diff --git a/changelog.d/6578.bugfix b/changelog.d/6578.bugfix
new file mode 100644
index 000000000..fae55a445
--- /dev/null
+++ b/changelog.d/6578.bugfix
@@ -0,0 +1 @@
+Fix a bug introduced in Synapse 1.7.0 which caused an error on startup when upgrading from versions before 1.3.0.
diff --git a/synapse/storage/engines/sqlite.py b/synapse/storage/engines/sqlite.py
index ddad17dc5..cbc74cd30 100644
--- a/synapse/storage/engines/sqlite.py
+++ b/synapse/storage/engines/sqlite.py
@@ -25,6 +25,9 @@ class Sqlite3Engine(object):
     def __init__(self, database_module, database_config):
         self.module = database_module
 
+        database = database_config.get("args", {}).get("database")
+        self._is_in_memory = database in (None, ":memory:",)
+
         # The current max state_group, or None if we haven't looked
         # in the DB yet.
         self._current_state_group_id = None
@@ -59,7 +62,12 @@ class Sqlite3Engine(object):
         return sql
 
     def on_new_connection(self, db_conn):
-        prepare_database(db_conn, self, config=None)
+        if self._is_in_memory:
+            # In memory databases need to be rebuilt each time. Ideally we'd
+            # reuse the same connection as we do when starting up, but that
+            # would involve using adbapi before we have started the reactor.
+            prepare_database(db_conn, self, config=None)
+
         db_conn.create_function("rank", 1, _rank)
 
     def is_deadlock(self, error):