I think we should modify the combination according to the title.

Both substances exert their effects mainly via NMDA antagonism and there is no data on potential mechanisms causing decrease of effects, which implies synergy.

Mushrooms cover multiple different psychoactive drugs. Especially nowadays with many things getting labeled as "mushroom gummies" commonly referring to Amanita Muscaria (and many of them being fake), I think it is best to be specific with what we are calling what and using more specific classifications.

Discussed in #85

Lithium + SSRIs
Safe

This interaction is used in medical settings without reported issues. If this combination is taken, caution would be recommended if any other drugs are planned to be taken on top of these that may have serotonergic activity.

Hawley CJ, Loughlin PJ, Quick SJ, Gale TM, Sivakumaran T, Hayes J, McPhee S. Efficacy, safety and tolerability of combined administration of lithium and selective serotonin reuptake inhibitors: a review of the current evidence. Hertfordshire Neuroscience Research Group. Int Clin Psychopharmacol. 2000 Jul;15(4):197-206. doi: 10.1097/00004850-200015040-00002. PMID: 10954059.
Müller-Oerlinghausen, B. Drug Interactions with Lithium. Mol Diag Ther 11, 41–48 (1999). https://doi.org/10.2165/00023210-199911010-00004
Bauer, Michael PhD, MD; Linden, Michael MD; Schaaf, Berthold; Weber, Hans J. MD. Adverse Events and Tolerability of the Combination of Fluoxetine/Lithium Compared With Fluoxetine. Journal of Clinical Psychopharmacology 16(2):p 130-134, April 1996.
Finley, P. R. (2016). Drug Interactions with Lithium: An Update. Clinical Pharmacokinetics, 55(8), 925–941. https://doi.org/10.1007/s40262-016-0370-y

4mmc + DXM

Dangerous

Risk of serotonin syndrome as both drugs raise serotonin levels. In addition to concerns of high blood pressure and unnecessary strain on the heart. As well as potentially causing anxiety and greater physical discomfort due to the combination.

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01499.x
https://jpet.aspetjournals.org/content/339/2/530
https://www.tandfonline.com/doi/full/10.1080/15563650701668625#:~:text=Introduction.,enough%20to%20cause%20serotonin%20syndrome.
https://go.drugbank.com/drugs/DB00514
https://pubmed.ncbi.nlm.nih.gov/1280529/
https://pubmed.ncbi.nlm.nih.gov/22526529/
https://pubmed.ncbi.nlm.nih.gov/22037396/

Opioids + Gabapentin

Dangerous

While this combination may be tolerated by those who are using these drugs as prescribed, recreational use of pregabalin and opioids increases risk of fatal overdose. Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Memory blackouts are likely.

Evoy, K. E., Sadrameli, S., Contreras, J., Covvey, J. R., Peckham, A. M., & Morrison, M. D. (2021). Abuse and misuse of pregabalin and gabapentin: A systematic review update. Drugs, 81(1), 125–156. https://doi.org/10.1007/s40265-020-01432-7

Lyndon, A., Audrey, S., Wells, C., Burnell, E. S., Ingle, S., Hill, R., Hickman, M., & Henderson, G. (2017). Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction, 112(9), 1580–1589. https://doi.org/10.1111/add.13843

Peckham, A.M., Fairman, K.A. & Sclar, D.A. All-Cause and Drug-Related Medical Events Associated with Overuse of Gabapentin and/or Opioid Medications: A Retrospective Cohort Analysis of a Commercially Insured US Population. Drug Saf 41, 213–228 (2018). https://doi.org/10.1007/s40264-017-0595-1

Gomes, Tara, et al. “Gabapentin, Opioids, and the Risk of Opioid-Related Death: A Population-Based Nested Case–Control Study.” PLOS Medicine, vol. 14, no. 10, Oct. 2017, p. e1002396, https://doi.org/10.1371/journal.pmed.1002396.

Additional source suggested by @zelixir25

Umemura, Y., Andrew, T. A., Jacobs, V. L., Giustini, A. J., Lewis, L. D., & Filiano, J. J. (2015). Fatal 251-NBOMe Intoxication: A New Recreational Risk. Academic Forensic Pathology, 5(1), 91–97. https://doi.org/10.23907/2015.009
#77

Discussed in #158

With Breads agreement, I'd like to move this combination forward. The sources aren't ideal for this however I don't see why this combination would be of notable concern past typical concern for these drugs on its own. I've linked pages to each of their pharmacology pages as sources to give more insight if someone wants to look further.

Mephedrone + Nitrous Oxide = Low Risk + Synergy
There is no apparent concern from this combination and there may also be synergy from mixing these two psychoactive drugs.

Carvalho, F., Carmo, H., Guedes de Pinho, P., Remião, F., de Lourdes Bastos, M., & Carvalho, M. (2014). Mephedrone. In P. Wexler (Ed.), Encyclopedia of Toxicology (Third Edition) (pp. 194–196). Academic Press. https://doi.org/10.1016/B978-0-12-386454-3.01189-1
Knuf, K., & Maani, C. V. (2024). Nitrous Oxide. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK532922/
4-Methylmethcathinone & Nitrous Oxide - Erowid Exp - “I Think That I Just Seen Another World.” (n.d.). Retrieved August 6, 2024, from https://www.erowid.org/experiences/exp.php?ID=112811

Lithium + Cocaine

Low Risk & Decrease

Lithium may inhibit some of the recreational effects of cocaine.

Flemenbaum, A. (1977). Antagonism of behavioral effects of cocaine by lithium. Pharmacology Biochemistry and Behavior, 7(1), 83–85. https://doi.org/10.1016/0091-3057(77)90015-6

Cronson, A. J., & Flemenbaum, A. (1981). Antagonism of Cocaine Highs by Lithium. In A. J. Schecter (Ed.), Drug Dependence and Alcoholism: Volume 1 Biomedical Issues (pp. 1139–1141). Springer US. https://doi.org/10.1007/978-1-4684-3614-3_132

Discussed in #74

Studies indicate that this combination is more dangerous than either drug on its own. Because cocaine can decrease some of the intoxicating effects of alcohol, some people may drink more than they otherwise would, leading to greater behavioral and physical health risks. Moreover, there is still some debate about cocaethylene, a metabolite produced when combining alcohol and cocaine, with some researchers positing that it is more cardiotoxic than cocaine on its own.

Unsafe

Source addition for Lithium and LSD

Edwards, C., Van Gerpen, S., & Anand, V. (2024). New-Onset Seizures in an Adolescent Following Use of LSD while on Low-Dose Lithium Therapy: A Case Study. South Dakota Medicine: The Journal of the South Dakota State Medical Association, 77(1), 31–35.

credit to @zelixir25

I think we should modify so that .

Same case with synergy as DXM + Ketamine (both substances exert their effects mainly via NMDA antagonism).

There may be also possible serotonin syndrome, as DXM is known to cause serotonin syndrome in combination with other serotonin reuptake inhibitors and there is research suggesting that MXE displays significant affinity towards the serotonin transporter, sources:

• https://doi.org/10.1371/journal.pone.0059334
• https://www.sciencedirect.com/science/article/abs/pii/S0014488621002442

If the suspicion about serotonin syndrome is true, then I don't know which of "unsafe" categories should it be marked? Probably "Unsafe"?

Other MXE interactions also need reviewing.

Lithium + MXE
= Dangerous

There is a risk of serotonin syndrome when combining Lithium with MXE, as Lithium can induce serotonin syndrome in conjunction with other serotonergic drugs, and MXE has shown a notable affinity for the serotonin transporter.

Lenox, R. H., & Hahn, C. G. (2000). Overview of the mechanism of action of lithium in the brain: fifty-year update. The Journal of clinical psychiatry, 61 Suppl 9, 5–15. - https://pubmed.ncbi.nlm.nih.gov/10826655/

Shahani, L. (2012). Venlafaxine Augmentation With Lithium Leading to Serotonin Syndrome. The Journal of Neuropsychiatry and Clinical Neurosciences, 24(3), E47–E47. https://doi.org/10.1176/appi.neuropsych.11080196

DeBattista, C., Sofuoglu, M., & Schatzberg, A. F. (1998). Serotonergic synergism: the risks and benefits of combining the selective serotonin reuptake inhibitors with other serotonergic drugs. Biological psychiatry, 44(5), 341–347. https://doi.org/10.1016/s0006-3223(98)00161-9

Massot, O. (1999). 5-HT1B Receptors: A Novel Target for Lithium Possible Involvement in Mood Disorders. Neuropsychopharmacology, 21(4), 530–541. https://doi.org/10.1016/S0893-133X(99)00042-1

Roth, B. L., Gibbons, S., Arunotayanun, W., Huang, X.-P., Setola, V., Treble, R., & Iversen, L. (2013). The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor. PLoS ONE, 8(3), e59334. https://doi.org/10.1371/journal.pone.0059334

Marti, M., Talani, G., Miliano, C., Bilel, S., Biggio, F., Bratzu, J., Diana, M., De Luca, M. A., & Fattore, L. (2021). New insights into methoxetamine mechanisms of action: Focus on serotonergic 5-HT2 receptors in pharmacological and behavioral effects in the rat. Experimental Neurology, 345, 113836. https://doi.org/10.1016/j.expneurol.2021.113836

Hi there,

I'd like to discuss the naming of 4mmc versus Mephedrone for the tripsit chart. I do not swing either way at the moment and am opening this for conversation.

As discussed in discussion 59, I suggest that there is an addition to the combination chart that adds a footnote. This would mention that both DXM and DPH are in advice in general/typically for recreational dosages. As some interactions will be the case at medical dosages, but in general it is in reference to recreational dosages.

Something on the lines of-

• Note: DPH and DXM interactions are listed for recreational dosages

#59
https://github.com/TripSit/drugs/discussions/59#discussioncomment-8606506)]

DPH + Benzodiazepines
Dangerous

Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.

Montoro, J., Bartra, J., Sastre, J., Dávila, I., Ferrer, M., Mullol, J., del Cuvillo, A., Jáuregui, I., & Valero, A. (2013). H1 antihistamines and benzodiazepines. Pharmacological interactions and their impact on cerebral function. Journal of investigational allergology & clinical immunology, 23 Suppl 1, 17–26.
https://www.ncbi.nlm.nih.gov/books/NBK526010/
https://www.ncbi.nlm.nih.gov/books/NBK470159/

From a user on discord:

"The reference for LSD+GHB in the combo chart. In the combo chart it states low risk/decrease, the reference stated said absolutely nothing about their interaction though. It only reports on polydrug use stats, not characterizing safety profiles on the usage. The same is true of Ketamine+GHB where there is a statement on compounding ataxia (the cited source says nothing about that), and GHB and Benzos.

This paper is used as a source for multiple combos, when in reality it doesn't say anything about the effects of combo use."

They're mostly talking about the wiki page: https://wiki.tripsit.me/wiki/Drug_combinations#Ketamine_&_GHB\GBL

Since the "sources" field in this database is fairly new, we haven't added the sources on the wiki to the database, but when we do, we should be careful to check these interactions

I propose a modification of Lithium + Nitrous Oxide to say "Low risk + No Synergy"

I have been able to find no reason to think the combination is of concern, except for flagging by https://go.drugbank.com/drugs/DB14509 - but they tend to flag most interactions for CNS depression, and I am unable to find a report of concerns for CNS depression caused by Lithium.

I am creating an issue as I would like this to be reviewed and checked by someone else before submitting it. But I am fairly certain about this interaction.

Just a additional source for Lithium + MDMA-

https://pubmed.ncbi.nlm.nih.gov/10826655/ / https://www.psychiatrist.com/read-pdf/13649/
Doesn't seem to have a DOI link

Lenox, R. H., & Hahn, C. G. (2000). Overview of the mechanism of action of lithium in the brain: fifty-year update. The Journal of clinical psychiatry, 61 Suppl 9, 5–15.

Kalant H. (2001). The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 165(7), 917–928.

de la Torre, R., Farré, M., Roset, P. N., Pizarro, N., Abanades, S., Segura, M., Segura, J., & Camí, J. (2004). Human pharmacology of MDMA: pharmacokinetics, metabolism, and disposition. Therapeutic drug monitoring, 26(2), 137–144. https://doi.org/10.1097/00007691-200404000-00009

This is a forwarding of a discussion from the google document (https://docs.google.com/document/d/1_n65NibeMNNMBahocEjLe-630hwpSlibbZgDQeDf7Y4/edit?usp=sharing)

Combination Classifications
Right now the combos have a mix of drug names and classifications. EG, LSD combines with all “benzodiazepines,” but the alprazolam entry does not have any combination info at all. This leads to some confusion/errors when doing combo checks.

"lsd": {
	"combos": {
    	"benzodiazepines": {
        	"status": "Low Risk & Decrease"
    	},
	},
"alprazolam": {
	"categories": [
    	"benzodiazepine",
    	"habit-forming",
    	"depressant",
    	"common"
	],
	},

To fix this, we need to basically add a bunch of combo information to each one of those classifications. For example, instead of relying on the “benzodiazepine” class to determine combos for alprazolam, we would add new “combos” section and define each combo with each drug. This may be tedious AF, but is the only way to ensure 100% accuracy. We can still keep and utilize the category info but this combo info will be necessary.

"lsd": {
		"combos": {
    		"alprazolam": {
        		"status": "Low Risk & Decrease"
    		},
		},

},
"alprazolam": {
"combos": {
"lsd": {
"status": "Low Risk & Decrease"
},
},
},

Below are the line items that have nonsensical/non-uniform data at present:

Data is not uniform: 2-methylamphetamine | Method: Undefined | formatted_onset
could not convert string to float: 'Insufflated'
Data will be defaulted to None: 2-methylamphetamine | Method: Undefined | formatted_onset

Data is not uniform: 2-methylamphetamine | Method: Undefined | formatted_duration
could not convert string to float: 'Insufflated'
Data will be defaulted to None: 2-methylamphetamine | Method: Undefined | formatted_duration

Data is not uniform: 4-aco-dpt | Method: Undefined | formatted_duration
could not convert string to float: 'Insufflated'
Data will be defaulted to None: 4-aco-dpt | Method: Undefined | formatted_duration

Data is not uniform: 4-cbc | Method: Oral | formatted_onset
invalid literal for int() with base 10: '60mg'
Data will be defaulted to None: 4-cbc | Method: Oral | formatted_onset

Data is not uniform: 4-cmc | Method: Undefined | formatted_aftereffects
could not convert string to float: 'Few'
Data will be defaulted to None: 4-cmc | Method: Undefined | formatted_aftereffects

Data is not uniform: 4f-php | Method: Undefined | formatted_onset
could not convert string to float: 'Insufflated'
Data will be defaulted to None: 4f-php | Method: Undefined | formatted_onset

Data is not uniform: 5-eapb | Method: Undefined | formatted_onset
could not convert string to float: 'Oral'
Data will be defaulted to None: 5-eapb | Method: Undefined | formatted_onset

Data is not uniform: 6-mapb | Method: Insufflated | formatted_onset
could not convert string to float: 'Within'
Data will be defaulted to None: 6-mapb | Method: Insufflated | formatted_onset

Data is not uniform: 6-mapb | Method: Oral | formatted_onset
could not convert string to float: 'Within'
Data will be defaulted to None: 6-mapb | Method: Oral | formatted_onset

Data is not uniform: bromo-dragonfly | Method: Undefined | formatted_onset
could not convert string to float: 'Up'
Data will be defaulted to None: bromo-dragonfly | Method: Undefined | formatted_onset

Data is not uniform: cyclizine | Method: Oral | formatted_duration
invalid literal for int() with base 10: '8 hours.'
Data will be defaulted to None: cyclizine | Method: Oral | formatted_duration

Data is not uniform: flubromazepam | Method: Undefined | formatted_aftereffects
could not convert string to float: '36+'
Data will be defaulted to None: flubromazepam | Method: Undefined | formatted_aftereffects

Data is not uniform: marinol | Method: Undefined | formatted_onset
could not convert string to float: 'Oral'
Data will be defaulted to None: marinol | Method: Undefined | formatted_onset

Data is not uniform: mem | Method: Undefined | formatted_onset
could not convert string to float: 'Within'
Data will be defaulted to None: mem | Method: Undefined | formatted_onset

Data is not uniform: metaclazepam | Method: Undefined | formatted_onset
could not convert string to float: 'duration'
Data will be defaulted to None: metaclazepam | Method: Undefined | formatted_onset

Data is not uniform: morpheridine | Method: Undefined | formatted_onset
could not convert string to float: 'Oral'
Data will be defaulted to None: morpheridine | Method: Undefined | formatted_onset

Data is not uniform: morpheridine | Method: Undefined | formatted_duration
could not convert string to float: 'Oral'
Data will be defaulted to None: morpheridine | Method: Undefined | formatted_duration

Data is not uniform: mxm | Method: Undefined | formatted_onset
could not convert string to float: 'Varying'
Data will be defaulted to None: mxm | Method: Undefined | formatted_onset

Data is not uniform: naphyrone | Method: Undefined | formatted_onset
could not convert string to float: 'Within'
Data will be defaulted to None: naphyrone | Method: Undefined | formatted_onset

Data is not uniform: parafluorobutyrfentanyl | Method: Undefined | formatted_onset
could not convert string to float: 'Insufflated'
Data will be defaulted to None: parafluorobutyrfentanyl | Method: Undefined | formatted_onset

Data is not uniform: pce | Method: Undefined | formatted_onset
could not convert string to float: 'Insufflated'
Data will be defaulted to None: pce | Method: Undefined | formatted_onset

Data is not uniform: phenazepam | Method: Undefined | formatted_aftereffects
could not convert string to float: '36+'
Data will be defaulted to None: phenazepam | Method: Undefined | formatted_aftereffects

Data is not uniform: phenazepam | Method: Undefined | formatted_duration
could not convert string to float: '18+'
Data will be defaulted to None: phenazepam | Method: Undefined | formatted_duration

Data is not uniform: quetiapine | Method: Oral | formatted_onset
could not convert string to float: 'IR'
Data will be defaulted to None: quetiapine | Method: Oral | formatted_onset

Data is not uniform: quetiapine | Method: Undefined | formatted_aftereffects
could not convert string to float: 'Can'
Data will be defaulted to None: quetiapine | Method: Undefined | formatted_aftereffects

Data is not uniform: thiopropamine | Method: Insufflated | formatted_onset
invalid literal for int() with base 10: '15mg.'
Data will be defaulted to None: thiopropamine | Method: Insufflated | formatted_onset

Data is not uniform: tma-2 | Method: Undefined | formatted_aftereffects
could not convert string to float: 'Possibility'
Data will be defaulted to None: tma-2 | Method: Undefined | formatted_aftereffects

Data is not uniform: tma-6 | Method: Undefined | formatted_aftereffects
could not convert string to float: 'Possibility'
Data will be defaulted to None: tma-6 | Method: Undefined | formatted_aftereffects

This data should be fact checked for accuracy and reformatted to only include floats/integers if possible to follow suit with the other substances in the dataset.

I think we should modify 3mmc so that one of the oral ROAs is removed, it seems to just be duplicated for some unknown reason.

Source addition for Lithium + NBOMEs

Umemura, Y., Andrew, T. A., Jacobs, V. L., Giustini, A. J., Lewis, L. D., & Filiano, J. J. (2015). Fatal 251-NBOMe Intoxication: A New Recreational Risk. Academic Forensic Pathology, 5(1), 91–97. https://doi.org/10.23907/2015.009

credit to @zexilir25

Dipenhydramine + Alcohol = Dangerous

The two substances potentiate each other strongly and unpredictably, and may rapidly lead to unconsciousness. They both increase each other's side effects such as ataxia, sedation, and CNS depression. Blackouts and memory loss are significantly increased. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position. Alcohol may also increase the deliriant effects of diphenhydramine. It should also be noted if the individual consuming alcohol typically has a flushing response to alcohol, diphenhydramine may reduce the reaction and mask some of the effects of the alcohol.

Diphenhydramine - an overview | ScienceDirect Topics. (n.d.). Retrieved September 4, 2024, from https://www.sciencedirect.com/topics/chemistry/diphenhydramine
Ethanol - an overview | ScienceDirect Topics. (n.d.). Retrieved September 4, 2024, from https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/ethanol
Miller, N. S., Goodwin, D. W., Jones, F. C., Gabrielli, W. F., Pardo, M. P., Anand, M. M., & Hall, T. B. (1988). Antihistamine blockade of alcohol-induced flushing in orientals. Journal of Studies on Alcohol, 49(1), 16–20. https://doi.org/10.15288/jsa.1988.49.16
Sicari, V., & Zabbo, C. P. (2024). Diphenhydramine. In StatPearls. StatPearls Publishing. http://www.ncbi.nlm.nih.gov/books/NBK526010/
Weathermon, R., & Crabb, D. W. (1999). Alcohol and Medication Interactions. Alcohol Research & Health, 23(1), 40–54. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761694/

https://www.ncbi.nlm.nih.gov/books/NBK526010/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761694/
https://pubmed.ncbi.nlm.nih.gov/3347071/
https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/ethanol
https://www.sciencedirect.com/topics/chemistry/diphenhydramine

We should go over all the caffeine interactions adding in "However, individual responses to caffeine can vary significantly, often influenced by factors like habitual versus occasional usage." this is a good point made by multiple users and is certainly true. We can also add the sources to go with this-

      "author": "Arthur Eumann Mesas, Luz M Leon-Muñoz, Fernando Rodriguez-Artalejo, Esther Lopez-Garcia",
      "title": "The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis ",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21880846/"
    },
    {
      "author": "M-L Nurminen, L Niittynen, R Korpela & H Vapaatalo",
      "title": "Coffee, caffeine and blood pressure: a critical review",
      "url": "https://www.nature.com/articles/1600899"

Discussed in #102

I would presume that this would also be a factor-
Both can dull each other's effects, so if one wears off before the other it's possible to overdose due to the lack of counteraction.

Benzodiazepines + 4mmc = Low Risk & Decrease
Both can dull each other's effects, so if one wears off before the other it's possible to overdose due to the lack of counteraction. The interaction is likely safe at lower dosages.

DPH + Tramadol

Caution or Dangerous

Both drugs increase the risk of serotonin syndrome. While at medical dosages this is unlikely to be of concern, recreational dosages should be avoided.

Saud, S., Khan, I., Asif, M., Ismail, O., Salam, A., Yang, T. J., & Norville, K. J. (2018). Serotonin Syndrome Presenting with Concomitant Tramadol and Diphenhydramine Use: A Case Report of an Unlikely Side-Effect. Cureus, 10(4). https://doi.org/10.7759/cureus.2421
Yeh, S. Y., Dersch, C., Rothman, R., & Cadet, J. L. (1999). Effects of antihistamines on 3,4-methylenedioxymethamphetamine-induced depletion of serotonin in rats. https://doi.org/10.1002/(sici)1098-2396(19990901)33:3<207::aid-syn5>3.0.co;2-8

@AlanaRm-rf-me this has a similar idea of the concern of SS. Do you think we should mark it as caution or dangerous?

Ampth > Lithium exists, but not the reverse interaction

Figure out why the combosToDrugs script didn't catch this and fix it

4mmc + MDMA

Dangerous

Risk of serotonin syndrome as both drugs raise serotonin levels. Stimulants also increase the neurotoxic effects of MDMA, in addition to concerns of high blood pressure and unnecessary strain on the heart. As well as potentially causing anxiety and greater physical discomfort due to the combination.

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/j.1476-5381.2011.01499.x
https://jpet.aspetjournals.org/content/339/2/530
https://pubmed.ncbi.nlm.nih.gov/1723797/
https://pubmed.ncbi.nlm.nih.gov/2881549/
https://pubmed.ncbi.nlm.nih.gov/11356903/
https://www.sciencedirect.com/science/article/abs/pii/S0091305701007110#:~:text=In%20the%20hot%20and%20crowded,emergencies%2C%20which%20occasionally%20prove%20fatal.
https://pubmed.ncbi.nlm.nih.gov/22037396/
https://link.springer.com/article/10.1007/BF00445556

Lithium + DXM = Dangerous

There is a risk of serotonin syndrome when combining Lithium with DXM.

Lenox, R. H., & Hahn, C. G. (2000). Overview of the mechanism of action of lithium in the brain: fifty-year update. The Journal of clinical psychiatry, 61 Suppl 9, 5–15. - https://pubmed.ncbi.nlm.nih.gov/10826655/

Shahani, L. (2012). Venlafaxine Augmentation With Lithium Leading to Serotonin Syndrome. The Journal of Neuropsychiatry and Clinical Neurosciences, 24(3), E47–E47. https://doi.org/10.1176/appi.neuropsych.11080196

DeBattista, C., Sofuoglu, M., & Schatzberg, A. F. (1998). Serotonergic synergism: the risks and benefits of combining the selective serotonin reuptake inhibitors with other serotonergic drugs. Biological psychiatry, 44(5), 341–347. https://doi.org/10.1016/s0006-3223(98)00161-9

Massot, O. (1999). 5-HT1B Receptors: A Novel Target for Lithium Possible Involvement in Mood Disorders. Neuropsychopharmacology, 21(4), 530–541. https://doi.org/10.1016/S0893-133X(99)00042-1

Navarro, A., Perry, C., & Bobo, W. V. (2006). A case of serotonin syndrome precipitated by abuse of the anticough remedy dextromethorphan in a bipolar patient treated with fluoxetine and lithium. General Hospital Psychiatry, 28(1), 78–80. https://doi.org/10.1016/j.genhosppsych.2005.06.008

Henderson, M. G., & Fuller, R. W. (1992). Dextromethorphan antagonizes the acute depletion of brain serotonin by p-chloroamphetamine and H75/12 in rats. Brain Research, 594(2), 323–326. https://doi.org/10.1016/0006-8993(92)91144-4

Navarro, A., Perry, C., & Bobo, W. V. (2006). A case of serotonin syndrome precipitated by abuse of the anticough remedy dextromethorphan in a bipolar patient treated with fluoxetine and lithium. General Hospital Psychiatry, 28(1), 78–80. https://doi.org/10.1016/j.genhosppsych.2005.06.008

Lithium + Amphetamines

Lithium may be neuroprotective when taken with amphetamines and Lithium may decrease the hyperactive effects of amphetamines. Studies indicate this combination is safe.

Ago, Y., Tanaka, T., Kita, Y., Tokumoto, H., Takuma, K., & Matsuda, T. (2012). Lithium attenuates methamphetamine-induced hyperlocomotion and behavioral sensitization via modulation of prefrontal monoamine release. Neuropharmacology, 62(4), 1634–1639. https://doi.org/10.1016/j.neuropharm.2011.10.004

Gould, T. D., O’Donnell, K. C., Picchini, A. M., & Manji, H. K. (2007). Strain Differences in Lithium Attenuation of d-Amphetamine-Induced Hyperlocomotion: A Mouse Model for the Genetics of Clinical Response to Lithium. Neuropsychopharmacology, 32(6), 1321–1333. https://doi.org/10.1038/sj.npp.1301254

Zhou, Z., Wang, Y., Tan, H., Bharti, V., Che, Y., & Wang, J.-F. (2015). Chronic treatment with mood stabilizer lithium inhibits amphetamine-induced risk-taking manic-like behaviors. Neuroscience Letters, 603, 84–88. https://doi.org/10.1016/j.neulet.2015.07.027
Silverstone, P. H., Pukhovsky, A., & Rotzinger, S. (1998). Lithium does not attenuate the effects of d-amphetamine in healthy volunteers. Psychiatry Research, 79(3), 219–226. https://doi.org/10.1016/S0165-1781(98)00037-7

Credit to @zelixir25

Tramadol and Lithium

Dangerous

Tramadol and Lithium both increase the risks of seizures, in addition to serotonin syndrome.

https://www.sciencedirect.com/science/article/abs/pii/0006322387900266
https://www.biologicalpsychiatryjournal.com/article/S0006-3223(98)00161-9/pdf
https://www.nature.com/articles/1395366
https://www.sciencedirect.com/science/article/abs/pii/S0002934318304029
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755854/
https://www.mdpi.com/1424-8247/15/10/1254
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714818/#:~:text=Tramadol%20and%20Serotonin%20Syndrome&text=SS%20may%20develop%20as%20a,direct%20agonism%20of%20serotonin%20receptors.

Opioids + Pregabalin

Dangerous

While this combination may be tolerated by those who are using these drugs as prescribed, recreational use of pregabalin and opioids increases risk of fatal overdose. Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. Memory blackouts are likely.

Evoy, K. E., Sadrameli, S., Contreras, J., Covvey, J. R., Peckham, A. M., & Morrison, M. D. (2021). Abuse and misuse of pregabalin and gabapentin: A systematic review update. Drugs, 81(1), 125–156. https://doi.org/10.1007/s40265-020-01432-7

Lyndon, A., Audrey, S., Wells, C., Burnell, E. S., Ingle, S., Hill, R., Hickman, M., & Henderson, G. (2017). Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction, 112(9), 1580–1589. https://doi.org/10.1111/add.13843

Elliott, Simon P., et al. “Determining the Toxicological Significance of Pregabalin in Fatalities.” Journal of Forensic Sciences, vol. 62, no. 1, 2017, pp. 169–73, https://doi.org/10.1111/1556-4029.13263.

credit to @zelixir25

Pregabalin + Tramadol

Dangerous

At higher dosages, the combination increases the risk of seizures. Central nervous system and/or respiratory-depressant effects may be additively or synergistically present.

https://pubmed.ncbi.nlm.nih.gov/22814011/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688538/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755854/
https://www.mdpi.com/1424-8247/15/10/1254
https://www.sciencedirect.com/science/article/abs/pii/S0002934318304029
https://www.tandfonline.com/doi/full/10.1080/24734306.2018.1458465#:~:text=Toxicity%20may%20occur%20after%20overdose,seizure%20with%20confirmatory%20serum%20concentrations
https://www.fda.gov/media/133681/download
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919607/
https://link.springer.com/article/10.1007/s11419-020-00569-0
https://www.tandfonline.com/doi/full/10.3109/15563650.2015.1036279

A suggestion by AlanaaBananaa has been to edit the current description of this combination, to include that it may cause increased blood pressure concerns in addition to heart rate.

Adding onto this, myself and ComedownKid agrees that this mixture can increase anxiety. I agree with the suggestion to move it to "caution"

MDMA + Alcohol
Caution

MDMA can inhibit alcohol's intoxicating effects leading to increased drinking, which may put individuals at risk for adverse physical effects and poorer decision making. Alcohol may also reduce some of the cognitive and stimulant effects of MDMA. In addition, this combination carries an increased risk of hyperthermia and dehydration and places increased strain on the cardiovascular system. Approach this combination with caution, moderation, and sufficient hydration.

Discussed in #76

credit to @zelixir25
thanks to immr.sun for the wording help

DPH + GHB/GBL = Dangerous

https://karger.com/nps/article-abstract/29/2/97/231769/Antihistamine-Effects-on-the-Central-Nervous
https://www.ncbi.nlm.nih.gov/books/NBK526010/
https://pubmed.ncbi.nlm.nih.gov/26256488/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462042/

Both substances are CNS depressants, potentiating each other strongly and unpredictably, raising the chances of memory loss, severe ataxia, and unconsciousness. The interaction will cause greater inhibition and risk of injury. If the user falls unconscious it is strongly recommended to put them into the recovery position and monitor breathing.

Credit to ronin for the help

Title

SSRIs + Opioids

There have been some case reports of serotonin syndrome in individuals who were given a combination of opioids and SSRIs . Other research has indicated a small increase in overdose risk for people who are prescribed CYP2D6-inhibiting SSRIs (e.g. fluoxetine and paroxetine) with oxycodone. Overall, risk is low with this combination but, as always, be mindful of your consumption.

worded by @zelixir25
(this is a rewording of the current interaction)

4mmc + Caffeine
Caution

This combination of stimulants is not generally necessary and may increase strain on the heart, as well as potentially causing anxiety and great physical discomfort. However, individual responses to caffeine can vary significantly, often influenced by factors like habitual versus occasional usage.

https://pubmed.ncbi.nlm.nih.gov/21880846/
https://www.nature.com/articles/1600899
https://www.ncbi.nlm.nih.gov/books/NBK223808/
https://pubmed.ncbi.nlm.nih.gov/22169943/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504998/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246659/

Discussed in #82

These are sources suggested by @zelixir25 which I agree should be added for MDMA + SSRI's

4mmc + MXE
Dangerous

There is a high risk of serotonin syndrome from this combination.

Hondebrink, L., Kasteel, E. E. J., Tukker, A. M., Wijnolts, F. M. J., Verboven, A. H. A., & Westerink, R. H. S. (2017). Neuropharmacological characterization of the new psychoactive substance methoxetamine. Neuropharmacology, 123, 1–9. https://doi.org/10.1016/j.neuropharm.2017.04.035
Marti, M., Talani, G., Miliano, C., Bilel, S., Biggio, F., Bratzu, J., Diana, M., De Luca, M. A., & Fattore, L. (2021). New insights into methoxetamine mechanisms of action: Focus on serotonergic 5-HT2 receptors in pharmacological and behavioral effects in the rat. Experimental Neurology, 345, 113836. https://doi.org/10.1016/j.expneurol.2021.113836
Roth, B. L., Gibbons, S., Arunotayanun, W., Huang, X.-P., Setola, V., Treble, R., & Iversen, L. (2013). The Ketamine Analogue Methoxetamine and 3- and 4-Methoxy Analogues of Phencyclidine Are High Affinity and Selective Ligands for the Glutamate NMDA Receptor. PLOS ONE, 8(3), e59334. https://doi.org/10.1371/journal.pone.0059334
DeLarge, A. F., Erwin, L. L., & Winsauer, P. J. (2017). Atypical binding at dopamine and serotonin transporters contribute to the discriminative stimulus effects of mephedrone. Neuropharmacology, 119, 62–75. https://doi.org/10.1016/j.neuropharm.2017.04.006
Kehr, J., Ichinose, F., Yoshitake, S., Goiny, M., Sievertsson, T., Nyberg, F., & Yoshitake, T. (2011). Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats: Mephedrone increases both DA and 5-HT in rat brain. British Journal of Pharmacology, 164(8), 1949–1958. https://doi.org/10.1111/j.1476-5381.2011.01499.x

4mmc + LSD
Caution

The anxiogenic and focusing effects of stimulants increase the chance of unpleasant thought loops, in addition to the possible negative side effects of coming down from said stimulant while on a psychedelic. In extreme cases, stimulants, especially in combination can result in severe vasoconstriction, tachycardia, hypertension, and heart failure. (open to this sentence getting adjusted)

These sources show 4mmc is a stimulant-
4mmc is a stimulant-
https://jpet.aspetjournals.org/content/339/2/530
https://pubmed.ncbi.nlm.nih.gov/22169943/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504998/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246659/
https://pubmed.ncbi.nlm.nih.gov/24795175/

Sources for the claim LSD is a stimulant/heart concerns-
https://pubmed.ncbi.nlm.nih.gov/25575620/
https://pubmed.ncbi.nlm.nih.gov/31733631/

Stimulants have concerns of severe vasoconstriction, tachycardia, hypertension, and heart failure.
https://pubmed.ncbi.nlm.nih.gov/19948186/#:~:text=They%20include%20amphetamine%20and%20its,their%20use%20as%20nasal%20decongestants.
https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15465
https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/jcph.1918
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10510945/#:~:text=Amphetamine%2Dinduced%20heart%20failure%20typically,including%20echocardiography%20and%20cardiac%20biomarkers.

I'm struggling to find sources to show that stimulants cause/raise anxiety. I also would appreciate if someone could read through all of this before this being pushed to the database. I feel relatively confident when it comes to the caution but uncertain that the sources demonstrate this.