This section is devoted to psychedelics that are not yet legal or approved by the FDA but show promise as possible safe and effective treatments for some psychiatric illnesses.

Psychedelics

MDMA is a synthetic phenethlamine that produces feelings of euphoria, empathy and social connectedness. It is often referred to as an “Empathogen” or an “Enactogen” as it makes people feel more connected to each other and increases tolerance to emotions.

There was a study demonstrating the prosocial behavior of an octopus who received MDMA. Edsinger et al. 2018. Octopi usually like to be alone but mix in MDMA and they want to hang out.

MDMA appears to increase fear extinction in animal models. Young et al 2015. This obviously has great possible implications for MDMA to be used in humans with PTSD.

MDMA appears to increase the window of tolerance between hypo and hyper arousal where individuals are able to recall traumatic events and reprocess/reconsolidate those memories in a way that promotes fear extinction. In other words it appears that MDMA in the proper therapeutic context has the potential to be a useful tool that can help people with their PTSD.

MDMA

3,4 Methelenedioxymethamphetamine

Physical Risks/Safety:

During acute intoxication symptoms can include: (In order as listed in Mitchell et al. 2021)

  • Muscle tightness

  • Nausea

  • Decreased appetite

  • Hyperhydrosis

  • Feeling hot/cold

  • Chest discomfort

  • Dry mouth

  • Chills

  • Jitteriness

  • Restlessness

  • Blurred vision

  • Bruxism (cleaning jaw)

    Nystagmus

  • Mydriasis

  • Tremor

1-2 days after acute dosing symptoms can include:

  • headache

  • nausea

  • decreased appetite

  • blurred vision

  • dry mouth

  • isomnia

  • brain fog

  • lethargy

Toxicity:

“Dosis sola facit venenum”

  • The dose makes the poison” Paracelsus 1598

Most research studies utilize a dose range of 0.75 mg/kg -1.5 mg/kg. Per Kalant et al. 2001, “Doses of 50 mg, 75 mg and 125 mg to healthy human volunteers produced peak blood concentrations of 106 ng/mL, 131 ng/mL and 236 ng/mL respectively.”

The article also states that a typical study dose leads to blood levels in the “range of 100–250 ng/mL, or 100–250 μg (0.1–0.25 mg) per litre. Most of the cases of serious toxicity or fatality have involved blood levels ranging from 0.5 mg/L to 10 mg/L, that is, up to 40 times higher than the usual recreational range.”

The medications even in lower blood levels could lead to:

  • Liver toxicity

  • Cardiac arrhythmia

  • Heart attack

  • Aneurism

  • Stroke

  • Hyperthermia

    • Rhabdomyolisis

    • Myoglobinuria

    • Liver Damage

    • Disseminated Intravascular Coagulopathy

  • Dehydration

  • Seizures

Per Mustafa et al 2020. “MDMA causes neurotoxicity through different mechanisms; either by acting directly on the neuronal brain activity or by other indirect pathways. Future studies regarding the treatment of the detrimental effects caused by MDMA should focus on the compounds that have the healing properties towards the abnormal neurotransmitter regulations and the damaged neurons.”

Pharmacology:

Pharmacodynamics:

  • MDMA appears to inhibit the reuptake of serotonin (SERT Inhibition) and cause release of serotonin into the synaptic cleft (Via VMAT-2 binding). It also appears to inhibit MAO (Monoamine oxidase).

  • MDMA also appears to increase the amount of dopamine and norepinephrine in the synaptic cleft via inhibition of DAT (Dopamine Transporter) and NET (Norepinephrine Transporter.

  • These increases in serotonin, dopamine and norepinephrine into the synaptic clefts appear to cause downstream release of oxytocin and arginine vasopressin (AVP).

Pharmacokinetics:

MDMA is absorbed in the GI tract and reaches peak plasma concentration approximately 2 hours after ingestion. The drug is primarily metabolized in the liver via the CYP2D6 enzyme pathway among others. Some of these other enzymatic pathways show saturation at low concentrations, raising concern for toxicity with increased oral dosing.

The half life of MDMA is about 8 hours. There appears to be active metabolites which may increase duration of effects beyond MDMA half life.

Kalant et al 2001

Altered Brain Activity:

In patients with PTSD there appears to be altered functioning in certain brain regions including the amygdala and hypocampus.

There are many studies that indicate MDMA causes functional changes in the brain.

According to Sripada et al. 2012, “veterans with PTSD showed greater positive connectivity between the amygdala and insula, reduced positive connectivity between the amygdala and hippocampus, and reduced anticorrelation between the amygdala and dorsal ACC and rostral ACC.”

According to Singleton et al. 2023, “Amygdala-insular functional connectivity is reliably implicated in PTSD and anxiety, and both regions are impacted by MDMA administration.”

Amygdala

Evidence:

  • Mitchell et al. 2021: This study was a multisite, randomized, double blinded, placebo control trial measuring efficacy and safety of MDMA vs Placebo in patients with PTSD. There was an N of 94 patients, 52 of which got MDMA and the other 42 patients got a placebo. (All of the patients received the same intensive psychotherapy.) Caps-5 score was the primary outcome measure. At 18 weeks after the study was initiated, the MDMA group had a reduction in their PTSD rating scales by almost twice as much when averaged. (-24.4 vs. -12.9 respectively) Effect Size was 0.91 (95% CI 0.44-1.37, SD 11.5) p<.0001 A key take away is that at 18 weeks after the study was started 37 of 52 (71.2%) participants in the MDMA group no longer met DSM-5 criteria for PTSD versus 20 of 42 (47.6%) participants in the placebo with therapy group. Furthermore, 24 of 52 (46.2%) participants in the MDMA-AT group and nine of 42 (21.4%) participants in the placebo with therapy group met remission criteria

  • Mitchell et al. 2023: This confirmatory study was a multisite, randomized, double blinded, placebo control trial measuring efficacy and safety of MDMA vs Placebo in patient with PTSD. There was an N of 95 patients that completed the study. 52 received MDMA while 43 received placebo. (1 patient was excluded from final analysis due to missing caps-5 score at t4 interval) Caps-5 score was the primary outcome measure. The mean change in CAPS-5 score (95% confidence interval (CI)) was −23.7 (−26.94, −20.44) for MDMA-AT versus −14.8 (−18.28, −11.28) for placebo with therapy (P < 0.001, d = 0.7). SDS was a secondary outcome measure. The mean change in SDS score (95% CI) was −3.3 (−4.03, −2.60) for MDMA-AT versus −2.1 (−2.89, −1.33) for placebo with therapy (P = 0.03, d = 0.4). Seven participants had a severe treatment emergent adverse event (TEAE) (MDMA-AT, n = 5 (9.4%); placebo with therapy, n = 2 (3.9%)). A key take away from this study was 46.2% in the MDMA group met criteria for remission vs. 21.4% in the placebo group at 18 week follow up.

Create your own user feedback survey

References:

  • MAPS MDMA Investigator Brochure

  • Rudnick, G. and S.C. Wall, The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proc Natl Acad Sci USA, 1992. 89(5): p. 1817-21.

  • Kalant H. The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ. 2001 Oct 2;165(7):917-28. PMID: 11599334; PMCID: PMC81503.

  • Sessa B, Higbed L, Nutt D. A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy. Front Psychiatry. 2019 Mar 20;10:138. doi: 10.3389/fpsyt.2019.00138. PMID: 30949077; PMCID: PMC6435835.

  • Cole, J.C. and H.R. Sumnall, The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA). Neurosci Biobehav Rev, 2003. 27(3): p. 199-217.

  • Mustafa NS, Bakar NHA, Mohamad N, Adnan LHM, Fauzi NFAM, Thoarlim A, Omar SHS, Hamzah MS, Yusoff Z, Jufri M, Ahmad R. MDMA and the Brain: A Short Review on the Role of Neurotransmitters in Neurotoxicity. Basic Clin Neurosci. 2020 Jul-Aug;11(4):381-388. doi: 10.32598/bcn.9.10.485. Epub 2020 Jul 1. PMID: 33613876; PMCID: PMC7878040.

  • Liechti ME, Saur MR, Gamma A, Hell D, Vollenweider FX. Psychological and physiological effects of MDMA ("Ecstasy") after pretreatment with the 5-HT(2) antagonist ketanserin in healthy humans. Neuropsychopharmacology. 2000 Oct;23(4):396-404. doi: 10.1016/S0893-133X(00)00126-3. PMID: 10989266.

  • Young, M.B., et al., 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning. Transl Psychiatry, 2015. 5: p. e634.

  • Verrico, C.D., Miller, G.M. & Madras, B.K. MDMA (Ecstasy) and human dopamine, norepinephrine, and serotonin transporters: implications for MDMA-induced neurotoxicity and treatment. Psychopharmacology 189, 489–503 (2007)

  • Edsinger E, Dölen G. A Conserved Role for Serotonergic Neurotransmission in Mediating Social Behavior in Octopus. Curr Biol. 2018 Oct 8;28(19):3136-3142.e4. doi: 10.1016/j.cub.2018.07.061. Epub 2018 Sep 20. PMID: 30245101.

  • Singleton SP, Wang JB, Mithoefer M, Hanlon C, George MS, Mithoefer A, Mithoefer O, Coker AR, Yazar-Klosinski B, Emerson A, Doblin R, Kuceyeski A. Altered brain activity and functional connectivity after MDMA-assisted therapy for post-traumatic stress disorder. Front Psychiatry. 2023 Jan 12;13:947622. doi: 10.3389/fpsyt.2022.947622. PMID: 36713926; PMCID: PMC9879604.

  • Sripada RK, King AP, Garfinkel SN, Wang X, Sripada CS, Welsh RC, Liberzon I. Altered resting-state amygdala functional connectivity in men with posttraumatic stress disorder. J Psychiatry Neurosci. 2012 Jul;37(4):241-9. doi: 10.1503/jpn.110069. PMID: 22313617; PMCID: PMC3380095.

  • Rabinak CA, Angstadt M, Welsh RC, Kenndy AE, Lyubkin M, Martis B, Phan KL. Altered amygdala resting-state functional connectivity in post-traumatic stress disorder. Front Psychiatry. 2011 Nov 14;2:62. doi: 10.3389/fpsyt.2011.00062. PMID: 22102841; PMCID: PMC3214721.

Psilocybin

Evidence

  • Raison et al. 2023: Randomized placebo control trial comparing single dose psilocybin (25mg) with niacin control in patients with MDD. (n = 104) The psilocybin group showed significantly reduced MADRS scores from baseline to day 43. (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001) It also showed significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. The key take away is that psilocybin was associated with a significant reduction of depression symptoms, functional disability without any series events.

  • Goodwin et al. 2022: Randomized controlled trial comparing 25 mg of psilocybin with 10 mg an 1 mg (used as control) in patients with treatment resistant depression. The primary outcome was measuring MADRS at baseline and week three after drug administration. The MADRS changes from baseline to week 3 were −12.0 for 25 mg, −7.9 for 10 mg, and −5.4 for 1 mg. Secondary outcomes included response which at week 3 was 37% in the 25-mg group, 19% in the 10-mg group, and 18% in the 1-mg group (odds ratio in the 25-mg group vs. the 1-mg group, 2.9 [95% CI, 1.2 to 6.6]; odds ratio in the 10-mg group vs. the 1-mg group, 1.2 [95% CI, 0.5 to 3.0]) Its important to keep keep in mind that STAR*D data indicates the chances of a patient having a response on a third trial of an antidepressant is only 16.8%. A key take away is that response at week 3 of 37% in the 25-mg group is numerically lower than that described for first-line treatment of major depressive disorder in several large trials but was higher than the incidences of response reported in the STAR*D trial for second-line or third line treatments.

  • Carhart-Harris et al. 2021: Randomized, double blinded, controlled trial comparing psilocybin (two 25 mg doses given 3 weeks apart + 6 weeks of placebo) with Psilocybin (two 1 mg doses given 3 weeks apart + 6 weeks of daily escitalopram. All patients received psychological support. The primary outcome was change from baseline in QIDS-RS-16 rating scale. The mean score changes from baseline to week 6 in the 25 mg group was −8.0±1.0 points and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). Secondary outcomes included response and remission rates. Response criteria as measured by the QIDS-SR-16 was 70% of the patients in the 25 mg psilocybin group and 48% of those in the escitalopram group. This had a between-group difference of 22 percentage points (95% CI, −3 to 48) Remission as measured by the QIDS-SR-16 occurred in 57% of the 25 mg psilocybin group and 28% of the escitalopram group for a between-group difference of 28 percentage points (95% CI, 2 to 54).

  • Davis et al 2021: Randomized clinical trial comparing immediate psilocybin treatment with delayed treatment in patients with MDD. Two dosing sessions were given at weeks 3 (20 mg/70 kg) and 4 (30 mg/70 kg) in the immediate group and weeks 11(20 mg/70 kg) and 12 (30 mg/70 kg) in the delayed group. All participants received supportive psychotherapy. The primary outcome measure was measured by GRID-HAMD scores at baseline and weeks 5 and 8 for the immediate group and weeks 13 and 16 for the delayed group. The mean (SD) GRID-HAMD scores at weeks 5 and 8 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. (this paper makes the timeline difficult to follow as they sometimes refer to “week 1” as 1 week post psilocybin treatment and other times to mean 1 week following study initiation) The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001) Secondary outcomes included remission and response rates. 71% of patients met criteria for response as measured by GRID-HAMD at 1 week and 4 weeks following psilocybin dosing. 58% of patients met remission criteria as measured by GRID-HAMD 1 week following psilocybin administration and 54% met remission criteria 4 weeks after administration of psilocybin.

References:

  • Raison CL, Sanacora G, Woolley J, Heinzerling K, Dunlop BW, Brown RT, Kakar R, Hassman M, Trivedi RP, Robison R, Gukasyan N, Nayak SM, Hu X, O'Donnell KC, Kelmendi B, Sloshower J, Penn AD, Bradley E, Kelly DF, Mletzko T, Nicholas CR, Hutson PR, Tarpley G, Utzinger M, Lenoch K, Warchol K, Gapasin T, Davis MC, Nelson-Douthit C, Wilson S, Brown C, Linton W, Ross S, Griffiths RR. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA. 2023 Sep 5;330(9):843-853. doi: 10.1001/jama.2023.14530. Erratum in: JAMA. 2024 Feb 27;331(8):710. PMID: 37651119; PMCID: PMC10472268.

  • Goodwin GM, Aaronson ST, Alvarez O, Arden PC, Baker A, Bennett JC, Bird C, Blom RE, Brennan C, Brusch D, Burke L, Campbell-Coker K, Carhart-Harris R, Cattell J, Daniel A, DeBattista C, Dunlop BW, Eisen K, Feifel D, Forbes M, Haumann HM, Hellerstein DJ, Hoppe AI, Husain MI, Jelen LA, Kamphuis J, Kawasaki J, Kelly JR, Key RE, Kishon R, Knatz Peck S, Knight G, Koolen MHB, Lean M, Licht RW, Maples-Keller JL, Mars J, Marwood L, McElhiney MC, Miller TL, Mirow A, Mistry S, Mletzko-Crowe T, Modlin LN, Nielsen RE, Nielson EM, Offerhaus SR, O'Keane V, Páleníček T, Printz D, Rademaker MC, van Reemst A, Reinholdt F, Repantis D, Rucker J, Rudow S, Ruffell S, Rush AJ, Schoevers RA, Seynaeve M, Shao S, Soares JC, Somers M, Stansfield SC, Sterling D, Strockis A, Tsai J, Visser L, Wahba M, Williams S, Young AH, Ywema P, Zisook S, Malievskaia E. Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. N Engl J Med. 2022 Nov 3;387(18):1637-1648. doi: 10.1056/NEJMoa2206443. PMID: 36322843.

  • Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med. 2021 Apr 15;384(15):1402-1411. doi: 10.1056/NEJMoa2032994. PMID: 33852780.

  • Davis AK, Barrett FS, May DG, Cosimano MP, Sepeda ND, Johnson MW, Finan PH, Griffiths RR. Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2021 May 1;78(5):481-489. doi: 10.1001/jamapsychiatry.2020.3285. Erratum in: JAMA Psychiatry. 2021 Feb 10;: PMID: 33146667; PMCID: PMC7643046.