine is a neurotransmitter of learning, and it does so via motivation and reward mechanisms. Hence, the repeated use of addictive substances could be viewed as a method of learning what in life produces a reward, then repeating the behavior to reinforce that reward. In addiction, it's a maladaptive process, usually after the substance has offered some initial benefit. Addiction ends up reducing and crowding out desires for natural rewards, creating a lack of motivation for things other than the drug reward.

Psychedelic substances may exert modulatory activity via 5HT receptors over areas of the brain that feed upon the NA such as the ventral tegmental area (VTA) [10]. Upregulation of brain-derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor (GDNF) in the VTA is associated with reduced addictive tendencies or craving [10-12]. Psychedelics can also exert modulatory control over opioid circuitry and are implicated in novel signaling mechanisms that hybridize 5HT and metabotropic glutamate receptors, which could lead to epigenetic changes that reduce substance use [13, 14]. Ibogaine has novel pharmacology that further targets known receptors for many addictive substances [15]. Collectively, these could represent novel mechanisms for biologic treatments for addiction.

Classes of psychedelics vary in their direct or indirect action on the dopamine system, which largely drives their addictive or anti addictive potential. We can discuss each class in more detail and further understand their propensity for reinforcement, habit formation, or addiction.

Low Addiction Risks with Classic Psychedelics: DMT, Psilocybin, LSD, and Mescaline

The classic psychedelics include psilocybin, DMT, LSD, and mescaline. Psilocybin and DMT are both tryptamines that work primarily to stimulate serotonin receptors [16]. They are not known to be rewarding or reinforcing and have data suggesting anti addictive effects, particularly for alcohol use disorders [17]. While LSD is not considered addictive, it can directly bind dopamine 2 (D2) receptors and has been found to have reinforcing properties [18]. Of note, LSD is antiaddictive in the treatment alcohol use disorders [19]. Therefore, LSD may represent a substance with both some reinforcing and anti addictive properties.

Mescaline is also not considered addictive, but due to its phenethylamine backbone it is likely to cause at least some release of dopamine. The long-acting nature of LSD and mescaline experiences could also be factors that reduce addiction potential since the rewarding effects occur over prolonged periods rather than rapidly like many powerfully addictive drugs (e.g. cocaine, heroin, nicotine, alcohol). Another anti-addictive factor could be the rapid and near complete tolerance (tachyphylaxis) with repeated dosing that occurs with most classic psychedelics and how this contrasts with the more insidious tolerance of addictive substances. This rapid tolerance, or greatly diminished responses even with higher doses, extends to LSD, psilocybin, and mescaline, which all also display cross-tolerance to one another, while DMT appears to lack tolerance to repeated dosing [20-25]. Notably, drugs with mechanisms that are relatively selective for serotonin such as selective serotonin reuptake inhibitors (SSRIs), buspirone (5HT agonist), and MAO-A inhibitors are not considered to be reinforcing or addictive and are not regulated as controlled substances. While classic psychedelics (5HT agonist) have very different psychological and neurobiological effects than other serotonergic psychotropics that could increase harms in unprepared users or unsafe environments, there is little about their overall pharmacology that would give us strong reason to suspect an addictive profile [26].

Could even classic psychedelics be overused, abused, or be associated with a Hallucinogen Use Disorder (HUD)? Certainly. Making claims that HUDs do not exist or that classic psychedelics are nonabusable is almost as outlandish as touting a high addiction and abuse potential. However, it is true that they are relatively uncommon to abuse, risk of harm is low, and most people find them to reduce addictive behavior and tendencies rather than exacerbate them. Some modern researchers have argued it is still reasonable to regulate classic psychedelics as controlled substances. One systematic analysis of psilocybin’s abuse potential has argued that categorizing it as a Schedule IV could be appropriate primarily based on the potential for dangerous behavior in unprepared, unsupervised users, and exacerbation of mental illness in those with or predisposed to psychotic disorders [26].

Moderate Addiction Risks with MDMA, Ketamine, and THC

Some psychedelic drugs  pose addiction risk while also displaying some antiaddictive properties. MDMA, tetrahydrocannabinol (THC), and ketamine  can all  be beneficial—MDMA through dopamine release, S-ketamine by binding opioid receptors, and THC by simulating CB1 receptors. At the same time, there are more reports of people developing ketamine, MDMA,  and cannabis use disorders than with classic psychedelics. Beyond having pleasurable and reinforcing properties, MDMA, ketamine, and THC also have relatively short durations of action and/or are commonly administered in methods other than oral. Drugs that are euphoric and last a shorter duration tend to be more addictive. Non-oral administration combined with a short latency of effect onset such as those common with ketamine (e.g. insufflation, intramuscular, or subcutaneous) or THC (inhalation) can increase intensity of experience, propensity for redosing, and addiction risk.

Addiction Potential of MDMA

MDMA, commonly known as ecstasy, is a serotonergic amphetamine belonging to the phenethylamine group of psychedelic substances. Mechanistically, it primarily releases serotonin while also releasing norepinephrine and dopamine, stimulating serotonin receptors, and releasing neuropeptides (oxytocin, vasopressin). MDMA has long been feared or sensationalized as having severe neurotoxic after-effects and high risks for addiction. While heavy and long-term ecstasy use is linked with damage to the serotonergic nervous system as well as mood dysregulation and cognitive problems, intermittent use in persons with PTSD in therapeutic environments has not suggested or detected any long-term neurocognitive problems or subsequent addiction [27-31].

In comparison to MDMA, methamphetamine releases little serotonin, but more dopamine and norepinephrine. Greater dopamine release (and use through inhalation, insufflation, or injection) tends to make methamphetamine’s addiction and neurotoxic potential higher than MDMA’s. Some novel psychedelics can release serotonin to a similar extent as MDMA, but they also release dopamine like methamphetamine does and they have shorter durations of action. This creates an intense short-term euphoria that is quickly gone, increasing the propensity and craving to re-dose the substance [8, 9]. Mescaline is the only classic psychedelic belonging to the phenethylamine group of psychedelics and is not thought of as addictive at all, which is perhaps surprising given it likely does have the ability to release dopamine. It could be that the predominant serotonergic mechanism and the ultra-long duration of action (mescaline experiences can last 12-18 hours) tip mescaline’s profile toward being anti-addictive overall [32].

Addiction Potential of Ketamine

Ketamine is an arylcyclohexylamine that is regulated as a Schedule III controlled substance, meaning that it has a recognized medical utility and is legal within the healthcare system as well as carrying some potential for abuse or addiction. It has traditionally been thought to work as a glutamate antagonist and dissociative anesthetic, although it has complex neuropharmacology that includes the ability of esketamine (S-isomer of ketamine) to bind, stimulate, and create rewarding or reinforcing effects via the opioid system [33, 34].

At subanesthetic doses ketamine has been used in recreational settings as well as for the treatment of depression, suicidality, and other psychiatric illnesses [35-38]. Ketamine is often administered through intranasal, intramuscular, or parenteral routes both in recreational and therapeutic settings. Ketamine use disorder can lead to neurocognitive problems and lower urinary tract symptoms [39, 40]. Exacerbated by high-profile deaths involving ketamine use, concerns in medical communities have increased as ketamine becomes more popular for the management of mental health conditions expands into telehealth settings. It is fair to consider the addictive potential of ketamine as a risk as clinical use increases, although reports of patients using ketamine therapy who develop substance use disorders are sparse.

Addiction Potential of THC

Cannabis, and particularly THC, producing a pleasurable and rewarding effect, can be habit forming and lead to cannabis use disorder. THC as a pharmaceutical formulation is regulated as a Schedule III controlled substance, while cannabis is variably regulated on a state level and regulated as a Schedule I or illicit substance at the federal level. THC has acute psychoactive effects that some persons experience as psychedelic or causes psychedelic effects (e.g. hallucination) when used by relatively naïve people, in large doses, or with concentrated products [41]. Thosey pioneering and touting results of cannabis-assisted therapy borrow heavily from the psychedelic therapy playbook in applying it to cannabis use [42].

Many find that cannabis use in a consistent and controlled or therapeutic manner is helpful for some conditions or can be used to replace other controlled substances that pose greater risk of addiction or physical danger. Swapping alcohol, sleep aids, opioids, or other narcotics with cannabis is likely a reasonable trade. Others find that its pleasurable and short-lived effects encourage re-dosing. Further, the unsupervised nature of even most medical cannabis programs makes it difficult to control use. While much anecdotal evidence supports these trades or benefits as possible, formal research is thin. For example, studies of the opioid-sparing effects of cannabis are controversial, some suggesting benefits and others not [43, 44].

Can Addictive Substances Have Anti-Addictive Effects?

There is a level of nuance to this conversation that is often neglected. It’s commonly thought that any drug with addictive potential will lead to addiction if the user already abuses a different substance. This is unlikely to be true in many cases. Even with MDMA, ketamine, and THC, which have real, albeit moderate, addictive properties, data supports benefits: ketamine-assisted therapy combined with a mindfulness training reducing cocaine cravings and use; a pilot study of MDMA-assisted therapy for alcohol use disorder [45, 46]. 

Even psychedelic substances that have moderate addiction risk can be anti-addictive when they are used within addiction treatment contexts. When used outside of treatment—without any of the accountability, protocol, or intention present in a therapeutic paradigm—they can be addictive or at least pose a greater risk of harm or uncontrolled use. It might be well advised for a patient to refrain from substances like MDMA if they have addictions with overlapping pharmacology, such as stimulant use disorders.

Can Psychedelics Address the Origins of Addiction?

 Addictive conditions have been misconstrued as some sort of personal flaw stemming from a lack of discipline or a hedonistic nature. We’ve already discussed how dopamine can lead to reward-based reinforcement that makes a behavior more likely to be repeated with use. Also central to the roots or etiology of addiction are trauma and adverse childhood experiences (ACEs). An individual’s ACE score— the number of difficult childhood events they experience before age 18—is predictive of substance use problems and mental and physical illness in adulthood.

 It is likely that as ACEs accumulate, or trauma repeats, it creates dysphoric, distressing, and dysregulated feelings and emotions. The individual begins to feel unwell and may also be in a neurodevelopmental stage characterized by desiring social acceptance and being susceptible to pressure from peers. Initial drug use provides feelings of pain relief, suspension of difficult emotions, social acceptance, confidence, or other benefits. With subsequent use, an insidious tolerance, craving, or physical dependence develops. The person needs the substance to feel normal and medicate the underlying pain, but they’re also feeling trapped in the addictive use pattern and begin experiencing turbulence associated with intoxication and withdrawal.

One hypothesis that could help explain the transdiagnostic potential, or the ability of psychedelics to work for several different conditions, involves their ability to effectively address past trauma. Research supports that psychedelics open “neurodevelopmental critical periods,” lead to psychological regression, and affect the amygdala and hippocampus to improve fear extinction learning [47-54]. For many people, addressing the past in a way that it can truly rest is going to be a big part of their healing journey with psychedelics and it’s pertinent in the recovery journey as well.

 Psychedelic therapies may truly address the etiology of painful experiences that shape the original motivations for substance use or at least partially drive continued use. As discussed below, psychedelics also can affect neuroplasticity, the functioning of the default mode network, spiritual experience, and therapy itself in the healing of trauma and in addiction recovery.  

Psychedelic Neuroscience and Addiction Medicine

From a neuroscientific standpoint, information is accumulating suggesting that psychedelics could be neuroplastic catalysts for change, enhance dynamic problem-solving capabilities, soften the rigidity of beliefs, increase divergent modes of thought, and reorganize the sense of self and how one relates to the world [55-58].

Some hypotheses regarding these changes center on the disruption by psychedelics of functionally interconnected brain regions comprising the default mode network (DMN). Psychedelics acutely diminish self-referential brain activity that is active at rest or when the brain is not focused on a task. This results in an entropic brain state in which neurons that often fire together do not and distant brain regions may communicate more. Key parts of the DMN include part of the prefrontal cortex as well as the amygdala. Psychologically, reduction of DMN activity is correlated with ego dissolution and the mystical experience. As the experience dissipates, a re-organization of DMN activity can occur that integrates the functional reset and new views of self into a user’s life [57, 59-61].

Other theories focus on changes to cortical processing or corticothalamic loops [62-66]. Many serotonin-based psychedelics that act on the 5HT2A receptor as well as ketamine acting on NMDA receptors act locally in the cortex, particularly in layer V pyramidal neurons. Their activity at these receptors changes cortical processing to reduce top-down control or strength of signals from transmodal association cortices while increasing bottom up signaling from deeper brain regions or simpler (unimodal) areas of the cortex. The overall effect may be a reduction in rigidity of existing beliefs, liberation of emotional content from the subconscious, and an allowance for novel experience due to relaxation of prior beliefs and a reinterpretation of perception.

The binding of 5HT2A or NMDA receptors by psychedelics can upregulate neurotrophic factors such as BDNF. Classic psychedelics were recently demonstrated to bind directly with tyrosine kinase receptors that increase BDNF signaling [67-69]. Psychedelics are known to stimulate dendritogenesis or spinogenesis, meaning they could shape new neural connections among existing neurons. Psychedelics such as ibogaine can also upregulate GDNF and have additional unique pharmacologic actions that could contribute to their anti-addictive pharmacology [11, 12].

Leveraging these theories of psychedelic action by translating them into behavioral neuroscience interventions that are embedded within psychedelic therapy could be a powerful way to enhance their efficacy and application toward changing habits or behaviors. If psychedelics offer a possibility for relearning, reinterpretation, and reorganization of a self-identity, we’ll likely get better results by coupling use with interventions that could foster neuroplasticity, leading to new habits and resting states.

Psychedelics, 12-step Programs, and Spirituality

A 12-step program recognizes addiction as a spiritually rooted illness. If you give yourself over to a higher power, admit that you are not in control of everything, and recognize and take responsibility for what is within your power, you are on a spiritual path. Many of the steps focus on acknowledgment and accountability for one’s past actions, including the harms they’ve done to others. Because the 12-step recovery path from addiction is inherently spiritual, it’s reasonable to assume some synergy between the 12-step program and psychedelic therapy.

From anthropological sources, we understand that for millennia psychedelics have traditionally been used for expanded consciousness, spiritual states, community ritual, and shamanic healing. Modern-day clinical research into mental illness was ignited by the study of psilocybin for the spiritual dimensions of consciousness or the mystical experience it opened up[70-73]. Marked by positive mood, sacredness, oceanic boundlessness, ineffability, or transcendence of time and space, the mystical experience consistently ranks in the top five most meaningful experiences of a person’s life. Most of the research supports that subjective experience including spiritual feelings, insights, or awareness is correlated with improvements in symptoms of mental health conditions, improved functioning, and greater overall well-being. The experiences evoked by psychedelics can often inspire adoption of spiritual practices that are also evidence-based therapies to support mental health, such as meditation or mind-body practices. Separation of “medical” from “spiritual” benefits is a false divide.

The psychedelic experience can be a powerful catalyst, granting expanded emotional and spiritual states that resolve ambivalence and motivate a person for change, but the person still has to take the steps down that path of change if they want to ultimately get better. The recovery steps—making a searching and fearless inventory of ourselves, listing all beings we've harmed and becoming willing to make amends to them all—are a tough process of engagement in deep work and a commitment to being accountable. psychedelics work better when they're coupled with a  mindful goal and a program  for accountability. It makes sense that those who are already seriously engaged in a 12-step recovery path may be open to psychedelics in therapeutic contexts as a valid part of their recovery path.

Clinical Research and Considerations for Substance Use Disorders

The research for treating addiction with psychedelics is not as extensive as that for treating PTSD with MDMA-assisted therapy or treatment-resistant depression with psilocybin-assisted therapy.,  However, there are some promising studies on treating substance use disorders with a number of psychedelics[74-77]. Psychedelics appear to have transdiagnostic utility, which could make them  helpful for many conditions currently managed with medications like antidepressants: depression, PTSD, OCD, generalized anxiety, and social anxiety.

All the first-line treatments for those conditions are SSRI antidepressants, although almost all classes of psychiatric medications can be used for refractory cases or symptoms. Despite extensive research, the data does not support SSRI antidepressants as addiction treatments in and of themselves, whereas the serotonergic psychedelics and ibogaine do seem to have that kind of effect or property to them. Therefore, psychedelic mechanisms represent novel discoveries in addiction medicine and are likely real breakthroughs. Their ability to improve comorbid psychiatric conditions that could increase risks of substance use is significant given the prevalence of dual diagnosis or the occurrence of both substance use disorder and mental illness within an individual.

Psychedelic therapies typically necessitate a wider framework beyond therapeutic supervision. Preparation and integration, along with attention to nonpharmacological factors (set and setting) shaping the experience  and are thought to be critical to achieving optimal outcomes and minimizing any risks of use [77]. In trials and studies that involve psychedelic therapy for substance use disorders, the therapy is adapted to involve a recovery-based framework.

Some substance use disorders can make psychedelic use risky, requiring a preparation phase that involves detoxification and/or a period of abstinence before psychedelics can be used safely. For example, abrupt discontinuation of heavy alcohol or benzodiazepine use can result in severe insomnia, suicidality, seizures, or even psychosis, all of which contraindicate use of or could be exacerbated by psychedelics in such acute contexts. Therefore, people who experience acute alcohol withdrawal may need to detox and stop or reduce benzodiazepines before being able to safely and effectively use psychedelics. Other combinations—such as amphetamines, cocaine, or serotonin reuptake-blocking opioids with MAOI-containing psychedelics like ayahuasca—can pose severe risks [78]. Ibogaine causes a reverse tolerance to many drugs, which can raise risks of arrhythmias or other problems if used in combination [79].

As far as human research, there are several positive trials. Collectively, classic psychedelics such as psilocybin, LSD, and mescaline are all anecdotally notorious for being able to reduce cravings for alcohol. A meta-analysis of older randomized trials supports this for LSD, while both pilot studies and a randomized trial conducted more recently support this for psilocybin [19, 80, 81]. Little formal data has been collected for mescaline, yet peyotism is documented in anthropological sources as helping Native Americans quit drinking alcohol. MDMA also has positive pilot study data for alcohol use disorder [46].

Psilocybin has a positive pilot study for tobacco cessation, ketamine could help reduce cocaine dependence, and ayahuasca has some pilot data for various substance use problems. Many more trials into other conditions, such as stimulant use disorders, are planned.

Ibogaine displays antiaddictive effects in preclinical models of substance use disorders for nicotine, alcohol, cocaine, and opioids [82]. There are also several cohort studies or case series observing antiaddictive effects of ibogaine in people with opioid or cocaine use disorders [1-3, 5, 6]. In addition to potentially addressing psychological dependence (cravings) associated with a variety of drugs with addictive potential, ibogaine is well known for its ability to rapidly detoxify people who are physically dependent on opioids. Due to these truly novel effects, it’s apparent there is a rich offering and probe into the neurobiology of addiction and medicinal treatments of it in ibogaine. The major rub is ibogaine’s unique potential for cardiotoxic and arrhythmogenic effects, although they can be mitigated with appropriate screening, safe use and access to emergency treatments, and other interventions to improve tolerability (e.g. IV magnesium sulfate) [83].

While all the existing data is glowing, and it is likely that psychedelics truly represent breakthroughs in addiction medicine, it is quite limited and insufficient to draw strong conclusions from. Overall, it is still much more reasonable to conclude that with mindful preparation and a therapeutic framework for use, psychedelics are more likely to help addictions than harm persons or cause them.

Contraindications - Conditions and Circumstances

Active Substance Use

Psychedelics are generally safe and well-tolerated substances. However, active substance use disorders that may involve erratic use of dangerous substances as well as the psychological and physical consequences of those use patterns can increase risks. As mentioned previously, a preparation phase that involves specific consideration to the substance use disorder, its severity, the risk in combination with the psychedelic, and possibly detoxification and an abstinence period may be necessary for safety and to optimize benefits. Psychedelic therapies can frequently benefit substance use disorders, yet severe substance use disorders can contraindicate psychedelic use until some treatment or therapy is started.

Psychosis or Mania

Psychiatric conditions that involve symptoms of psychosis or mania such as schizophrenia or bipolar I disorder are commonly thought to contraindicate psychedelic use due to potential for exacerbation of the condition. The contraindication is very strong when there is a hereditary risk involving several family members or the symptoms of psychosis or mania are present outside substance intoxication and withdrawal periods. The contraindication is less strong and more relative when symptoms of psychosis or mania have historically occurred solely in the context of substance intoxication or withdrawal, especially upon an isolated historical instance with extreme circumstance that may otherwise explain the symptoms that occurred. Intoxication with amphetamines, cocaine, and other stimulants can precipitate mania or psychosis along with withdrawal from sedatives like alcohol or benzodiazepines. If you have a history of psychosis, or mania resulting from psychedelic use alone or in the context of using them with other drugs, it is reasonable to seek specialized evaluation before using psychedelics.

Seizures and Epilepsy

Neurological conditions such as seizure disorders and epilepsy are also commonly thought to contraindicate psychedelic use. There are some reports of seizures occurring with psychedelics use, yet they lack data characterizing their potential to cause seizures. Persons with a history of seizures that are isolated to periods of intoxication or withdrawal could likely use at least classic psychedelics or ketamine safely. Taking epilepsy medication regularly, having  seizures regularly with or without medications, and a history of severe or prolonged seizures would contraindicate psychedelic use.

Cardiovascular Conditions

As most psychedelics can increase blood pressure and heart rate, and older people and those with certain advanced cardiovascular conditions have been excluded from clinical trials. Reports of heart attacks or strokes with classic psychedelics are sparse, although there are a few in medical literature and  anecdotal reports. People with a history of heart attack, stroke, valvular heart disease, pulmonary hypertension, clotting conditions (DVT, PE), heart failure, arrhythmia, angina, or coronary artery disease may need careful screening or be contraindicated from using psychedelics.

When conditions are severe, cause complications, have debilitating symptoms, impair the ability to consent, or require heavy medication, it may be reasonable to consider them contraindications to using psychedelics until more safety information is available.

Contraindications - Psychiatric Medications

 Several interactions between traditional psychiatric medications and psychedelics are clinically significant. For example, several medications that work on the serotonin nervous systems—SSRI or SNRI antidepressants, lithium, trazodone, mirtazapine, buspirone, atypical antipsychotics, and MAOIs—carry potential drug interaction risks with most serotonergic psychedelics. Others that likely pose significant drug interaction potential with serotonergic psychedelics and ketamine are those that work by facilitating gamma-aminobutyric acid (GABA) neurotransmission such as benzodiazepines and (at higher ends of their dosing spectrum) gabapentinoids such as gabapentin or pregabalin. Many of these drug interactions result in diminished psychedelic activity and may not carry high risks of physical harm, but could pose significant barriers to meaningful psychedelic therapy. Others can truly be dangerous depending on the psychedelic substance and medication in question.

 Tapering psychiatric medications may be challenging and lead to  destabilizing withdrawal or worsened symptoms of psychiatric illness. If psychiatric medications are part of recovery or stabilization efforts at a time of crisis and are working well, psychedelic therapy that requires tapering and flushing out of medications needs serious consideration about whether it can be undertaken safely. On the other hand, many people begin  taking medication while using substances and experience minimal or no symptoms when they stop taking them. After doing a lot of work on themselves, they may feel tapering and discontinuing medication followed by psychedelic therapy is the right next step for them on their healing journey, recovery, or personal and spiritual growth path. To the maximum extent possible, people should work with their providers to collaboratively taper and stop medications and seek individualized information if unsure about interaction risks and experience planning. Most drug interaction risks, particularly with classic psychedelics, are rather gray overall. In the true spirit of set and setting, medication management is an important aspect of safe and effective psychedelic therapy.

Many other psychiatric and nonpsychiatric medications could carry some drug interaction risk with psychedelics. Controlled substances such as stimulants, opioids, and those previously mentioned could modulate experience or raise risks of use. Medications prescribed for medical conditions are less likely to directly interact with psychedelics as they do not target the brain or central nervous system. However, every medication is a surrogate marker for an underlying illness and every condition should be given some thought as to whether it poses risks.

Dosing and Approach to Psychedelic Use

Moderate doses of psychedelics taken within a therapeutic framework that can create spiritual experiences or mystical effects are the “gold standard”— the evidence-based way of approaching recovery from substance use or addressing symptoms of mental health conditions. People on a recovery path may truly prefer to use psychedelics in a controlled, ritualized, facilitated, and supervised manner in contrast to the uncontrolled manner of substance use. This may help to create a meaningful distinction between past substance use and current psychedelic use,  providing reassurance that their therapeutic use of a mind-altering substance is not the same as active substance use or inconsistent with a recovery path.

 All this said, many persons considering psychedelics may be well advanced on their recovery path and not necessarily approaching psychedelics because they want or need to have large spiritual experiences. Perhaps they are interested in seeing if microdosing, or taking very small amounts of a psychedelic on a semi-consistent and cyclical basis, can deepen their meditation practice or improve regular talk-therapy sessions. The research on microdosing is less mature than on psychedelic-assisted therapy. We now have phase II and III trials with MDMA, psilocybin, ketamine, and placebos in psychedelic-assisted therapy for patients with various illnesses and conditions . Almost every trial has produced an unprecedented positive result for psychiatry. Whereas most microdosing surveys suggest great benefit,  clinical trials suggest minimal effects, placebo, or expectancy bias-related effects. Microdosing experiments have mostly had few or single doses in lab conditions, featured healthy people and those with previous experience using psychedelics. Further research in natural environments and coupling with different therapeutic frameworks may be positive future directions.

Summary and Conclusions on Psychedelics and Addiction

 There are many facets of psychedelic therapies and experience that could help people recover or further an addiction recovery path including healing of trauma, reduction in psychiatric illness, spiritual experience, neuroplasticity and potential for change, supportive therapeutic frameworks, and antiaddictive neurochemical effects. Little data supports that psychedelics have a high potential for abuse, although some psychedelics do have abuse potential and reinforcing effects. Information is rapidly increasing to support psychedelic therapy’s positive benefits on substance use disorder or mental illness. Careful screening and management of existing medications and conditions may be required for safe and beneficial use of psychedelics. Pairing substance use disorder treatment or recovery from substance use disorders with a therapeutic framework that considers aspects specific to addiction increases safety and benefits. Overall, mindful psychedelic use could augment 12-step programs such as Psychedelics in Recovery.

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