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MDMA

MDMA

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Ecstasy
Figure 1. MDMA in pill form, aka Ecstasy

MDMA, commonly known as ecstasy or Molly, is a synthetic empathogen that induces both amphetamine-like stimulation and mild hallucinations. MDMA is used clinically in the treatment of anxiety, depression and PTSD.

Clinical Dosage

Dosage is usually around 0.75-1.5mg per kg and is often performed in the following stages...[1]

1. Recruitment and medical screening. Start tapering of other medicines if needed.

2. Prep sessions 1 and spaced over 2 weeks.

3. 3rd preparation session. Finish tapering off medications.

4. 1st MDMA assisted session 80mg + 40 mg booster dose (@ 90 minutes).

5. 1 month (aprox) break with a 90-minute integration session each week.

6. 2nd MDMA session 80mg or 120mg plus half dose booster.

7. 1 month (aprox) break with a 90-minute integration session each week.

8. 3rd MDMA session 80mg or 120mg plus half dose booster.

9. Last, 1 month (aprox) with a 90-minute integration session each week.

10. Final integration session.

Mechanism of Action

Pharmacology

MDMA works by altering the brains neurochemistry:

  • Increasing (↑) dopamine by reducing how it is reabsorbed post release.
  • Increasing (↑↑↑) serotonin by reducing how it is reabsorbed post release.
  • Increasing oxytocin (neuromodulator) concentration.

Neurophysiology

The change in neural activity coupled with the release of the neurochemicals / neuromodulators above cause a reduction in communication between the medial temporal lobe and the medial prefrontal cortex, which play roles in emotional control. Collectively, these effects work contrary to the patterns observed in individuals experiencing anxiety.[2][3]

Effects

Short Term

The dynamic of an MDMA trip is not linear, it takes effect at 30-45 minutes and peaks at 2 hours.
Figure 1. MDMA Time-Effect Curve

When ingested orally, the effects of MDMA typically begin within 30 to 45 minutes and can last for three to six hours. The experience induced by MDMA is usually milder compared to traditional psychedelics. It is characterised by heightened feelings of excitement, empathy, and a sense of trust. MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C.

Unlike substances like ketamine, which are known for their dissociative effects, MDMA is often described as having affiliative properties, promoting a sense of connection and sociability.

Long Term

MDMA has been shown to assist in improving emotional understanding and management, as well as coping strategies. This is primarily due to its ability to enhance the fear memory extinction and alter the brain's association with trauma, resulting in reduced activation of the amygdala. Such changes can lead to a shifted perspective and more effective processing of traumatic experiences. Additionally, MDMA may influence the reconsolidation of fear memories, possibly through its effects on oxytocin or the activation of serotonin 5HT1B receptors. These effects have been observed to enhance social behaviors in animal studies.

Clinical Use

MDMA is often quoted as being used to treat the "shadow self". This is deemed by many as important before going into a full psychedelic experience as it can resolve hidden trauma which may arise during the psychedelic experience.

Other Effects

Interoception

MDMA is known to enhance interoception, the ability to sense and perceive internal bodily sensations. This heightened awareness covers a range of physiological states, enabling individuals to more acutely recognize internal sensations. These sensations include the heartbeat, respiratory patterns, and feelings related to hunger or fullness, as well as activities of the autonomic nervous system connected to emotional reactions. The insular cortex, a part of the brain that maintains a comprehensive map of the body's current state, plays a key role in this process. The connection between the insular cortex and the amygdala is believed to be a critical factor in understanding the mechanistic basis of PTSD.

Sexual Relationships

It is likely that MDMA increases sexual desire and intensifies orgasm and that dose, ‘set and setting’, and timing relative to MDMA administration make major differences in ability of men to achieve the erectile quality necessary for ejaculation[4].

MDMA has a stronger effect in women

Women are more affected by MDMA's psychoactive effects than males[5]. Women especially have greater perceptual changes, thought disturbances, and fear of loss of body control. In addition, acute adverse effects and sequelae were also more frequent in female than in male subjects. In contrast, men showed higher increases in blood pressure than women.

Coadministration

It is thought that the effects of MDMA might be further potentiated by administration with psilocybin termed a hippie flip[6]. Therapeutically, MDMA is often used first in order to build the therapeutic alliance and increase the patient’s openness to change, leading to enhanced resilience and lowered stress levels. Once further changes were noticed, such as improved self-regulation, less negative self-perception, and increased tolerance to trauma exposure, a psychedelic such as psilocybin was introduced to assist psychotherapy. The deepening of the therapeutic process led to improvement per clinical judgment, without adverse events.[7]

Adverse Effects

MDMA at high doses can be neurotoxic, in addition, due to its amphetamine component MDMA can increase blood pressure, meaning its use is contraindicated in people with preexisting hypertension.

Toxicity

Historically, there was a significant study that suggested MDMA (ecstasy) was toxic. However, this study was later retracted. Despite this retraction, MDMA is still commonly believed to be potentially neurotoxic, potentially causing an overload of dopamine in the brain. Yet, according to a long-term study, there's little proof of any decline in cognitive abilities in people who use ecstasy, except for a noted decrease in strategic self-regulation. This could indicate a tendency towards increased impulsivity in users.[8].

When caffeine is administered alongside MDMA in rats, it significantly increases the immediate toxic effects of MDMA. These effects include elevated core body temperature, rapid heart rate, and a higher death rate. Furthermore, combining caffeine with MDMA also amplifies the long-term damage to the brain's serotonin system caused by MDMA.[9].

MDMA Comedown

There is a wide amount of anecdotal evidence and some scientific evidence[10][11] to suggest that after using MDMA there is an emotional comedown potentially due to prolactin release[12] reported colloquially as "Blue Mondays". However, a recent, low powered study found that there was little evidence for this[13].

MDMA Toxicity Protection

Some animal and human studies have suggested taking a range of supplements before MDMA administration to protect the user from MDMA induced neurotoxicity.

  • Alpha lipoic acid (ALA): 300 milligrams (mg) of ALA at the same time as MDMA, followed by 100 – 150 mg of ALA every 1-2 hours thereafter for the duration of the trip. (Conservative practitioners suggest a maximum dose of 2,400 mg of ALA in a 24-hour period.)
  • Acetyl-L carnitine (ALC): 500 mg of ALC three hours before taking MDMA, 500mg one hour after the MDMA, and 500 mg four hours later (five hours after the MDMA), for a total dose of 1,500 mg of ALC. (Conservative practitioners suggest a maximum dose of 2,500mg of ALC per 24-hour period.)
  • N-acetyl cysteine (NAC): 900 mg of NAC on an empty stomach, shortly before the MDMA and again at the end of the session.
  • Vitamin C: 500 – 2,000 mg (half a gram – 2 grams) of sodium ascorbate every two hours the day of the MDMA session. (Sodium ascorbate is a form of vitamin C that’s less likely to cause an upset stomach than regular ascorbic acid.) Reduce the dose if loose stools occur.

In addition, it is suggested that 5-HTP supplements can be used after the 5-HTP dose to replenish lost neurotransmitters, however, taking 5-HTP too soon after MDMA can cause a serious and potentially life-threatening condition known as serotonin syndrome. (The same goes for combining 5-HTP with SSRI antidepressants.) For that reason, it is recommend that people wait 48 hours after taking MDMA before starting a 5-HTP supplement. Dosage is around 100 to 400 mg daily for two weeks after taking MDMA, starting two days after the MDMA experience.

References

  1. ↑ MDMA-assisted therapy for moderate to severe PTSD: a randomized, placebo-controlled phase 3 trial, Jennifer M. Mitchell, Published: 14 September 2023, accessed 4 Dec via https://www.nature.com/articles/s41591-023-02565-4
  2. ↑ 3,4-Methylenedioxymethamphetamine (MDMA) impairs the extinction and reconsolidation of fear memory in rats. Hake, H. S. et al. Physiol. Behav. 199, 343–350 (2019). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557441/
  3. ↑ Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nardou, R. et al. Nature 569, 116–120 (2019). https://doi.org/10.1038%2Fs41586-019-1075-9
  4. ↑ Does MDMA have treatment potential in sexual dysfunction? A systematic review of outcomes across the female and male sexual response cycles. Wexler A, Dubinskaya A, Suyama J, Komisaruk BR, Anger J, Eilber K.. Sex Med Rev. 2023 Oct 26:qead046. doi: 10.1093/sxmrev/qead046. Epub ahead of print. PMID: 37888490.
  5. ↑ Gender differences in the subjective effects of MDMA. Psychopharmacology (Berl). Liechti ME, Gamma A, Vollenweider FX.  2001 Mar 1;154(2):161-8. doi: 10.1007/s002130000648. PMID: 11314678. Accessed on 10 May 2023 via: https://pubmed.ncbi.nlm.nih.gov/11314678/
  6. ↑ Co-use of MDMA with psilocybin/LSD may buffer against challenging experiences and enhance positive experiences. Zeifman, R. J., Kettner, H., Pagni, B. A., Mallard, A., Roberts, D. E., Erritzoe, D., Ross, S., & L., R. (2023). Scientific Reports, 13(1), 1-11. https://doi.org/10.1038/s41598-023-40856-5
  7. ↑ Therapeutic role of psilocybin and 3,4-methylenedioxymethamphetamine in trauma: A literature review. Fonseka LN, Woo BK. World J Psychiatry. 2023 May 19;13(5):182-190. doi: 10.5498/wjp.v13.i5.182. PMID: 37303932; PMCID: PMC10251361.
  8. ↑ Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs. Addiction. Halpern JH, Sherwood AR, Hudson JI, Gruber S, Kozin D, Pope HG Jr. 2011 Apr;106(4):777-86. doi: 10.1111/j.1360-0443.2010.03252.x. Epub 2011 Feb 15. PMID: 21205042; PMCID: PMC3053129.
  9. ↑ Caffeine provokes adverse interactions with 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') and related psychostimulants: mechanisms and mediators. Vanattou-Saïfoudine N, McNamara R, Harkin A. Br J Pharmacol. 2012 Nov;167(5):946-59. doi: 10.1111/j.1476-5381.2012.02065.x. PMID: 22671762; PMCID: PMC3492978.
  10. ↑ Safety pharmacology of acute MDMA administration in healthy subjects. J Psychopharmacol 31: 576–588. Vizeli P, Liechti ME. (2017) Accessed on 20 Nov 2023 via https://pubmed.ncbi.nlm.nih.gov/28443695/
  11. ↑ Gender differences in the subjective effects of MDMA. Liechti ME, Gamma A, Vollenweider FX. (2001) Psychopharmacology 154: 161–168. Accessed on 20 Nov 2023: https://pubmed.ncbi.nlm.nih.gov/11314678/
  12. ↑ Ecstasy (MDMA) mimics the post-orgasmic state: impairment of sexual drive and function during acute MDMA-effects may be due to increased prolactin secretion. Passie T, Hartmann U, Schneider U, Emrich HM, Krüger TH. Med Hypotheses. 2005;64(5):899-903. doi: 10.1016/j.mehy.2004.11.044. PMID: 15780482.
  13. ↑ Debunking the myth of 'Blue Mondays': No evidence of affect drop after taking clinical MDMA. J Psychopharmacol. 2022 Mar;36(3):360-367. doi: 10.1177/02698811211055809. Epub 2021 Dec 13. . Ben Sessa, Jacob S Aday, Steve O'Brien, H Valerie Curran, Fiona Measham, Laurie Higbed, David J Nutt. https://pubmed.ncbi.nlm.nih.gov/34894842/
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