Overview

• Synthetic amphetamine derivative, sometimes referred to as ecstasy
• Primary effects result from 5-HT serotonergic release and reuptake inhibition, as well as dopamine and norepinephrine release and reuptake inhibition[6]
• Serotonergic effects lead to increased euphoria, energy, extroversion, and empathy.[7]
• Typical dose is 75 to 150 mg, onset between 20 mins to 1 hour, and peak concentrations at 2 hours. Half-life is approximately 40 hours, but active metabolites may persist after clearance of the drug.[8]
• Typically taken orally; insufflation and injection are less common[8]

Approaching recreational challenges with MDMA

• Medical Risks
  • Cardiac risks
    • Risk of significant increases in heart rate and blood pressure[9], consider medical comorbidities, avoid use in those with cardiac disease
    • Can cause valvopathy secondary to activation of 5HT2B receptors in the heart
      • In a study of 29 chronic MDMA users, valvular abnormalities were found in 28% of users compared to 0% of age- and gender-matched individuals.[10]
  • Hyponatremia and hyperthermia
    • Risk is especially increased in certain naturalistic settings including at dance parties or raves due to increased physical activity leading to diaphoresis, decreased awareness leading to not engaging in typical behaviors for thermoregulation[11]
    • Greater risk of hyponatremia in females[12], possibly due to sex-based pharmacokinetic differences[13]
    • Hyperthermia can occur even at typical recreational doses due to metabolism variations or drug interactions.[11]
      • It is important to note that hyponatremia and hyperthermia can occur even when MDMA is used alone.[14]
  • Neurotoxicity
    • Risk is theoretically higher with chronic use, repeated use without breaks.[11]
    • Multiple possible causes of neurotoxicity including direct effect of toxic metabolites, oxidative stress, hyperthermia. However, no definitive evidence of MDMA-induced serotonergic or dopaminergic neurotoxicity in humans.[15]
    • In rat models, high doses can affect memory and lead to increased risk of negative effects.[16]
  • Serotonin syndrome
    • Acute confusional state with hyperthermia, hyperreflexia, and clonus
    • Unlikely with SSRIs/SNRIs, possibly due to their inhibitory effects counteracting MDMA’s transporter reversal.[17]

• Risks with Comorbid Psychiatric illness
  • Depression and suicidality
    • "Suicide Tuesdays": Rebound depression and lethargy after acute use[18]
      • Depletion of serotonin may contribute to transient depressive symptoms, compounded by increased impulsivity[18]
    • Increased risk of depression, impulsiveness and sleep disturbances in chronic users compared to controls which may not remit after abstinence[19][20]
    • Case studies have demonstrated greater risk of psychotic symptoms, anxiety and manic attacks, delusions, hallucinations or illusions after MDMA use. However, there were varying levels of use and dosing.[21]

• Drug interactions[22][23]
  
  • Overview
    • Primarily metabolized by CYP2D6[8], metabolism of MDMA or other drugs can be affected by inhibition or up-regulation of these enzymes.
    • Increased risk of mortality when used with other substances, especially those associated with cardiac adverse events[23][24]
  • Antidepressants
    • Theoretical risk exists but appears clinically low[17]. In fact, SSRI/SNRI/TCA administration with MDMA may actually attenuate subjective effects of MDMA. [17]
      • However, more people who used ecstasy with antidepressants reported more muscle rigidity, nystagmus, and dizziness compared to those who did not use other pharmaceutical drugs with ecstasy.[25]
    • MAOIs are contraindicated due to high serotonin syndrome risk.[17]
    • Tricyclic antidepressants have additional sympathomimetic effects that may increase risk of cardiac side effects.
  • Stimulants
    • With concurrent methylphenidate, additive sympathomimetic effects may increase risk of arrythmia, hypertension, vasoconstriction (increased MI risk).[22]
  • Antipsychotics
    • Few studies on combination, however on one study of healthy volunteers, pretreatment with haldol attenuated MDMA-induced euphoric and manic-like effects [22]
  • Benzodiazepines
    • Generally safe, though caution is needed with other CNS depressants such as opioids. Often used as a treatment for acute agitation in the setting of MDMA use.[26]
  • Opioids
    • Serotonergic opioids (ex. tramadol) can theoretically increase risk of serotonin syndrome.
    • Opioid overdose remains a risk, especially with fentanyl.
  • Other drugs
    • Over-the-counter supplements such as St John’s Wort may increase risk of serotonin syndrome.[22]
    • Individuals who use MDMA may also take supplements as a means to reduce harm of MDMA use, including magnesium and 5-HTP.[27]
    • Consider use of other pharmaceuticals to reduce side effects and enhance experiences on MDMA, such as sildenafil[25]

• Use with other substances
  • Alcohol: Concurrent use of MDMA and alcohol increases risk of hyperthermia, dehydration and hyponatremia[28]. Concurrent use can also increase in MDMA concentrations.[22]
  • THC: One trial that demonstrated THC did not alter MDMA plasma concentrations but did decrease heart rate.[22]
  • Caffeine: Combined with MDMA to reduce drowsiness and fatigue, can be consumed via various products such as energy drinks and caffeine tablets, but also found as an adulterant in ecstasy.[22]

• Harm-reduction strategies
  
  • Screen for adulterants
    • Patients should be encouraged to test substances before use.[29] Various organizations promote drug testing kits that can be purchased online.
    • Offer naloxone due to possible opioid-containing adulterants, encourage use with sober trip sitter.
  • Adjust frequency and dosing
    • Encourage appropriate dosing and avoiding high doses of MDMA, including using weight scales to measure appropriate dose (avoid "eye-balling" amount).
    • Avoid repeated dosing on consecutive days, take drug holidays to reduce risk of neurotoxicity.[11]
  • Monitor acute mood or psychiatric symptoms post use
    • Ensure safety planning and access to crisis resources.
    • Encourage patients to spend time with supports in the days after use.
  • Assess for drug interactions
    • Perform medication history and reconciliation with patients before use, ask about supplements such as St. John’s Wort that may affect metabolism and levels of MDMA.
    • Discuss with patients possible surreptitious use of pharmaceuticals to enhance effects of MDMA, including use of sildenafil.[25]
  • Advise on reduction of risk related to hyponatremia and hyperthermia
    • Encourage patients to avoid excessive fluid intake, limit to 500 mL to 1 L per hour during intense activity.[13]
    • Take regular breaks from physical activity when using MDMA.
    • Avoid combination with alcohol as this may increase risk of hyperthermia.[28]

Overview

• Primarily acts as an antagonist on NMDA receptors in the central nervous system.[30]
• Dose-dependent dissociative state typically with perceptual disturbances, derealization, and hallucinations. At high doses, users may experience marked dissociation and detachment, often referred to as a "k-hole".[30][31]
• Most common negative symptoms experienced by users in naturalistic settings include unexpected confusion, abrupt mood changes, and memory impairment[32]
• In recreational settings, most commonly administered via insufflation or smoking.[30] Primarily eliminated via kidneys.[30]
• Many ketamine users report a lack of adequate education and resources on its risks and treatment.[33]

Approaching recreational challenges with Ketamine

• Medical risks
  • Acute cardiovascular and respiratory effects
    • Sympathomimetic effects can increase heart rate and blood pressure, increasing risk of complications in those with preexisting cardiovascular disease.[30]
    • Respiratory depression is less common. Ketamine does not affect respiratory drive (and thus has less risk of death due to overdose secondary to sedation)[34], however risk can increase with adulterants or concurrent use of other substances.[30]
  • Acute neuropsychiatric effects and neurocognitive impairment
    • Intoxication may impair working, episodic, and semantic memory, symptoms can persist hours to days post use[31][35]
    • Semantic memory impairments typically resolve after ketamine discontinuation in recreational users but episodic memory Impairments and attentional functioning may persist after cessation.[36]
    • Heavy use is particularly associated with negative cognitive and psychological outcomes.[37]
  • Chronic use and urological complications
    • Particular risk with immunocompromised individuals or those with underlying kidney or urological disease.
    • Long term use of ketamine can lead to ketamine induced ulcerative cystitis, with symptoms of urinary frequency, urgency, dysuria, urge incontinence, and hematuria.[30]
      • This is distinct from interstitial cystitis, which typically does not present with urinary incontinence.[30]
    • In a survey of those using ketamine, bladder problems were the most cited physical complaint from ketamine use[33].
  • Hepato-biliary and GI effects
    • Chronic ketamine use can lead to cholangiopathy.[30]
    • Regular users report abdominal pain and vomiting as a side effect of use, typically referred to as "K cramps." Users often will use more ketamine to relieve these symptoms, which complicates cessation efforts. Symptoms often resolve with discontinuation.[30][34]
      • Anecdotal reports (e.g., “swallowing the drips”) lack empirical support, however, this does not appear to be an accurate cause of these symptoms.[34]
• Comorbid psychiatric illness
  • Acute psychiatric effects
    • Transient psychotic symptoms have been noted with acute intoxication of ketamine.[34]
    • While ketamine has been used in the psychiatric setting to treat major depressive disorder, increased depressive symptoms were observed in daily and ex-ketamine users over the course of a year, however, they did not meet clinical criteria for a major depressive disorder. Infrequent users did not exhibit worsening symptoms.[34]
    • In one study, higher doses of ketamine were associated with worsening depressive and anxiety symptoms.[38]
  • Co-occuring bipolar or psychotic disorders
    • Frequent use has been linked to elevated delusional thinking compared to infrequent and non-users[35], which may persist after discontinuation.[36]
    • Patients with schizophrenia who use ketamine noted a resurgence of their psychotic symptoms after use of ketamine.[34]
  • Behavioral disinhibition and accidental death secondary to dissociative effects
    • The primary mortality risk is accidental death during intoxication.[34]
  • Dependence and addiction potential
    • Repeated dosing leads to rapid tolerance (tachyphylaxis), leading to escalation of use.[34] Some users report compulsive use until depletion.[34]
    • High potential for psychological dependence, especially in individuals with prior SUD history. Mild withdrawal symptoms may include mood lability, anxiety, and cravings. [30][33]
• Drug interactions
  • Antipsychotics: In clinical use of ketamine for depression, clozapine, risperidone, and haloperidol may attenuate effects. [39]
  • Mood stabilizers: In clinical use, ketamine appears safe with lithium, though lamotrigine may blunt effects.[39]
  • Stimulants: May elevate acute cardiovascular risk.[34]
• Use with other substances
  • Increases risk of overdose and mortality when used with other substances. In one study examining deaths involving ketamine in Australia, 95.5% of ketamine-associated fatalities involved co-ingestion[40]
  • Concurrent use of ketamine and alcohol exacerbate urological risk[41]. In mouse models, combination of ketamine and alcohol resulted in renal and hepatic toxicity.[42]
• Approach to Harm Reduction
  • Reduce frequency of use and dose
    • Increasing inter-session intervals and reducing dose may lower cumulative harm.[32][35]
    • Those who use ketamine can also space out re-dosing within a session.[32]
    • Reducing dose may also reduce psychosocial risk secondary to acute intoxication and dissociation.
  • Encourage trip-sitters during acute use
    • Most ketamine-related deaths are accidental; encourage patients to have a sober trip-sitter that can remain with the patient while they are acutely intoxicated.[34]
  • Screen for adulterants
    
    • Given risk of adulterants in drugs, offer naloxone to those using ketamine. In one study, opioids were the most common co-ingested substance in deaths involving ketamine.[40]
    • Similar to MDMA, drug testing is available (see MDMA above).
  • Monitor for side effects
    • Validated instruments (e.g., Ketamine Side Effect Tool – Revised) can support side effect tracking and facilitate motivational interviewing.[43]

Overview

• Psychoactive tryptamine, most commonly from genus Psilocybe, taken orally in mushrooms, sometimes in chocolates/edibles due to bitter taste
• Variations in potency depending on species[44]
• Rapidly metabolized into active metabolite psilocin[45]
• Primary mechanism is agonism at the 5-HT2A serotonin receptor, and can cause alterations of perception, emotion, and cognition.[46]
• Generally safe in isolation, even at higher doses (LD50 likely greater than 250 mg/kg)[47][48]
• Psilocybin exhibits rapid tolerance (tachyphylaxis) and lacks reinforcing properties, and therefore has low addiction potential.[47]

Approaching recreational challenges with Psilocybin

• Medical comorbidities
  • Unlikely to cause medical issues even at higher doses, but has not been studied in those with structural heart issues[10]
    • Has been safely used in patients with late-stage cancer[47]
  • Can cause adrenergic-mediated elevations in heart rate and blood pressure, possibly due to phenylethylamine content found in mushrooms[44]
  • There are rare cases of serious cardiac adverse events when taken at high doses and mixed with other substances.
  • QT prolongation and ST-segment changes have been observed, though risk is minimal at standard doses of 25 mg.[10]
  • There is also the theoretical risk of 5-HT2B-mediated valvopathy, not observed clinically.[10]

• Comorbid psychiatric conditions:
  • Clinical trials are conducted with trained staff under controlled settings, limiting generalizability -- much of what is found may not be applicable to naturalistic setting.[46]
  • Classic psychedelics are generally well tolerated in clinical trials. The few serious adverse events occurred in individuals with pre-existing psychiatric illness.[49]
  • Most trials exclude individuals with personal or familial psychotic spectrum disorders (therefore, less data).[46]
  • Increasing use among younger individuals who may not have had an exposure that increases the risk of developing first episode of a primary psychotic or affective disorder[50]
    • In a cross sectional study of adolescents who used LSD or psilocybin, psychedelic use was associated with lower rates of psychotic and manic symptoms, though risk increases with genetic vulnerability.[51]
  • Self-reported outcomes in individuals with bipolar disorder suggest possible symptom exacerbation within two weeks post-use.[52]
    • However, many reported achieving their aims for use.[52]
  • Lifetime psychedelic use is linked to increased visual phenomena, particularly in those with genetic risk.[53]
  • Emergency department presentations involving hallucinogens showed a 21-fold increased schizophrenia risk vs. general population.[54]

• Psychotropic Drug Interactions: Limited data exists on psilocybin’s interaction with psychotropics
  • SSRIs – SSRIs/SNRIs may blunt subjective effects
    • Escitalopram pretreatment for 14 days: did not attenuate altered state, reduced anxious distress, did not markedly affect QTc.[17]
    • Alternatively, survey data of those that used psychedelics in the naturalistic setting suggests that SSRIs/SNRIs attenuate effects.[55]
  • Lithium – Survey data suggest increased seizure risk with lithium [56]. Lithium and other mood stabilizers may be associated with increased difficulty during challenging experiences[57]
  • Antipsychotics – D2 and 5HT2A antagonism (especially latter, possibly given MOA of psilocybin) may dampen psychedelic effects,[17] Haloperidol, lacking 5-HT2A blockade, may worsen subjective experience
  • Benzodiazepines – no literature on combination with psilocybin, but benzodiazepines are commonly used in trials to manage acute anxietys[46]

• Use of Psilocybin with Other Substances:
  • Overview
    • Co-use with other substances increases risk of adverse effects.
    • In a survey of those who had challenging experiences with psilocybin in the naturalistic setting, 53% used cannabis and 19% used alcohol before or during use.[5]
    • Of 4,055 poison center calls, two deaths involved co-ingestion (e.g., fentanyl, methamphetamine).[58]
  • Cannabis/THC
    
    • THC and cannabis may potentiate effects, increasing risk of dysphoria.[5]
      • Some users desire the enhanced effects with co-administered psilocybin and THC, and some users report cannabis helps mitigate distress.[57]
    • Clinicians should be mindful that cannabis and THC-containing products vary in potency and are not regulated by the FDA.
  • Alcohol
    • Lack of studies on concurrent alcohol-psilocybin use
    • However, unlikely to have a synergistic effect with psilocybin based on pharmacology
    • Alcohol may impair judgment, increasing behavioral risk.
    • Patients in the naturalistic setting may be considering use of psilocybin as “treatment” of alcohol-use disorder.[45] However:
      • At this time, there is a lack of evidence that psilocybin is an effective treatment for alcohol use disorder despite promising preliminary results.
      • The naturalistic setting is not comparable to the clinical setting where promising results were found.[2]
      • Psilocybin does not mitigate withdrawal symptoms or risk of delirium tremens, and therefore patients who discontinue alcohol after psilocybin use should be monitored for withdrawal, especially if they have a history of complicated withdrawal or extensive alcohol use history.
  • MDMA:
    • The combined use (aka ’candy-flipping’) intensifies effects of both substances.
    • Serotonergic action of MDMA + psilocybin theoretically increases risk of serotonin syndrome, though empirical evidence for serotonin syndrome remains lacking.[17]
    • Adulterants in MDMA are greater risk here (see section on MDMA and harm reduction).[29]
• Challenging experiences
  • Acutely distressing episodes, commonly termed ‘bad trips’[57]
  • Distress may stem from onset effects or uncontrolled context, being in the wrong environment or mindset, being without psychological support and using close to a major life event.[57]
  • Distress can occur from the “come-up” or side effects from substances as well.
  • Among those requesting EMTs in setting of psilocybin intoxication, primary triggers were negative mindset and unsuitable environment.[44]
  • In survey data, people who used psychedelic substances promoted positive experiences through:[5]
    • Ensuring social support and having trust for others
    • Physical comfort and safety of environment
    • Addressing emotional state before use
  • In survey of psilocybin users, 25% used alone, 25% had a “guide” or sitter, and only 2.7% had a “trusted and sober guide present who was experienced in supporting psychedelic sessions.”[5] Most tried to calm their mind or change locations, some used cannabis or drank alcohol.[5]
  • Five cases of increased suicidality (one with firearm), six cases of reduced suicidality related to these experiences[5]
    • However, important to note that despite challenges, many participants described these as among the most meaningful experiences of their lives[5]